157 results on '"Soo Ok Lee"'
Search Results
2. Inhibition of IL‐6‐JAK/Stat3 signaling in castration‐resistant prostate cancer cells enhances the NK cell‐mediated cytotoxicity via alteration of PD‐L1/NKG2D ligand levels
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LiJun Xu, XiaoDong Chen, MingJing Shen, Dong‐Rong Yang, Laifu Fang, Guobin Weng, Ying Tsai, Peter C. Keng, Yuhchyau Chen, and Soo Ok Lee
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castration‐resistant prostate cancer ,IL‐6 ,JAK ,NK cell cytotoxicity ,NKG2D ,programmed death receptor ligand 1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
To investigate whether IL‐6 signaling affects the susceptibility of castration‐resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL‐6 levels) were developed by lentiviral transduction. While observing no secreted IL‐6 level in parental C4‐2 and CWR22Rv1 cells, we found the IL‐6 expression/secretion in these cells was induced after the transduction process and the IL‐6 level difference in C4‐2siIL‐6/sc and CWR22siIL‐6/sc cell CRPC cell sets could be detected. We then found that IL‐6‐knockdown cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD‐L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL‐6‐expressing cell‐derived tumors were more resistant to NK cell action than the tumors of IL‐6‐knockdown cells. Further, we discovered that JAK‐Stat3 is the most critical IL‐6 downstream signaling that modulates PD‐L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4‐2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD‐L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL‐6 signaling (or its downstream signaling) may enhance the NK cell‐mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat patients with CRPC.
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- 2018
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3. Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition
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Li Yang, MingJing Shen, Li Jun Xu, Xiaodong Yang, Ying Tsai, Peter C. Keng, Yuhchyau Chen, and Soo Ok Lee
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Medicine ,Science - Abstract
Abstract Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell’s function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells.
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- 2017
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4. Antibiotic use in South Korea from 2007 to 2014: A health insurance database-generated time series analysis.
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Juhee Park, Euna Han, Soo Ok Lee, and Dong-Sook Kim
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Medicine ,Science - Abstract
Inappropriate antibiotic use significantly contributes to antibiotic-resistance, resulting in reduced antibiotic efficacy and increasing physical burden and cost of disease. The goal of this study was to explore antibiotic usage patterns in South Korea using 2007-2014 health insurance claims data.We used the Health Insurance Review & Assessment Service data, which represents nearly the entire population of South Korea, to discern patterns in antibiotic prescribing practices. The daily dose, as defined by the World Health Organization ([defined daily doses]/1000 inhabitants/day, [DID]), was used as a measure of antibiotic use. Subgroup analyses were performed on the basis of patient characteristics (sex, age, and disease) and provider characteristics (type of medical institution).Antibiotic use in DID increased from 23.5 in 2007 to 27.7 in 2014. The ≤ 6 years old age group showed the highest level of usage at 59.21 DID in 2014, and showed an increasing trend each year. DIDs of beta-lactam antibacterials, penicillins (J01C), other beta-lactam antibacterials (J01D), lincosamides and streptogramins (J01F), quinolone antibacterials (J01M), and other antibacterials (J01X) increased over time.This study provides valuable statistics regarding antibiotic usage in South Korea; this is important for guiding health policy with regard to antibiotic usage. There is a need for further study exploring antibiotics use and resistance.
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- 2017
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5. Common CYP7A1 promoter polymorphism associated with risk of neuromyelitis optica
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Ho Jin Kim, Hyun-Young Park, Eunkyung Kim, Kwang-Soo Lee, Kwang-Kuk Kim, Byung-Ok Choi, Seung Min Kim, Joon Seol Bae, Soo Ok Lee, Ji Yong Chun, Tae Joon Park, Hyun Sub Cheong, Inho Jo, and Hyoung Doo Shin
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Genome-wide association study ,Neuromyelitis optica ,CYP7A1 ,Promoter variant ,Single-nucleotide polymorphism ,Korean population ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Neuromyelitis optica (NMO) is a severe idiopathic inflammatory disease of the central nervous system primarily affecting the optic nerves and spinal cord. In this study, we generated genome-wide SNP data from NMO patients and normal controls (53 cases and 240 controls), and followed up on the association signals with samples from a larger number of inflammatory demyelinating diseases, including NMO (n=93), multiple sclerosis (MS, n=71), idiopathic recurrent transverse myelitis (IRTM, n=57), and normal controls (n=240). Statistical analyses revealed that a common promoter SNP in CYP7A1 has a protective/gene dose-dependent effect on the risk of NMO (P=0.0004). A stronger association between the variables and subsequently, a higher protective effect (lower OR) on the risk of NMO were observed among patients carrying the “G/G” genotype of rs3808607 than those with the “T/G” genotype (OR=0.38/P=0.01 vs. OR=0.12/P=0.0004, respectively). The associations which were only observed in patients with NMO suggest that there are differences in the genetic etiology of the inflammatory demyelinating diseases (NMO, classical MS, and IRTM).
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- 2010
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6. Supplementary Figures 1 - 4 from Endothelial Cells Enhance Prostate Cancer Metastasis via IL-6→Androgen Receptor→TGF-β→MMP-9 Signals
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Chawnshang Chang, Shuyuan Yeh, Lei Li, Jie Luo, Qi Jiang, Shujie Xia, Soo Ok Lee, and Xiaohai Wang
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PDF file - 267K, Fig. s1. HMECs induce the PCa cells invasion in vitro. Fig. s2. ECs down-regulated AR signaling in PCa cells. Fig. s3. Cytokines/chemokines level changes in ECs upon PCa cells co-culture. Fig. s4. EMT markers expressions changes in PCa cells upon ECs co-culture.
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- 2023
7. Data from Endothelial Cells Enhance Prostate Cancer Metastasis via IL-6→Androgen Receptor→TGF-β→MMP-9 Signals
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Chawnshang Chang, Shuyuan Yeh, Lei Li, Jie Luo, Qi Jiang, Shujie Xia, Soo Ok Lee, and Xiaohai Wang
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Although the potential roles of endothelial cells in the microvascules of prostate cancer during angiogenesis have been documented, their direct impacts on the prostate cancer metastasis remain unclear. We found that the CD31-positive and CD34-positive endothelial cells are increased in prostate cancer compared with the normal tissues and that these endothelial cells were decreased upon castration, gradually recovered with time, and increased after prostate cancer progressed into the castration-resistant stage, suggesting a potential linkage of these endothelial cells with androgen deprivation therapy. The in vitro invasion assays showed that the coculture of endothelial cells with prostate cancer cells significantly enhanced the invasion ability of the prostate cancer cells. Mechanism dissection found that coculture of prostate cancer cells with endothelial cells led to increased interleukin (IL)-6 secretion from endothelial cells, which may result in downregulation of androgen receptor (AR) signaling in prostate cancer cells and then the activation of TGF-β/matrix metalloproteinase-9 (MMP-9) signaling. The consequences of the IL-6→AR→TGFβ→MMP-9 signaling pathway might then trigger the increased invasion of prostate cancer cells. Blocking the IL-6→AR→TGFβ→MMP-9 signaling pathway either by IL-6 antibody, AR-siRNA, or TGF-β1 inhibitor all interrupted the ability of endothelial cells to influence prostate cancer invasion. These results, for the first time, revealed the important roles of endothelial cells within the prostate cancer microenvironment to promote the prostate cancer metastasis and provide new potential targets of IL-6→AR→TGFβ→MMP-9 signals to battle the prostate cancer metastasis. Mol Cancer Ther; 12(6); 1026–37. ©2013 AACR.
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- 2023
8. Data from Prostate-Specific Antigen Modulates Genes Involved in Bone Remodeling and Induces Osteoblast Differentiation of Human Osteosarcoma Cell Line SaOS-2
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Allen C. Gao, Haitao Zhang, Jeffrey M. Conroy, Jason S. Kirk, Farideh Mehraein-Ghomi, Soo Ok Lee, Wei Lou, and Nagalakshmi Nadiminty
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Purpose: The high prevalence of osteoblastic bone metastases in prostate cancer involves the production of osteoblast-stimulating factors by prostate cancer cells. Prostate-specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serologic marker for prostate cancer. In this study, we examined the role of PSA in the induction of osteoblast differentiation.Experimental Design: Human cDNA containing a coding region for PSA was transfected into human osteosarcoma SaOS-2 cells. SaOS-2 cells were also treated with exogenously added PSA. We evaluated changes in global gene expression using cDNA arrays and Northern blot analysis resulting from expression of PSA in human osteosarcoma SaOS-2 cells.Results: SaOS-2 cells expressing PSA had markedly up-regulated expression of genes associated with osteoblast differentiation including runx-2 and osteocalcin compared with the controls. Consistent with these results, the stable clones expressing PSA showed increased mineralization and increased activity of alkaline phosphatase in vitro compared with controls, suggesting that these cells undergo osteoblast differentiation. We also found that osteoprotegerin expression was down-regulated and that the receptor activator of NF-κB ligand expression was up-regulated in cells expressing PSA compared with controls.Conclusions: Modulation of the expression of osteogenic genes and alteration of the balance between osteoprotegerin–receptor activator of NF-κB ligand by PSA suggests that PSA produced by metastatic prostate cancer cells may participate in bone remodeling in favor of the development of osteoblastic metastases in the heterogeneous mixture of osteolytic and osteoblastic lesions. These findings provide a molecular basis for understanding the high prevalence of osteoblastic bone metastases in prostate cancer.
