8 results on '"Mangala LS"'
Search Results
2. A-to-I-edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis.
- Author
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Xu X, Wang Y, Mojumdar K, Zhou Z, Jeong KJ, Mangala LS, Yu S, Tsang YH, Rodriguez-Aguayo C, Lu Y, Lopez-Berestein G, Sood AK, Mills GB, and Liang H
- Subjects
- Animals, Antigens, CD genetics, Cell Line