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- 2023
9. Supplementary Table 1 from Prostate-Specific Antigen Modulates Genes Involved in Bone Remodeling and Induces Osteoblast Differentiation of Human Osteosarcoma Cell Line SaOS-2
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Allen C. Gao, Haitao Zhang, Jeffrey M. Conroy, Jason S. Kirk, Farideh Mehraein-Ghomi, Soo Ok Lee, Wei Lou, and Nagalakshmi Nadiminty
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Supplementary Table 1 from Prostate-Specific Antigen Modulates Genes Involved in Bone Remodeling and Induces Osteoblast Differentiation of Human Osteosarcoma Cell Line SaOS-2
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- 2023
10. Retraction notice to 'FASN-TGF-β1-PD-L1 axis contributes to the development of resistance to NK cell cytotoxicity of cisplatin-resistant lung cancer cells' [BBA - Molecular and Cell Biology of Lipids 1863/3 (March 2018) 313-322]
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Yuhchyau Chen, Mingjing Shen, Ying Tsai, Soo Ok Lee, Rongying Zhu, Peter C. Keng, and Yongbing Chen
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biology ,Chemistry ,PD-L1 ,biology.protein ,Cisplatin resistant ,medicine ,Cancer research ,Cell Biology ,Lung cancer ,medicine.disease ,Molecular Biology ,NK Cell Cytotoxicity ,Transforming growth factor - Published
- 2021
11. IL-6 signaling contributes to radioresistance of prostate cancer through key DNA repair-associated molecules ATM, ATR, and BRCA 1/2
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Xiang Xue, Yuhchyau Chen, Feng Chen, Lijun Xu, Yu Ren, Xiaodong Chen, Soo Ok Lee, Peter C. Keng, and Guobin Weng
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Male ,0301 basic medicine ,Cancer Research ,DNA Repair ,DNA repair ,Mice, Nude ,Ataxia Telangiectasia Mutated Proteins ,Radiation Tolerance ,Stat3 Signaling Pathway ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Radioresistance ,Transcriptional regulation ,Animals ,Humans ,Clonogenic assay ,BRCA2 Protein ,BRCA1 Protein ,Interleukin-6 ,Chemistry ,Prostatic Neoplasms ,General Medicine ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,In vitro ,Comet assay ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Signal Transduction - Abstract
To study an association between IL-6 signaling and resistance to radiotherapy of prostate cancer (PCa) and explore the molecular mechanisms involved. IL-6 expressing C4-2 and CWR22Rv1 (C4-2IL-6/CWRIL-6) and vector control (C4-2vec/CWRvec) cell lines were developed. Radiation-sensitivities of these cells were compared in clonogenic assay, Comet assay, and γH2AX staining. In xenograft animal studies, radiation-sensitivity of C4-2IL-6 cell-derived tumors vs. C4-2vec cell-derived tumors was investigated. To reveal IL-6 downstream molecules involved in DNA repair after radiation, qPCR and Western blot analyses as well as immunofluorescence staining were performed. Transcriptional control of IL-6 on ATM and ATR molecules was also investigated. We found C4-2IL-6 and CWRIL-6 cells survived better than their vector control cells after irradiation, and animal studies confirmed such in vitro results. We discovered that DNA repair-related molecules such as ATM, ATR, BRCA1, and BRCA2 were significantly upregulated in irradiated IL-6 expressing cells compared with vector control cells. We further defined that IL-6 signaling regulated cellular expressions of ATM and ATR at the transcriptional level through the activation of Stat3 signaling pathway. IL-6 leads to PCa resistance to radiation through upregulation of DNA repair associated molecules ATM, ATR, BRCA1, and BRCA2.
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- 2019
12. Correction: Targeting the unique methylation pattern of androgen receptor (AR) promoter in prostate stem/progenitor cells with 5-aza-2'-deoxycytidine (5-AZA) leads to suppressed prostate tumorigenesis
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Lei Li, Liang Liang, Jie Luo, Chiung-Kuei Huang, Chawnshang Chang, Soo Ok Lee, Jing Tian, and Yuanjie Niu
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business.industry ,Methylation ,Cell Biology ,Biology ,medicine.disease_cause ,Biochemistry ,Androgen receptor ,chemistry.chemical_compound ,medicine.anatomical_structure ,Text mining ,chemistry ,Prostate ,Cancer research ,medicine ,Deoxycytidine ,Progenitor cell ,Carcinogenesis ,business ,Molecular Biology - Abstract
Background: There is a specific silencing of AR gene expression in prostate stem cells.
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- 2020
13. Glucocorticoid receptor upregulation increases radioresistance and triggers androgen independence of prostate cancer
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Feng Chen, Soo Ok Lee, Xiaodong Chen, Peter C. Keng, Yu Ren, Yuhchyau Chen, and Guobin Weng
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Male ,0301 basic medicine ,Urology ,Biology ,Radiation Tolerance ,Metastasis ,Mice ,03 medical and health sciences ,Prostate cancer ,Receptors, Glucocorticoid ,0302 clinical medicine ,Glucocorticoid receptor ,Downregulation and upregulation ,Cell Line, Tumor ,Radioresistance ,LNCaP ,medicine ,Animals ,Humans ,Radiotherapy ,Cell growth ,Prostatic Neoplasms ,Dose-Response Relationship, Radiation ,medicine.disease ,Xenograft Model Antitumor Assays ,Up-Regulation ,Androgen receptor ,Disease Models, Animal ,030104 developmental biology ,Oncology ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Androgens ,Disease Progression ,Cancer research - Abstract
Background Despite the overall success of radiotherapy, a significant number of patients develop radioresistance, which leads to local regional recurrence and distant metastasis. We studied whether repeated radiation treatment promotes androgen-independent survival of prostate cancer (PCa) cells and their metastatic potential. We also studied whether glucocorticoid receptor (GR) increase in radioresistant cells is associated with acquisition of these aggressive characteristics. Methods Radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) PCa sublines were developed by repeated radiation treatments of parental cells. Levels and activations of androgen receptor (AR) and GR in radioresistant PCa cells and respective parental cells were investigated in quantitative real-time polymerase chain reaction/Western blot analyses and immunofluorescence staining. Androgen-independent survival of radioresistant cells was tested in in vitro cell growth assays and the castration-resistant survival of these cell-derived tumors were investigated in mouse xenografts. Results Higher GR levels, but lower AR levels were detected in radioresistant cells than in parental cells. Radiation-induced GR upregulation was associated with increased intracellular cyclic adenosine monophosphate. As a consequence of GR activation, LNCaPR18 cells survived well in an androgen-depleted culture condition while parental cells could not. Results of in vivo mouse studies showed survival of LNCaPR18 cell-derived tumors in castrated mice while parental cell-derived tumors regressed. The growth of LNCaPR18 cell-derived tumors in castrated mice was impaired when treated with the anti-GR agent mifepristone. In experiments with C4-2/C4-2R26 cell sets, GR activation in C4-2R26 cells increased their metastatic potential. Conclusion GR activation in radioresistant cells mediates androgen independence and facilitates PCa progression.
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- 2020
14. In vitro -induced M2 type macrophages induces the resistance of prostate cancer cells to cytotoxic action of NK cells
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Dong-Rong Yang, Lijun Xu, Mingjing Shen, Xiaodong Chen, Peter C. Keng, Yuhchyau Chen, Ying Tsai, and Soo Ok Lee
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Cytotoxicity, Immunologic ,Male ,0301 basic medicine ,Cell ,In Vitro Techniques ,Biology ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,PD-L1 ,Tumor Cells, Cultured ,medicine ,Humans ,Cytotoxic T cell ,Secretion ,Receptor ,Interleukin 6 ,Cell Proliferation ,Macrophages ,Prostatic Neoplasms ,Cell Differentiation ,Cell Biology ,NKG2D ,In vitro ,Killer Cells, Natural ,030104 developmental biology ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,Culture Media, Conditioned ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Signal Transduction - Abstract
Previous reports, including our experimental results, showed that macrophages migrate to prostate cancer (PCa) cells. We tested whether the migrated macrophages affect the susceptibility of castration-resistant PCa (CRPC) cells to cytotoxic actions of natural killer (NK) cells. We found treatment of tumor cells with the conditioned media (CM) of the PMA/IL-4 treated THP-1 cells (M2 type macrophages) (THP-1 CM) decreased the susceptibility of tumor cells to NK cell cytotoxicity, as a result of increased programmed death receptor ligand 1 (PD-L1) and decreased NK group 2D (NKG2D) ligands in CRPC cells. Meanwhile, the decreased susceptibility of tumor cells was also detected when NK cells were treated with THP-1 CM and used in NK cell cytotoxicity tests. Therefore, we observed higher resistance of CRPC cells when both tumor and NK cells were treated with THP-1 CM than when tumor cells or NK cells were individually treated. We further discovered that the PMA/IL-4 treated THP-1 cells secrete a high level of IL-6, so blocking the IL-6 action significantly decreased the PD-L1 level while recovering the NKG2D ligands, thus increasing the susceptibility of CRPC cells to NK cell action. Moreover, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling in triggering the THP-1 CM effect. Consequently, we found the susceptibility of CRPC cells to NK cells was increased when either JAK or Stat 3 inhibitor was added when tumor cells were treated with THP-1 CM, and that the best effect was observed when the JAK inhibitor and PD-L1 Ab were added together.
- Published
- 2018
15. RETRACTED: FASN-TGF-β1-PD-L1 axis contributes to the development of resistance to NK cell cytotoxicity of cisplatin-resistant lung cancer cells
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Yuhchyau Chen, Yongbing Chen, Mingjing Shen, Ying Tsai, Soo Ok Lee, Rongying Zhu, and Peter C. Keng
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0301 basic medicine ,Lung Neoplasms ,medicine.medical_treatment ,B7-H1 Antigen ,Transforming Growth Factor beta1 ,03 medical and health sciences ,0302 clinical medicine ,PD-L1 ,medicine ,Humans ,Lung cancer ,Receptor ,Cytotoxicity ,Molecular Biology ,Cisplatin ,Immunity, Cellular ,Gene knockdown ,biology ,Chemistry ,Cell Biology ,Immunotherapy ,medicine.disease ,Neoplasm Proteins ,Fatty Acid Synthase, Type I ,Killer Cells, Natural ,Fatty acid synthase ,030104 developmental biology ,A549 Cells ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Signal Transduction ,medicine.drug - Abstract
Cisplatin remains the most effective therapy for non-small cell lung cancer (NSCLC). We previously have found cisplatin-resistant lung cancer cells (A549CisR and H157CisR) were more resistant to natural killer (NK) cell-mediated cytotoxicity than parental cells. We also discovered that fatty acid synthase (FASN) levels in cisplatin-resistant cells were significantly higher than in parental cells. To reveal whether a link exists between the up-regulated FASN levels and higher resistance to NK cell cytotoxicity, we performed inhibition studies using a FASN inhibitor and applied the FASN knockdown approach. In both approaches, we found that the FASN inhibition/knockdown significantly increased the susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We further found such decreased susceptibility was associated with an increased programmed death receptor ligand (PD-L1) level in cisplatin-resistant cells. In mechanisms studies, TGF-β1 was found to be the FASN downstream signaling molecule that was responsible for modulating the PD-L1 levels in cisplatin-resistant cells. Accordingly, TGF-β1 inhibition resulted in significantly increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We suggest that the inhibition of FASN-TGFβ1-PD-L1 axis may improve the efficacy of immunotherapy in treating cisplatin-resistant lung cancer.
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- 2018
16. Adipocytes affect castration‐resistant prostate cancer cells to develop the resistance to cytotoxic action of NK cells with alterations of PD‐L1/NKG2D ligand levels in tumor cells
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Peter C. Keng, Yuhchyau Chen, Xiaodong Chen, Lijun Xu, Mingjing Shen, Dong-Rong Yang, Ying Tsai, Soo Ok Lee, and Rongying Zhu
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Cytotoxicity, Immunologic ,Male ,STAT3 Transcription Factor ,0301 basic medicine ,NK Cell Lectin-Like Receptor Subfamily K ,Urology ,Cell ,Down-Regulation ,Adipose tissue ,Ligands ,urologic and male genital diseases ,B7-H1 Antigen ,Stat3 Signaling Pathway ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Paracrine signalling ,0302 clinical medicine ,3T3-L1 Cells ,Cell Line, Tumor ,Adipocyte ,Adipocytes ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Janus Kinases ,Interleukin-6 ,NKG2D ,Killer Cells, Natural ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Signal Transduction - Abstract
Background Obesity affects prostate cancer (PCa) progression, and the periprostatic adipose tissue adjacent to the prostate is considered a driving force of disease progression. Adipocytes are the main cell population in adipose tissues and their paracrine role contributes to PCa progression, however its implication in modulating immune reactions remains largely unknown. We investigated the adipocyte role in controlling the susceptibility of castration-resistant PCa (CRPC) cells to the cytotoxic action of natural killer (NK) cells. Methods Using primary NK cells as the NK cell source, NK cell cytotoxicities to CRPC cells, either control media treated or adipocyte-conditioned media (CM) treated, were tested in lactate dehydrogenase (LDH) release-based assays. The levels of programmed death receptor ligand (PD-L1) and NK group 2D (NKG2D) ligands in adipocyte CM-treated CRPC cells were analyzed in qPCR analyses. Effects of blocking adipocyte action on altering PD-L1/NKG2D ligand levels and the susceptibility of CRPC cells to NK cell cytotoxicity were investigated. Results We found NK cell cytotoxicity to CRPC cells decreases when tumor cells are treated with adipocyte CM associated with PD-L1 and NKG2D ligand level alterations. Further, we discovered that the JAK/Stat3 signaling pathway was responsible for the adipocyte CM effect. Two adipokine molecules, IL-6 and leptin, were shown to be important in activation of the JAK/Stat3 signaling in CRPC cells to modulate the PD-L1/NKG2D ligand level alteration. Adding the inhibitors of JAK/Stat3 signaling or neutralizing antibodies of IL-6 or leptin increased the susceptibility of CRPC cells to NK cell action. Conclusions Blocking the adipocyte effect by inhibiting the IL-6/leptin-JAK/Stat3 signaling axis may enhance NK cell mediated immunity to CRPC cells and this strategy may help to develop future therapeutics to treat obese PCa patients.
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- 2018
17. Inhibition of IL‐6‐JAK/Stat3 signaling in castration‐resistant prostate cancer cells enhances the NK cell‐mediated cytotoxicity via alteration of PD‐L1/NKG2D ligand levels
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Yuhchyau Chen, Laifu Fang, Ying Tsai, Dong-Rong Yang, Xiaodong Chen, Soo Ok Lee, Mingjing Shen, Lijun Xu, Guobin Weng, and Peter C. Keng
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0301 basic medicine ,Cytotoxicity, Immunologic ,Male ,Cancer Research ,Cell ,B7-H1 Antigen ,NKG2D ,Mice ,0302 clinical medicine ,Cytotoxic T cell ,Receptor ,Cytotoxicity ,STAT3 ,Research Articles ,General Medicine ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Cell biology ,Killer Cells, Natural ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Heterografts ,Intercellular Signaling Peptides and Proteins ,Immunotherapy ,Research Article ,castration‐resistant prostate cancer ,STAT3 Transcription Factor ,NK cell cytotoxicity ,programmed death receptor ligand 1 ,Primary Cell Culture ,Mice, Nude ,Biology ,GPI-Linked Proteins ,lcsh:RC254-282 ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Janus Kinases ,Stat3 ,Interleukin-6 ,IL‐6 ,JAK ,030104 developmental biology ,Cell culture ,biology.protein ,Cancer research - Abstract
To investigate whether IL‐6 signaling affects the susceptibility of castration‐resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL‐6 levels) were developed by lentiviral transduction. While observing no secreted IL‐6 level in parental C4‐2 and CWR22Rv1 cells, we found the IL‐6 expression/secretion in these cells was induced after the transduction process and the IL‐6 level difference in C4‐2siIL‐6/sc and CWR22siIL‐6/sc cell CRPC cell sets could be detected. We then found that IL‐6‐knockdown cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD‐L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL‐6‐expressing cell‐derived tumors were more resistant to NK cell action than the tumors of IL‐6‐knockdown cells. Further, we discovered that JAK‐Stat3 is the most critical IL‐6 downstream signaling that modulates PD‐L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4‐2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD‐L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL‐6 signaling (or its downstream signaling) may enhance the NK cell‐mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat patients with CRPC.
- Published
- 2018
18. Retraction Note: Radiation-induced glucocorticoid receptor promotes CD44 + prostate cancer stem cell growth through activation of SGK1-Wnt/β-catenin signaling
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Feng, Chen, Xiaodong, Chen, Yu, Ren, Guobin, Weng, Peter C, Keng, Yuhchyau, Chen, and Soo Ok, Lee
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Drug Discovery ,Molecular Medicine ,Genetics (clinical) - Published
- 2021
19. Retraction notice to 'Neuroendocrine differentiation contributes to radioresistance development and metastatic potential increase in non-small cell lung cancer' [Biochim. Biophys. Acta, Mol. Cell Res. Volume 1865, Issue 12, December 2018, Pages 1878–1890]
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Rongying, Zhu, Xiaodong, Yang, Xiang, Xue, Mingjing, Shen, Feng, Chen, Xiaodong, Chen, Ying, Tsai, Peter C, Keng, Yongbing, Chen, Soo Ok, Lee, and Yuhchyau, Chen
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Cell Biology ,Molecular Biology - Published
- 2021
20. Physicians’ and pharmacists’ perceptions on real-time drug utilization review system: a nationwide survey
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Soo-Ok Lee, Seung-Mi Lee, and Dong Sook Kim
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Adult ,Male ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Attitude of Health Personnel ,media_common.quotation_subject ,Pharmacist ,Pharmacy ,Pharmacists ,03 medical and health sciences ,Drug Utilization Review ,0302 clinical medicine ,Physicians ,Surveys and Questionnaires ,Perception ,Republic of Korea ,medicine ,Humans ,Medication Errors ,030212 general & internal medicine ,Hospital pharmacy ,Medical prescription ,media_common ,Pharmacies ,Primary Health Care ,business.industry ,030503 health policy & services ,Health Policy ,Public Health, Environmental and Occupational Health ,General Medicine ,Odds ratio ,Middle Aged ,Confidence interval ,Family medicine ,Female ,Guideline Adherence ,0305 other medical science ,business - Abstract
Objective To identify healthcare providers' experience and satisfaction for the drug utilization review (DUR) system, their impact on prescription changes following alerts, and difficulties experienced in the system by surveying primary healthcare centers and pharmacies. Design A cross-sectional nationwide survey. Setting and participants Approximately 2000 institutions were selected for the survey by a simple random sampling of nationwide primary healthcare centers and community pharmacy approximately practices, and 358 replied. Main outcomes measures The questionnaire included questions on experience and recognition of DUR alerts, personal attitude and respondents' biographical information. Space was included for respondents to suggest improvements of the DUR system. Results The DUR system scored 71.5 out of 100 points for satisfaction by physicians and pharmacists, who reported that the alerts prevent medication-related errors; most respondents (96.6%) received the alerts. Several respondents (10.9%) replied that they prescribe or dispense prescriptions as they are without following the alerts. Physicians (adjusted odds ratio, 8.334; 95% confidence interval, 3.449-20.139) are more likely to change the prescription than pharmacists and persons with alert experience (4.605; 1.080-19.638). However, current practice in metropolitan areas (0.478; 0.228-1.000) and frequent alerts regarding co-administration incompatibilities within prescriptions (0.135; 0.031-0.589) negatively influence adherence to DUR alerts. Conclusions Although most surveyed physicians and pharmacists receive the alerts, some do not or reported that they would not follow the alerts. To increase adherence, the DUR system should be improved to ensure a preferential and intensive approach to detecting potentially high-risk drug combinations.
- Published
- 2017
21. Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition
- Author
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Mingjing Shen, Li Jun Xu, Ying Tsai, Soo Ok Lee, Xiaodong Yang, Li Yang, Yuhchyau Chen, and Peter C. Keng
- Subjects
0301 basic medicine ,Lung Neoplasms ,MAP Kinase Signaling System ,Science ,Biology ,Article ,B7-H1 Antigen ,03 medical and health sciences ,Interleukin 21 ,Mice ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Cytotoxic T cell ,Animals ,Humans ,IL-2 receptor ,A549 cell ,Multidisciplinary ,Lymphokine-activated killer cell ,Janus kinase 3 ,Neoplasms, Experimental ,NKG2D ,Antibodies, Neutralizing ,Coculture Techniques ,3. Good health ,Cell biology ,Killer Cells, Natural ,030104 developmental biology ,A549 Cells ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Interleukin 12 ,Medicine ,Female ,Cisplatin - Abstract
Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell’s function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells.
- Published
- 2017
22. Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway
- Author
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Peter C. Keng, Ying Tsai, Soo Ok Lee, Yuhchyau Chen, Li Jun Xu, Yongbing Chen, Li Yang, and Ming Jing Shen
- Subjects
PD-L1 ,0301 basic medicine ,MAPK/ERK pathway ,Cell ,Biology ,NKG2D ,03 medical and health sciences ,0302 clinical medicine ,Radioresistance ,medicine ,Cytotoxic T cell ,Lung cancer ,Cytotoxicity ,NK cytotoxicity ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,biology.protein ,MEK/Erk ,Research Paper ,radioresistant lung cancer - Abstract
// Ming Jing Shen 1, 2 , Li Jun Xu 1, 2 , Li Yang 1 , Ying Tsai 1 , Peter C. Keng 1 , Yongbing Chen 2 , Soo Ok Lee 1 and Yuhchyau Chen 1 1 Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA 2 Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China Correspondence to: Yuhchyau Chen, email: Yuhchyau_Chen@urmc.rochester.edu Soo Ok Lee, email: Soook_Lee@urmc.rochester.edu Keywords: PD-L1, NKG2D, NK cytotoxicity, MEK/Erk, radioresistant lung cancer Received: April 12, 2017 Accepted: June 28, 2017 Published: July 12, 2017 ABSTRACT We investigated whether radiation influences the susceptibility of non-small cell lung cancer (NSCLC) cells to NK cell mediated cytotoxicity. We found radiation treatment increased expression of programmed cell death ligand 1 (PD-L1), but decreased NK group 2, member D (NKG2D) ligand expressions in A549 and H157 NSCLC cells. Both types of changes would have protected tumor cells from the cytotoxic action of NK cells. Consistently, we detected similar alteration in these molecules in radioresistant A549R26-1 and H157R24-1 subline cells. Higher PD-L1 level was also observed in tumors of A549R26-1 cell-derived xenografts than tumors of parental A549 (A549P) cell-derived xenografts. Accordingly, we found radioresistant cells were more resistant to the cytotoxic action of NK cells than parental cells, and such resistance was decreased when neutralizing antibody (Ab) of PD-L1 was added to the radioresistant cell/NK cell co-cultures. In mechanism studies, we found that IL-6-MEK/Erk signaling contributed most significantly to the up-regulation of PD-L1/down-regulation of NKG2D ligands in radioresistant cells. The addition of the MEK/Erk inhibitor increased the susceptibility of A549R26-1 and H157R24-1 cells to NK-cell cytotoxicity while no significant effect was observed in parental cells. Moreover, we detected enhanced NK-cell cytotoxicity to radioresistant cells when PD-L1 Ab and MEK/Erk inhibitor were added together to co-cultures of tumor/NK cells compared to when PD-L1 Ab was used alone. We suggest that combined use of PD-L1 Ab and MEK/Erk inhibitor may offer better therapeutic benefits than PD-L1 Ab alone to treat NSCLC patients who are receiving radiotherapy or who are at the radioresistant stage.
- Published
- 2017
23. Corrigendum to ‘New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells’
- Author
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Soo Ok Lee, Shuyuan Yeh, Yuanjie Niu, Chiuan-Ren Yeh, Qi Jiang, Lei Li, Kuo Pao Lai, Chawnshang Chang, Jing Tian, Tzuhua Lin, Liang Liang, Jie Luo, Zhifang Ma, Chiung-Kuei Huang, and Shinichi Yamashita
- Subjects
business.industry ,Cell Biology ,General Medicine ,medicine.disease ,Androgen receptor ,Prostate cancer ,Text mining ,Genetics ,Cancer research ,Medicine ,Progenitor cell ,business ,Molecular Biology ,Progenitor - Published
- 2020
24. Increased infiltration of macrophages to radioresistant lung cancer cells contributes to the development of the additional resistance of tumor cells to the cytotoxic effects of NK cells
- Author
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Rongying Zhu, Mingjing Shen, Lijun Xu, Xiang Xue, Peter C. Keng, Yuhchyau Chen, Yongbing Chen, Ying Tsai, and Soo Ok Lee
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cytotoxicity, Immunologic ,Cancer Research ,Lung Neoplasms ,NK Cell Lectin-Like Receptor Subfamily K ,Cell ,Biology ,Ligands ,Radiation Tolerance ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Cytotoxic T cell ,Humans ,Cytotoxicity ,Cell Proliferation ,Cell growth ,Interleukin-6 ,Macrophages ,Articles ,Cell cycle ,NKG2D ,Antibodies, Neutralizing ,Killer Cells, Natural ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Culture Media, Conditioned ,Cancer research ,Neoplastic Stem Cells ,Tetradecanoylphorbol Acetate ,Signal Transduction - Abstract
In this study, in order to investigate the effects of increased macrophage infiltration to radioresistant lung tumors in regulating natural killer (NK) cell-mediated immunity, we examined whether the treatment of radioresistant cells with conditioned medium (CM) from phorbol myristate acetate (PMA)/interleukin (IL)-4 treated THP-1 cells (used as a tumor-associated macrophage source) leads to the development of the additional resistance of tumor cells to NK cell cytotoxicity. We found that the susceptibility of THP-1 CM-treated radioresistant cells to NK cell cytotoxicity was decreased compared to the non-treated cells. In addition, it was found that such a decreased susceptibility was associated with increased programmed death receptor ligand 1 (PD-L1) and decreased natural killer group 2D (NKG2D) ligand levels in tumor cells. We further discovered that the THP-1 cells secreted a high level of IL-6, and that blocking IL-6 action by the addition of a neutralizing antibody (Ab) for IL-6 into the THP-1 CM decreased the resistance of THP-1 CM-treated radioresistant cells to NK cell cytotoxicity. Moreover, we discovered that MEK/Erk was the most critical IL-6 downstream signaling pathway in triggering the THP-1 CM effect; thus, the addition of MEK/Erk inhibitor to THP-1 CM enhanced the susceptibility of the THP-1 CM-treated radioresistant cells to NK cell cytotoxicity. On the whole, the findings of this study suggest the existence of a malignant loop characterized by increased macrophage infiltration into radioresistant cells which, in turn, promotes the development of the additional resistance of these cells to NK cell cytotoxicity.
- Published
- 2020
25. Radiation-induced glucocorticoid receptor promotes CD44+ prostate cancer stem cell growth through activation of SGK1-Wnt/β-catenin signaling
- Author
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Feng, Chen, Xiaodong, Chen, Yu, Ren, Guobin, Weng, Peter C, Keng, Yuhchyau, Chen, and Soo Ok, Lee
- Subjects
Male ,Mice, Nude ,Prostatic Neoplasms ,Protein Serine-Threonine Kinases ,Immediate-Early Proteins ,Neoplasm Proteins ,Mice ,Hyaluronan Receptors ,Receptors, Glucocorticoid ,Gamma Rays ,Cell Line, Tumor ,Neoplastic Stem Cells ,Animals ,Humans ,Wnt Signaling Pathway ,beta Catenin - Abstract
We observed cancer stem cell (CSC) population increase in radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) prostate cancer (PCa) cells compared with respective parental cells. Since the CD44 level increase was most significant in radioresistant PCa cells compared with parental cells among CSC markers tested, we isolated the CD44+ population from LNCaP/LNCaPR18 and C4-2/C4-2R26 cell sets via the immunomagnetic separation method and used them as CSC sources. We detected lower AR level, but higher glucocorticoid receptor (GR) level in CD44+ CSCs than CD44- non-CSCs. Higher GR level in CD44+ CSCs than CD44- cells was also detected when cells were isolated from mouse tumor tissues of LNCaPR18 cell and C4-2R26 cell-derived human xenografts and grown in culture. We then found blocking the GR signaling by adding the anti-GR agent mifepristone into the cell culture inhibited the CD44+ CSC growth while the addition of the anti-AR agent enzalutamide enhanced the CSC growth. In xenograft mouse studies in which tumors were developed from the injection of CD44+ CSCs of LNCaPR18 or C4-2R26 cell lines, retarded tumor growth in mifepristone-injected mice was observed compared with vehicle-treated mice. We next discovered the GR regulation of Wnt/β-catenin signaling pathway. We further found that the serum/glucocorticoid regulated kinase 1 (SGK1) is the GR downstream molecule that mediates Wnt/β-catenin signaling activation. Therefore, inhibition of either SGK1 or Wnt/β-catenin signaling impaired the in vitro CD44+ CSC growth. From these results, we suggest that blocking GR signaling or its downstream SGK1-Wnt/β-catenin signaling axis may suppress the radiation-induced CSC increase in PCa. KEY MESSAGES: Higher CSC population exists in radioresistant PCa cells than parental cells. Higher GR levels (and lower AR level) in CD44+ CSCs than CD44- non-CSCs. Use of anti-GR agent blocked the growth of CD44+ CSCs in in vitro/in vivo tests. GR downstream SGK1-Wnt/β-catenin signaling axis mediates the CSC increase. Targeting this signaling axis may enhance the radiotherapy efficacy in treating PCa.
- Published
- 2019
26. Correction: Differential androgen deprivation therapies with anti-androgens Casodex/bicalutamide or MDV3100/enzalutamide versus anti-androgen receptor ASC-J9® lead to promotion versus suppression of prostate cancer metastasis
- Author
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Tzu-Hua Lin, Soo Ok Lee, Yuanjie Niu, Defeng Xu, Liang Liang, Lei Li, Shauh-Der Yeh, Naohiro Fujimoto, Shuyuan Yeh, and Chawnshang Chang
- Subjects
Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2020
27. Strategic development of multiplication problem solving: Patterns of students' strategy choices
- Author
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Yi Ding, Dake Zhang, Jinsong Chen, and Soo Ok Lee
- Subjects
Strategic planning ,Multivariate analysis ,05 social sciences ,050301 education ,Latent class model ,Education ,Correlation ,Consistency (negotiation) ,Mathematics education ,0501 psychology and cognitive sciences ,Multiplication ,Mathematics instruction ,0503 education ,050104 developmental & child psychology ,Strategic development ,Mathematics - Abstract
Low mathematics achievement is a persistent problem in the United States, and multiplication is a fundamental area in which many students manifest learning difficulties. This study examined the strategic developmental levels of multiplication problem solving among 121 elementary school students in Grades 3 through 5. A latent class analysis modeling was used to identify three valid groups representing different patterns of strategy choices for each of three types of multiplication problems. Findings indicated intra-group variability for problem-solving accuracy, for frequency of using different strategies, and for accuracy of executing direct retrieval/algorithm (DR/AG) strategies. Students demonstrated relative consistency in their strategy choices for solving the three problem types. Students who used DR/AG strategies most frequently showed the highest problem-solving accuracy and the highest accuracy of executing the DR/AG strategies. Students who most frequently relied on incorrect operations ...
- Published
- 2016
28. A FASN-TGF-β1-FASN regulatory loop contributes to high EMT/metastatic potential of cisplatin-resistant non-small cell lung cancer
- Author
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Yuhchyau Chen, Ying Tsai, Soo Ok Lee, Xin Wang, Peter C. Keng, Li Yang, Fuquan Zhang, and Kuang-Hsiang Chuang
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,Antineoplastic Agents ,fatty acid synthase (FASN) ,Metastasis ,Transforming Growth Factor beta1 ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,TGF-β1 ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Animals ,Humans ,cisplatin-resistance ,Epithelial–mesenchymal transition ,Lung cancer ,non-small cell lung cancer ,Cisplatin ,biology ,business.industry ,EMT ,medicine.disease ,Cerulenin ,Fatty Acid Synthase, Type I ,Fatty acid synthase ,030104 developmental biology ,Oncology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Growth inhibition ,business ,medicine.drug ,Research Paper - Abstract
// Li Yang 1 , Fuquan Zhang 1 , Xin Wang 1 , Ying Tsai 1 , Kuang-Hsiang Chuang 1 , Peter C. Keng 1 , Soo Ok Lee 1 , Yuhchyau Chen 1 1 Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA Correspondence to: Yuhchyau Chen, email: Yuhchyau_Chen@urmc.rochester.edu Soo Ok Lee, email: Soook_Lee@urmc.rochester.edu Keywords: non-small cell lung cancer, EMT, cisplatin-resistance, fatty acid synthase (FASN), TGF-β1 Received: May 04, 2016 Accepted: July 11, 2016 Published: July 25, 2016 ABSTRACT Cisplatin-resistant A549CisR and H157CisR cell lines were developed by treating parental A549 (A549P) and H157 (H157P) cells. These cisplatin-resistant cells showed slight growth retardation, but exhibited higher epithelial-mesenchymal transition (EMT) and increased metastatic potential compared to parental cells. We observed a highly up-regulated fatty acid synthase (FASN) level in A549CisR and H157CisR cells compared to parental cells and the up-regulation of FASN was also detected in A549P and H157P cells after short time treatment with cisplatin, suggesting that the high level of FASN in cisplatin-resistant cells may be from the accumulated cellular responses during cisplatin-resistance developmental process. We next investigated whether the inhibition of FASN by using a specific FASN inhibitor, cerulenin, can influence growth and EMT/metastatic potential of A549CisR and H157CisR cells. There was slight growth inhibition, but significantly reduced EMT/metastatic potential in cisplatin-resistant cells upon inhibitor treatment. The in vitro result was further investigated in orthotopic xenograft mouse models established with luciferase-tagged H157P and H157CisR cells. Mice were injected with cerulenin or vehicle after tumors were developed. No significant tumor regression was detected at the end of cerulenin treatment, but IHC staining showed higher expression of EMT/metastasis markers in H157CisR cell-derived tumors than H157P cell-derived tumors, and showed dramatic reduction of these markers in tumor tissues of cerulenin-treated mice, confirming the in vitro results. In mechanism dissection studies, we revealed the existence of the FASN-TGF-β1-FASN positive loop in A549CisR and H157CisR cells, but not in parental cells, which is believed to augment the FASN function in cisplatin-resistant cells.
- Published
- 2016
29. Cisplatin treatment increases stemness through upregulation of hypoxia‐inducible factors by interleukin‐6 in non‐small cell lung cancer
- Author
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Ying Tsai, Soo Ok Lee, Peter C. Keng, Yuhchyau Chen, Fuquan Zhang, Shanzhou Duan, and Yongbing Chen
- Subjects
non‐small cell lung cancer ,0301 basic medicine ,Proteasome Endopeptidase Complex ,Cancer Research ,Lung Neoplasms ,Mice, Nude ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell, Molecular, and Stem Cell Biology ,Downregulation and upregulation ,Cancer stem cell ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Animals ,Lung cancer ,Interleukin 6 ,Cisplatin ,biology ,Interleukin-6 ,Original Articles ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,030104 developmental biology ,Oncology ,Hypoxia-inducible factors ,hypoxia‐inducible factor ,interleukin‐6 ,030220 oncology & carcinogenesis ,cisplatin‐resistance ,Immunology ,biology.protein ,Cancer research ,Original Article ,Female ,Hypoxia-Inducible Factor 1 ,Signal transduction ,Signal Transduction ,medicine.drug - Abstract
Cisplatin-resistant A549 and H157 (A549CisR and H157CisR) non-small cell lung cancer cells show increased stemness of cancer stem cells (CSCs) compared to their parental cells. We investigated whether interleukin-6 (IL-6) signaling contributes to this increased stemness in cisplatin-resistant cells. When A549CisR and H157CisR cells were treated with neutralizing IL-6 antibody, decreased cisplatin resistance was observed, whereas IL-6 treatment of parental cells resulted in increased cisplatin resistance. Expression of the CSC markers was significantly upregulated in IL-6-expressing scramble cells (in vitro) and scramble cell-derived tumor tissues (in vivo) after cisplatin treatment, but not in IL-6 knocked down (IL-6si) (in vitro) cells and in IL-6si cell-derived tumor tissues (in vivo), suggesting the importance of IL-6 signaling in triggering increased stemness during cisplatin resistance development. Hypoxia inducible factors (HIFs) were upregulated by IL-6 and responsible for the increased CSC stemness on cisplatin treatment. Mechanism dissection studies found that upregulation of HIFs by IL-6 was through transcriptional control and inhibition of HIF degradation. Treatment of HIF inhibitor (FM19G11) abolished the upregulation of CSC markers and increased sphere formations in IL-6 expressing cells on cisplatin treatment. In all, IL-6-mediated HIF upregulation is important in increasing stemness during cisplatin resistance development, and we suggest that the strategies of inhibiting IL-6 signaling or its downstream HIF molecules can be used as future therapeutic approaches to target CSCs after cisplatin treatment for lung cancer.
- Published
- 2016
30. Targeting fatty acid synthase with ASC-J9 suppresses proliferation and invasion of prostate cancer cells
- Author
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Hengheng Gao, Yanjun Li, Yuanjie Niu, Zhiqun Shang, Fu-Ju Chou, Chawnshang Chang, Soo Ok Lee, Simeng Wen, and Shuyuan Yeh
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,urologic and male genital diseases ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,DU145 ,Internal medicine ,LNCaP ,medicine ,Enzalutamide ,Molecular Biology ,PI3K/AKT/mTOR pathway ,biology ,medicine.disease ,Androgen receptor ,Fatty acid synthase ,030104 developmental biology ,Endocrinology ,chemistry ,030220 oncology & carcinogenesis ,Dihydrotestosterone ,biology.protein ,Cancer research ,medicine.drug - Abstract
Fatty acid synthase (FASN) is the key enzyme for the control of fatty acid synthesis that contributes significantly to the prostate cancer (PCa) progression. It was reported that androgens were able to induce FASN expression in PCa, and addition of the anti-androgen Casodex might suppress the androgen-induced FASN expression. However, here we found androgen-deprivation-therapy (ADT) with anti-androgens Bicalutamide (Casodex) or Enzalutamide (MDV3100) had little effect to suppress FASN expression and FASN-mediated cell growth and invasion during the castration resistant stage when the androgen concentration is 1 nM DHT (dihydrotestosterone). In contrast, the newly developed androgen receptor (AR) degradation enhancer ASC-J9® suppressed FASN expression and FASN-mediated cell growth and invasion in various PCa cell lines at 1 nM DHT. Mechanism dissection found ASC-J9® could suppress significantly the FASN expression and FASN-mediated PCa progression via the AR-dependent pathway involving AR→SREBP-1→FASN signaling in AR-positive C4-2 and LNCaP cells and via the AR-independent pathway involving the modulation of PI3K/AKT→SREBP-1→FASN signaling in AR-negative PC-3 and DU145 cells. Together, these results suggest that FASN is one of the important mechanism why the current ADT eventually fails. ASC-J9® might represent a new potential therapeutic approach to suppress FASN-mediated PCa progression via both AR-dependent and AR-independent pathways during the castration resistant stage of PCa. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
31. Tiering ‘Drug Combinations to Avoid’ and ‘Drug-age Precaution’ DUR Alerts by Severity Level and its Application
- Author
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Dong Sook Kim, In Ok Hwang, Bang Ok Cheun, Soo Ok Lee, and Nam Kyung Je
- Subjects
Drug ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Emergency medicine ,medicine ,Severity level ,business ,media_common - Published
- 2015
32. Corrigendum to 'Suppression of androgen receptor enhances the self-renewal of mesenchymal stem cells through elevated expression of EGFR' [Biochim. Biophys. Acta. 2013 May; 1833 (5): 1222–34]
- Author
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M.Y. Tsai, Soo Ok Lee, Cecilia H. Chang, Chiung-Kuei Huang, Hong-Yo Kang, and Jie Luo
- Subjects
Androgen receptor ,Chemistry ,Mesenchymal stem cell ,Cancer research ,Cell Biology ,Molecular Biology - Published
- 2020
33. Corrigendum to 'In vitro-induced M2 type macrophages induces the resistance of prostate cancer cells to cytotoxic action of NK cells'[Exp Cell Res 364 (2018) 113–123]
- Author
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Yuhchyau Chen, Lijun Xu, Mingjing Shen, Peter C. Keng, Dong-Rong Yang, Ying Tsai, Soo Ok Lee, and Xiaodong Chen
- Subjects
Prostate cancer ,medicine.anatomical_structure ,Cell ,medicine ,Cancer research ,Cytotoxic T cell ,Cell Biology ,Biology ,medicine.disease ,In vitro - Published
- 2020
34. NFκB and TNFα as individual key molecules associated with the cisplatin-resistance and radioresistance of lung cancer
- Author
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Mingjing Shen, Rongying Zhu, Ying Tsai, Soo Ok Lee, Xiang Xue, Yuhchyau Chen, Peter C. Keng, and Yongbing Chen
- Subjects
0301 basic medicine ,Lung Neoplasms ,DNA Repair ,Cell Survival ,Cell ,Mice, Nude ,Biology ,Radiation Tolerance ,03 medical and health sciences ,0302 clinical medicine ,Radioresistance ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Radiosensitivity ,Lung cancer ,Cisplatin ,Gene knockdown ,Tumor Necrosis Factor-alpha ,NF-kappa B ,Cell Biology ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Tumor necrosis factor alpha ,Female ,medicine.drug - Abstract
Cisplatin-resistant (A549CisR and H292CisR) and radioresistant (A549R26 and H292R22) sub-line non-small cell lung cancer (NSCLC) cells were developed in our lab by long term treatment of parental cells with cisplatin or radiation. Our data showed no cross-resistance between these two sets of cell lines, indicating that molecular mechanisms of developing each resistance may be different. Using these sub-line cells, we sought to reveal the most significantly up-regulated molecules in cisplatin-resistant and radioresistant lung cancer cells, compared with parental cells. In qPCR analyses of screening DNA repair and cell survival-associated molecules, we identified NFκB and TNFα as the most significantly up-regulated molecules in cisplatin-resistant and radioresistant lung cancer cells, respectively, compared with parental cells. Western blot analysis of parental vs. resistant cells and the IHC staining of tumor tissues of A549P, A549CisR, and A549R26 cell-derived xenografts in mice confirmed such results. Next, studies using specific inhibitors of NFκB and TNFα and experiments using NFκB and TNFα-knocked down cells showed that inhibition or knockdown of NFκB overcame cisplatin-resistance, while inhibition or knockdown of TNFα increased radiosensitivity of radioresistant lung cancer cells. Therefore, these two molecules may be used as markers of the prognosis/diagnosis of individual resistance development during lung cancer treatment.
- Published
- 2018
35. RETRACTED: Neuroendocrine differentiation contributes to radioresistance development and metastatic potential increase in non-small cell lung cancer
- Author
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Xiaodong Yang, Ying Tsai, Soo Ok Lee, Mingjing Shen, Xiang Xue, Yongbing Chen, Feng Chen, Xiaodong Chen, Peter C. Keng, Rongying Zhu, and Yuhchyau Chen
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,MAP Kinase Signaling System ,Neuroendocrine differentiation ,Radiation Tolerance ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Radioresistance ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Cyclic AMP ,Animals ,Humans ,Radiosensitivity ,Lung cancer ,Interleukin 6 ,Molecular Biology ,biology ,Chemistry ,Interleukin-6 ,Adenine ,Cell Biology ,medicine.disease ,Antibodies, Neutralizing ,Neurosecretory Systems ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Immunohistochemistry ,Signal transduction ,Neoplasm Transplantation - Abstract
Radiation treatment induces neuroendocrine differentiation (NED) in non-small cell lung cancer (NSCLC) A549 and H157 cells, so higher NE-like features in radioresistant A549 (A549R26-1) and H157 (H157R24-1) cells are observed than in parental cells. We detected higher NED marker expressions in A549R26-1 cell-derived tumors than in A549 cell-derived tumors. In mechanism studies, we found that NED induction in A549R26-1 and H157R24-1 cells was accompanied by increased intracellular cAMP and IL-6 levels. Treatment of radioresistant lung cancer cells with the inhibitor (SQ22536) of adenylate cyclase (AC) which is the enzyme responsible for the cAMP production, or the neutralizing antibody (Ab) of IL-6, resulted in decreased NE-like features in radioresistant lung cancer cells. In addition, we found MEK/Erk is the signaling pathway that triggers the cAMP- and IL-6-mediated NED induction in radioresistant lung cancer cells. Also, we found that MEK/Erk signaling pathway inhibition decreased NED in radioresistant cells. Radioresistant lung cancer cells exhibiting high NE-like features also showed higher radioresistance and higher metastatic potential than parental cells. When we inhibited cAMP-, or IL-6-mediated pathways, or the downstream MEK/Erk signaling pathway, radiosensitivity of radioresistant lung cancer cells was significantly increased and their metastatic potential was significantly reduced. In in vivo mouse studies, reducing NED by treating mice with the MEK/Erk inhibitor increased radiosensitivity. Immunohistochemical staining of tumor tissues lowered expressions of the NED/epithelial-mesenchymal transition (EMT)/metastatic markers when mice were treated with the MEK/Erk inhibitor.
- Published
- 2018
36. Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer
- Author
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Ying Tsai, Soo Ok Lee, Mingjing Shen, Peter C. Keng, Yongbing Chen, Yuhchyau Chen, Xiaodong Yang, Li Yang, and Fuquan Zhang
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,DNA repair ,MAP Kinase Signaling System ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Biology ,03 medical and health sciences ,Inhibitory Concentration 50 ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Lung cancer ,Pharmacology ,Cisplatin ,Correction ,medicine.disease ,Xenograft Model Antitumor Assays ,Up-Regulation ,Cytosol ,030104 developmental biology ,Cell culture ,A549 Cells ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Cancer research ,Molecular Medicine ,Myeloid Cell Leukemia Sequence 1 Protein ,Female ,medicine.drug ,Research Paper - Abstract
Development of cisplatin-resistance is an obstacle in non-small cell lung cancer (NSCLC) therapeutics. To investigate which molecules are associated with cisplatin-resistance, we analyzed expression profiles of several DNA repair and anti-apoptosis associated molecules in parental (A549P and H157P) and cisplatin-resistant (A549CisR and H157CisR) NSCLC cells. We detected constitutively upregulated nuclear ATM and cytosolic Mcl-1 molcules in cisplatin-resistant cells compared with parental cells. Increased levels of phosphorylated ATM (p-ATM) and its downstream molecules, CHK2, p-CHK2, p-53, and p-p53 were also detected in cisplatin-resistant cells, suggesting an activation of ATM signaling in these cells. Upon inhibition of ATM and Mcl-1 expression/activity using specific inhibitors of ATM and/or Mcl-1, we found significantly enhanced cisplatin-cytotoxicity and increased apoptosis of A549CisR cells after cisplatin treatment. Several A549CisR-derived cell lines, including ATM knocked down (A549CisR-siATM), Mcl-1 knocked down (A549CisR-shMcl1), ATM/Mcl-1 double knocked down (A549CisR-siATM/shMcl1) as well as scramble control (A549CisR-sc), were then developed. Higher cisplatin-cytotoxicity and increased apoptosis were observed in A549CisR-siATM, A549CisR-shMcl1, and A549CisR-siATM/shMcl1 cells compared with A549CisR-sc cells, and the most significant effect was shown in A549CisR-siATM/shMcl1 cells. In in vivo mice studies using subcutaneous xenograft mouse models developed with A549CisR-sc and A549CisR-siATM/shMcl1 cells, significant tumor regression in A549CisR-siATM/shMcl1 cells-derived xenografts was observed after cisplatin injection, but not in A549CisR-sc cells-derived xenografts. Finally, inhibitor studies revealed activation of Erk signaling pathway was most important in upregulation of ATM and Mcl-1 molcules in cisplatin-resistant cells. These studies suggest that simultaneous blocking of ATM/Mcl-1 molcules or downstream Erk signaling may recover the cisplatin-resistance of lung cancer.
- Published
- 2017
37. IL-6 Mediates Macrophage Infiltration after Irradiation via Up-regulation of CCL2/CCL5 in Non-small Cell Lung Cancer
- Author
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Xiaodong Yang, Yuhchyau Chen, Kuang-Hsiang Chuang, Li Yang, Ying Tsai, Soo Ok Lee, Peter C. Keng, and Xin Wang
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Cell ,Biophysics ,CCL2 ,CCL5 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Movement ,Carcinoma, Non-Small-Cell Lung ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Lung cancer ,Chemokine CCL5 ,Chemokine CCL2 ,A549 cell ,Radiation ,Chemistry ,Interleukin-6 ,Macrophages ,medicine.disease ,In vitro ,Up-Regulation ,030104 developmental biology ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Tumor progression ,A549 Cells ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Cancer research ,Female ,Infiltration (medical) ,Signal Transduction - Abstract
Radiotherapy is effective in reducing primary tumors, however, it may enhance macrophage infiltration to tumor sites, accelerating tumor progression in several ways. We investigated whether radiation can increase macrophage infiltration into non-small cell lung carcinoma (NSCLC) cells. Analysis of in vitro macrophage (differentiated THP-1 cells) migration to either nonirradiated or irradiated tumor cells showed increased migration to the irradiated tumor cells. Because the IL-6 levels in A549 and H157 cells were significantly increased after irradiation, we then investigated whether this increased IL-6 level contributes to radiation-induced macrophage migration. Radiation-induced macrophage infiltration was reduced when IL-6 was knocked down in tumor cells, indicating a positive IL-6 role in this process. To validate this in vitro result, an orthotopic mouse model was developed using a luciferase-tagged H157siIL-6/scramble control (sc) cell set. After tumors developed, the lungs were irradiated, and infiltration of endogenous macrophages and tail-vein injected fluorescent macrophages to tumor sites was investigated. In both groups, increased macrophage infiltration was observed in H157sc cell-derived xenografts compared to H157siIL-6 cell-derived xenografts, confirming the positive IL-6 role in the radiation-induced macrophage infiltration process. In mechanistic dissection studies, radiation-induced up-regulation of CCL2 and CCL5 by IL-6 was detected, and blocking the action of CCL2/CCL5 molecules significantly reduced the number of migrated macrophages to tumor cells after irradiation. These results demonstrate that targeting the IL-6 signaling or CCL2/CCL5 molecules in combination with conventional radiotherapy potentially blocks undesired radiation-induced macrophage infiltration.
- Published
- 2017
38. Antibiotic use in South Korea from 2007 to 2014: A health insurancedatabase-generated time series analysis
- Author
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Euna Han, Juhee Park, Dong Sook Kim, and Soo Ok Lee
- Subjects
Male ,0301 basic medicine ,Pediatrics ,Databases, Factual ,Economics ,Antibiotics ,lcsh:Medicine ,Social Sciences ,Patient characteristics ,Disease ,Geographical locations ,0302 clinical medicine ,Medicine and Health Sciences ,Ethnicities ,030212 general & internal medicine ,Practice Patterns, Physicians' ,lcsh:Science ,Multidisciplinary ,Antimicrobials ,Drugs ,Health insurance database ,Anti-Bacterial Agents ,Korean People ,Female ,Seasons ,Research Article ,medicine.medical_specialty ,Asia ,medicine.drug_class ,Microbiology ,History, 21st Century ,03 medical and health sciences ,Health Economics ,Antibiotic resistance ,Microbial Control ,South Korea ,Environmental health ,Republic of Korea ,medicine ,Health insurance ,Humans ,Antibiotic use ,Health policy ,Pharmacology ,Insurance, Health ,business.industry ,lcsh:R ,Biology and Life Sciences ,Penicillin ,Drug Utilization ,Health Care ,030104 developmental biology ,Age Groups ,Antibiotic Resistance ,Antibacterials ,lcsh:Q ,Population Groupings ,Antimicrobial Resistance ,People and places ,business ,Health Insurance - Abstract
Background Inappropriate antibiotic use significantly contributes to antibiotic-resistance, resulting in reduced antibiotic efficacy and increasing physical burden and cost of disease. The goal of this study was to explore antibiotic usage patterns in South Korea using 2007–2014 health insurance claims data. Methods We used the Health Insurance Review & Assessment Service data, which represents nearly the entire population of South Korea, to discern patterns in antibiotic prescribing practices. The daily dose, as defined by the World Health Organization ([defined daily doses]/1000 inhabitants/day, [DID]), was used as a measure of antibiotic use. Subgroup analyses were performed on the basis of patient characteristics (sex, age, and disease) and provider characteristics (type of medical institution). Results Antibiotic use in DID increased from 23.5 in 2007 to 27.7 in 2014. The ≤ 6 years old age group showed the highest level of usage at 59.21 DID in 2014, and showed an increasing trend each year. DIDs of beta-lactam antibacterials, penicillins (J01C), other beta-lactam antibacterials (J01D), lincosamides and streptogramins (J01F), quinolone antibacterials (J01M), and other antibacterials (J01X) increased over time. Conclusion This study provides valuable statistics regarding antibiotic usage in South Korea; this is important for guiding health policy with regard to antibiotic usage. There is a need for further study exploring antibiotics use and resistance.
- Published
- 2017
39. Androgen Receptor Enhances Kidney Stone-CaOx Crystal Formation via Modulation of Oxalate Biosynthesis & Oxidative Stress
- Author
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Chiung-Kuei Huang, Liang Liang, Luke S. Chang, David A. Bushinsky, Soo Ok Lee, Chawnshang Chang, Lei Li, Jing Tian, Qiang Dang, Shuyuan Yeh, Erdal Erturk, and Dalin He
- Subjects
Male ,Curcumin ,030232 urology & nephrology ,Calcium oxalate ,medicine.disease_cause ,Kidney Calculi ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,medicine ,Animals ,Humans ,Sex Distribution ,Receptor ,Molecular Biology ,Original Research ,030304 developmental biology ,Mice, Knockout ,Sex Characteristics ,0303 health sciences ,Kidney ,NADPH oxidase ,Calcium Oxalate ,biology ,HEK 293 cells ,Hep G2 Cells ,General Medicine ,medicine.disease ,Mice, Inbred C57BL ,Androgen receptor ,Oxidative Stress ,HEK293 Cells ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Receptors, Androgen ,Case-Control Studies ,Proteolysis ,biology.protein ,Female ,Kidney stones ,Oxidative stress - Abstract
Males develop kidney stones far more frequently than females with a ratio of 2-3:1, suggesting that androgen receptor (AR) signaling might play a key role in the development of nephrolithiasis. Using the cre-loxP system to selectively knock out AR in glyoxylate-induced calcium oxalate (CaOx) crystal mouse models, we found that the mice lacking hepatic AR had less oxalate biosynthesis, which might lead to lower CaOx crystal formation, and that the mice lacking kidney proximal or distal epithelial AR also had lower CaOx crystal formation. We found that AR could directly up-regulate hepatic glycolate oxidase and kidney epithelial NADPH oxidase subunit p22-PHOX at the transcriptional level. This up-regulation might then increase oxalate biosynthesis and oxidative stress that resulted in induction of kidney tubular injury. Targeting AR with the AR degradation enhancer ASC-J9 led to suppression of CaOx crystal formation via modulation of oxalate biosynthesis and oxidative stress in both in vitro and in vivo studies. Taken together, these results established the roles of AR in CaOx crystal formation.
- Published
- 2014
40. TR4 nuclear receptor promotes prostate cancer metastasisviaupregulation of CCL2/CCR2 signaling
- Author
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Shicheng Yu, Chawnshang Chang, Liqun Xia, Dong-Rong Yang, Soo Ok Lee, Ya-Ling Chen, Xianfan Ding, Gonghui Li, Yuanjie Niu, and Shin-Jen Lin
- Subjects
Cancer Research ,CCR2 ,CCL2 ,Biology ,urologic and male genital diseases ,medicine.disease ,Metastasis ,Prostate cancer ,Oncology ,Downregulation and upregulation ,Nuclear receptor ,Cancer research ,medicine ,Luciferase ,Chromatin immunoprecipitation - Abstract
Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might contribute to aging. Our recent clinical tumor tissue staining results showed higher expression of TR4 in prostate cancer (PCa) patients with high Gleason scores compared to the tissues with the low Gleason scores. In vitro migration/invasion assays after manipulation of the TR4 expression in PCa cells showed that TR4 promoted PCa cells migration/invasion. Mechanism dissection found that the CCL2/CCR2 signal plays the key role in the mediation of TR4-promoted PCa cells migration/invasion. Chromatin immunoprecipitation and Luciferase assays further confirmed TR4 modulation of CCL2 at the transcriptional level and addition of the CCR2 antagonist led to interruption of the TR4-enhanced PCa cells migration/invasion. Finally, the orthotopic xenografted mice studies using the luciferase expressing CWR22Rv1 cells found that TR4 enhanced PCa metastasis and this increased metastasis was reversed when the CCR2 antagonist was injected into the mice. Together, these in vitro and in vivo results revealed a positive role of TR4 in PCa metastasis and demonstrated CCL2/CCR2 signaling as an important mediator in exerting TR4 action. This finding suggests that TR4 may represent a biomarker related to PCa metastasis and targeting the TR4-CCL2/CCR2 axis may become a new therapeutic approach to battle PCa metastasis.
- Published
- 2014
41. TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system
- Author
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Soo Ok Lee, Shin Jen Lin, Chawnshang Chang, Hiroshi Miyamoto, Dong Rong Yang, Yi-Fen Lee, and Gonghui Li
- Subjects
Male ,Cancer Research ,DNA Repair ,Transcription, Genetic ,DNA damage ,DNA repair ,Gene Expression ,Original Manuscript ,Ataxia Telangiectasia Mutated Proteins ,Biology ,medicine.disease_cause ,law.invention ,Nuclear Receptor Subfamily 2, Group C, Member 2 ,Mice ,Prostate cancer ,law ,Cell Line, Tumor ,medicine ,Animals ,Humans ,P-Chloroamphetamine ,Mice, Knockout ,Prostatic Intraepithelial Neoplasia ,Tumor Suppressor Proteins ,PTEN Phosphohydrolase ,Prostatic Neoplasms ,Cancer ,General Medicine ,medicine.disease ,Immunohistochemistry ,humanities ,Disease Models, Animal ,Cell Transformation, Neoplastic ,Nuclear receptor ,Immunology ,Cancer research ,Suppressor ,Carcinogenesis ,DNA Damage - Abstract
Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, plays important roles in metabolism, fertility and aging. The linkage of TR4 functions in cancer progression, however, remains unclear. Using three different mouse models, we found TR4 could prevent or delay prostate cancer (PCa)/prostatic intraepithelial neoplasia development. Knocking down TR4 in human RWPE1 and mouse mPrE normal prostate cells promoted tumorigenesis under carcinogen challenge, suggesting TR4 may play a suppressor role in PCa initiation. Mechanism dissection in both in vitro cell lines and in vivo mice studies found that knocking down TR4 led to increased DNA damage with altered DNA repair system that involved the modulation of ATM expression at the transcriptional level, and addition of ATM partially interrupted the TR4 small interfering RNA-induced tumorigenesis in cell transformation assays. Immunohistochemical staining in human PCa tissue microarrays revealed ATM expression is highly correlated with TR4 expression. Together, these results suggest TR4 may function as a tumor suppressor to prevent or delay prostate tumorigenesis via regulating ATM expression at the transcriptional level.
- Published
- 2014
42. Androgen receptor (AR) positive vs negative roles in prostate cancer cell deaths including apoptosis, anoikis, entosis, necrosis and autophagic cell death
- Author
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Chawnshang Chang, Simeng Wen, Yuanjie Niu, and Soo Ok Lee
- Subjects
Male ,Programmed cell death ,Cell type ,Entosis ,Antineoplastic Agents, Hormonal ,Cell ,urologic and male genital diseases ,Article ,Androgen deprivation therapy ,Prostate cancer ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Anoikis ,Cell Proliferation ,Cell Death ,business.industry ,Prostatic Neoplasms ,General Medicine ,medicine.disease ,Androgen receptor ,medicine.anatomical_structure ,Oncology ,Receptors, Androgen ,Immunology ,Cancer research ,business ,Signal Transduction - Abstract
Androgen/androgen receptor (AR) signaling plays pivotal roles in the prostate development and homeostasis as well as in the progression of prostate cancer (PCa). Androgen deprivation therapy (ADT) with anti-androgens remains as the main treatment for later stage PCa, and it has been shown to effectively suppress PCa growth during the first 12-24 months. However, ADT eventually fails and tumors may re-grow and progress into the castration resistant stage. Recent reports revealed that AR might play complicated and even opposite roles in PCa progression that might depend on cell types and tumor stages. Importantly, AR may influence PCa progression via differential modulation of various cell deaths including apoptosis, anoikis, entosis, necrosis, and autophagic cell deaths. Targeting AR may induce PCa cell apoptosis, autophagic cell deaths and programmed necrosis, yet targeting AR may suppress cell deaths via anoikis and entosis that may potentially lead to increased metastasis. These differential functions of AR in various types of PCa cell death might challenge the current ADT with anti-androgens treatment. Further detailed dissection of molecular mechanisms by which AR modulates different PCa cell deaths will help us to develop a better therapy to battle PCa.
- Published
- 2014
43. Determination of androgen receptor degradation enhancer ASC-J9® in mouse sera and organs with liquid chromatography tandem mass spectrometry
- Author
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Yinhan Gong, Chiung-Kuei Huang, Shu Fang Soh, Chawnshang Chang, Shuyuan Yeh, Eu Leong Yong, Soo Ok Lee, Jun Li, and Defeng Xu
- Subjects
Male ,Curcumin ,Clinical Biochemistry ,Pharmaceutical Science ,Tandem mass spectrometry ,Article ,Analytical Chemistry ,Mice ,Prostate cancer ,Pharmacokinetics ,Limit of Detection ,Tandem Mass Spectrometry ,In vivo ,Liquid chromatography–mass spectrometry ,Prostate ,Testis ,Drug Discovery ,medicine ,Animals ,Tissue Distribution ,Spectroscopy ,Cell Proliferation ,Chromatography ,Chemistry ,Reproducibility of Results ,medicine.disease ,Molecular biology ,Androgen receptor ,Spinal and bulbar muscular atrophy ,medicine.anatomical_structure ,Liver ,Receptors, Androgen ,Calibration ,Androgens ,Linear Models ,Chromatography, Liquid ,Half-Life - Abstract
A novel androgen receptor (AR) degradation enhancer ASC-J9(®) has displayed beneficial effects during the in vitro and in vivo studies for treatment of prostate cancer, liver cancer, bladder cancer and spinal and bulbar muscular atrophy (SBMA). It works mainly via the degradation of AR with minimal side effects on the tested mice. Here we developed a fast, robust and more sensitive method for the quantification of ASC-J9(®) in 100μL of mouse serum by using liquid chromatography tandem mass spectrometry (LC-MS/MS). The limit of quantification (LOQ) was found to be 5nM for ASCJ9(®). This method was successfully applied to investigate the pharmacokinetics of ASC-J9(®) in mice serum samples and also the distribution of the drug in various mice organs after single dose injection with results showing that ASC-J9(®) could be quickly absorbed in vivo and had a relatively slow elimination half-life of 5.45h. The ASC-J9(®) also exhibited a higher tendency to accumulate in organs such as liver, testes and prostate.
- Published
- 2014
44. Abstract 1520: IL-6 up-regulates pd-l1 and facilitates lung cancer escape from NK cell immune function through its downstream MEK-ERK signaling
- Author
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Soo Ok Lee, Rongying Zhu, Xiang Xue, Donglai Cchen, Shanzhou Duan, Mingjing Shen, Feng Chen, Ying Tsai, Peter Keng, Yongbing Chen, and Yuhchyau chen
- Subjects
Cancer Research ,Oncology - Abstract
Background: We previously reported that IL-6 was associated with therapy resistance to radiotherapy and cisplatin chemotherapy, the two most common treatments for non-small cell lung cancer (NSCLC). Emerging in vivo evidence shows that natural killer (NK) cells have an important role in immune defense. In this study, we examined the role of IL-6 modulation in lung cancer PD-L1 expression and the impact on NK cell cytotoxicity. We also revealed the key molecular signaling pathway involved in this process, which serves as the potential therapeutic target to improve clinical lung cancer treatments. Methods: We examined the prevalence of IL-6 in tumors of NSCLC in immunohistochemical staining. The susceptibility of IL-6 expressing scramble control (A549sc and H157sc) cells and IL-6 knocked down (A549siIL-6 and H157siIL-6) cells were investigated in in vitro and in vivo human tumor xenograft studies in mice. In in vivostudies, tumors were developed by luciferase tagged A549siIL-6 vs. A549sc cell injection, and primary human NK cells were injected intravenously at the early stage of tumor development. IL-6 regulation of PD-L1 at the transcriptional level was investigated and NK cell binding to tumor cells was also examined. Results: We found the ubiquitous presence of IL-6 in NSCLC. We found IL-6 expressing lung cancer cells were more resistant to NK cell cytotoxicity than IL-6 knocked-down cells. In addition, we found higher expressions of programmed death receptor 1 ligand (PD-L1) in IL-6 expressing lung cancer cells than IL-6 knocked-down cells. In excised human tumor xenografts and in human NSCLC tumors, co-localization of IL-6 signaling and PD-L1 expression was observed. Furthermore, we discovered that IL-6 promoted PD-L1 expression at the transcriptional level via the regulation of its downstream MEK/Erk signaling pathway. In addition, we found that IL-6-MEK/Erk signaling also contributed to diverting NK cells away from binding to tumor cells. Conclusions and Impact: In conclusion, we found that IL-6 develops the resistance to NK cell actions by inducing PD-L1 in NSCLC cells and diverts NK cells away from tumor cells via its downstream MEK/Erk signaling. NK cell-mediated immune function plays an important role in cancer surveillance, invasion, and metastasis, but its role in lung cancer is not clear. In in vivo studies, we proved the importance of NK cell-mediated immune reaction. Our discovery of revealing the IL-6 downstream signaling, MEK/Erk, in triggering the PD-L1 up-regulation and in blocking NK cell binding with lung cancer cells is novel. Data from this investigation support that blocking MEK/Erk signaling pathway has the potential to enhance NK cell immune function to NSCLC by overcoming IL-6 mediated NK cell resistance. Citation Format: Soo Ok Lee, Rongying Zhu, Xiang Xue, Donglai Cchen, Shanzhou Duan, Mingjing Shen, Feng Chen, Ying Tsai, Peter Keng, Yongbing Chen, Yuhchyau chen. IL-6 up-regulates pd-l1 and facilitates lung cancer escape from NK cell immune function through its downstream MEK-ERK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1520.
- Published
- 2019
45. Loss of androgen receptor promotes adipogenesis but suppresses osteogenesis in bone marrow stromal cells
- Author
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Soo Ok Lee, Meng-Yin Tsai, Chiung-Kuei Huang, Hong-Yo Kang, Yuhchyau Chen, Kuo-Pao Lai, Jie Luo, and Chawnshang Chang
- Subjects
Male ,medicine.medical_specialty ,Stromal cell ,Cellular differentiation ,Bone Marrow Cells ,Cell Growth Processes ,Biology ,Article ,Gene Knockout Techniques ,Mice ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Osteogenesis ,Internal medicine ,medicine ,Animals ,Humans ,Protein kinase B ,030304 developmental biology ,Medicine(all) ,0303 health sciences ,Adipogenesis ,Cell Differentiation ,Osteoblast ,Cell Biology ,General Medicine ,Cell biology ,Androgen receptor ,Endocrinology ,medicine.anatomical_structure ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Osteoporosis ,Female ,Bone marrow ,Stromal Cells ,Signal transduction ,Signal Transduction ,Developmental Biology - Abstract
Gender differences have been described in osteoporosis with females having a higher risk of osteoporosis than males. The differentiation of bone marrow stromal cells (BMSCs) into bone or fat is a critical step for osteoporosis. Here we demonstrated that loss of the androgen receptor (AR) in BMSCs suppressed osteogenesis but promoted adipogenesis. The mechanism dissection studies revealed that AR deficiency suppressed osteogenesis-related genes to inhibit osteoblast differentiation from BMSCs. Knockout of AR promoted adipogenesis of BMSCs via Akt activation through IGFBP3-mediated IGF signaling, and the 5′ promoter assay and chromatin immunoprecipitation assays further proved that AR could modulate IGFBP3 expression at the transcriptional level. Finally, addition of IGF inhibitors successfully masked the AR deficiency-induced Akt activation, and inhibitions of Akt, IGF1, and IGF2 pathways reversed the AR depletion effects on the adipogenesis process. These results suggested that AR-mediated changes in IGFBP3 might modulate the IGF–Akt axis to regulate adipogenesis in BMSCs.
- Published
- 2013
46. Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver
- Author
-
Soo Ok Lee, Chawnshang Chang, Ta-Min Chang, and Shuyuan Yeh
- Subjects
Cancer Research ,Cell type ,medicine.medical_specialty ,medicine.drug_class ,Biology ,medicine.disease_cause ,Metastasis ,Prostate ,Neoplasms ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Hormone metabolism ,Receptor ,Molecular Biology ,Androgen ,medicine.disease ,Hormones ,Androgen receptor ,Endocrinology ,medicine.anatomical_structure ,Receptors, Androgen ,Cancer research ,Carcinogenesis ,Signal Transduction - Abstract
The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression. This review will discuss the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.
- Published
- 2013
47. Differential Androgen Deprivation Therapies with Anti-androgens Casodex/Bicalutamide or MDV3100/Enzalutamide versus Anti-androgen Receptor ASC-J9® Lead to Promotion versus Suppression of Prostate Cancer Metastasis
- Author
-
Defeng Xu, Shuyuan Yeh, Shauh Der Yeh, Liang Liang, Soo Ok Lee, Chawnshang Chang, Yuanjie Niu, Tzuhua Lin, Naohiro Fujimoto, and Lei Li
- Subjects
Male ,urologic and male genital diseases ,Biochemistry ,Metastasis ,Tosyl Compounds ,Androgen deprivation therapy ,Mice ,chemistry.chemical_compound ,Prostate cancer ,Anilides ,Neoplasm Metastasis ,Molecular Bases of Disease ,Primary tumor ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Matrix Metalloproteinase 9 ,Benzamides ,Androgens ,Additions and Corrections ,medicine.drug ,medicine.medical_specialty ,Curcumin ,Bicalutamide ,medicine.drug_class ,Transplantation, Heterologous ,Down-Regulation ,Mice, Nude ,Biology ,Gene Expression Regulation, Enzymologic ,Transforming Growth Factor beta1 ,In vivo ,Cell Line, Tumor ,Internal medicine ,Nitriles ,Phenylthiohydantoin ,Androgen Receptor Antagonists ,medicine ,Animals ,Humans ,Enzalutamide ,Neoplasm Invasiveness ,Smad3 Protein ,Molecular Biology ,Prostatic Neoplasms ,Neoplasms, Experimental ,Cell Biology ,Prostate-Specific Antigen ,Androgen ,medicine.disease ,Xenograft Model Antitumor Assays ,Endocrinology ,chemistry ,Cancer research ,Neoplasm Transplantation - Abstract
Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9® and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 μm Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9® led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-β1/Smad3/MMP9 pathway, but ASC-J9® and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9® to battle PCa metastasis at the castration-resistant stage.
- Published
- 2013
48. Increased Chemosensitivity via Targeting Testicular Nuclear Receptor 4 (TR4)-Oct4-Interleukin 1 Receptor Antagonist (IL1Ra) Axis in Prostate Cancer CD133+ Stem/Progenitor Cells to Battle Prostate Cancer
- Author
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Jin Zhu, Ronghao Wang, Dong-Rong Yang, Chawnshang Chang, Yuhchyau Chen, Xianfan Ding, Chiung-Kuei Huang, Yuxi Shan, Jie Luo, Gonghui Li, Soo Ok Lee, and Shin-Jen Lin
- Subjects
Male ,Receptors, Steroid ,Population ,Docetaxel ,Biology ,urologic and male genital diseases ,Biochemistry ,Prostate cancer ,Antigens, CD ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Humans ,AC133 Antigen ,Progenitor cell ,education ,Molecular Biology ,Etoposide ,Glycoproteins ,education.field_of_study ,Gene knockdown ,Receptors, Thyroid Hormone ,Prostatic Neoplasms ,Cell Biology ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Interleukin 1 Receptor Antagonist Protein ,Interleukin 1 receptor antagonist ,Nuclear receptor ,Drug Resistance, Neoplasm ,Cell culture ,Gene Knockdown Techniques ,Neoplastic Stem Cells ,Cancer research ,Taxoids ,Peptides ,Octamer Transcription Factor-3 - Abstract
Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.
- Published
- 2013
49. Suppression of Androgen Receptor Enhances the Self-renewal of Mesenchymal Stem Cells Through Elevated Expression of EGFR
- Author
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Meng-Yin Tsai, Chawnshang Chang, Soo Ok Lee, Jie Luo, Hong-Yo Kang, and Chiung-Kuei Huang
- Subjects
MAPK/ERK pathway ,medicine.medical_specialty ,Cellular differentiation ,Bone Marrow Cells ,Mesenchymal Stem Cell Transplantation ,Article ,Cell Line ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Adipocytes ,Androgen Receptor Antagonists ,medicine ,Animals ,Epidermal growth factor receptor ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Mesenchymal stem cell ,Cell Differentiation ,Cell Biology ,Flutamide ,3. Good health ,ErbB Receptors ,Transplantation ,Androgen receptor ,Endocrinology ,chemistry ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Mesenchymal stem cells ,Self-renewal ,Androgen receptor knockout ,Hydroxyflutamide ,Signal Transduction - Abstract
Bone marrow derived mesenchymal stem cells (BM-MSCs) have been widely applied in several clinical trials of diseases, such as myocardial infarction, liver cirrhosis, neurodegenerative disease, and osteogenesis imperfecta. Although most studies demonstrated that transplantation of BM-MSCs did exert a temporary relief and short-term therapeutic effects, eventually all symptoms recur, therefore it is essential to improve the therapeutic efficacy of transplantation by either elevating the self-renewal of BM-MSCs or enhancing their survival rate. Herein we demonstrated that the BM-MSCs and adipocyte derived mesenchymal stem cells (ADSCs) isolated from the androgen receptor (AR) knockout mice have higher self-renewal ability than those obtained from the wild-type mice. Knockdown of AR in MSC cell lines exhibited similar results. Mechanistic dissection studies showed that the depletion of AR resulted in activation of Erk and Akt signaling pathways through epidermal growth factor receptor (EGFR) activation or pathway to mediate higher self-renewal of BM-MSCs. Targeting AR signals using ASC-J9® (an AR degradation enhancer), hydroxyflutamide (antagonist of AR), and AR-siRNA all led to enhanced self-renewal of MSCs, suggesting the future possibility of using these anti-AR agents in therapeutic approaches.
- Published
- 2013
50. Targeting androgen receptor in bone marrow mesenchymal stem cells leads to better transplantation therapy efficacy in liver cirrhosis
- Author
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Chiung-Kuei Huang, Soo Ok Lee, Chawnshang Chang, Wen Lung Ma, Meng Yin Tsai, Kuo Pao Lai, Tzuhua Lin, and Jie Luo
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,medicine.medical_treatment ,Thioacetamide ,Biology ,Liver transplantation ,Mesenchymal Stem Cell Transplantation ,Mice ,Paracrine signalling ,Internal medicine ,medicine ,Animals ,RNA, Small Interfering ,Carbon Tetrachloride ,Mice, Knockout ,Hepatology ,Receptors, Interleukin-1 ,medicine.disease ,Hepatic stellate cell activation ,ErbB Receptors ,Androgen receptor ,Transplantation ,Disease Models, Animal ,Phenotype ,Treatment Outcome ,Endocrinology ,Matrix Metalloproteinase 9 ,Receptors, Androgen ,Cancer research ,Female ,Liver cancer ,Signal Transduction - Abstract
Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat liver cirrhosis, an irreversible disease that may eventually lead to liver cancer development. However, low survival rate of the BM-MSCs leading to unsatisfactory efficacy remains a major concern. Gender differences have been suggested in BM-MSCs therapeutic application, but the effect of the androgen receptor (AR), a key factor in male sexual phenotype, in this application is not clear. Using two liver cirrhosis mouse models induced by CCl4 or thioacetamide, we showed that targeting AR in the BM-MSCs improved their self-renewal and migration potentials and increased paracrine effects to exert anti-inflammatory and anti-fibrotic actions to enhance liver repair. Mechanism dissection studies suggested that knocking out AR in BM-MSCs led to improved self-renewal and migration by alteration of the signaling of epidermal growth factor receptor and matrix metalloproteinase 9 and resulted in suppression of infiltrating macrophages and hepatic stellate cell activation through modulation of interleukin (IL)1R/IL1Ra signaling. Therapeutic approaches using either AR/small interfering RNA or the AR degradation enhancer, ASC-J9®, to target AR in BM-MSCs all led to increased efficacy for liver repair. Conclusion: Targeting AR, a key factor in male sexual phenotype, in BM-MSCs improves transplantation therapeutic efficacy for treating liver fibrosis. (HEPATOLOGY 2013;57:1550–1563)
- Published
- 2013
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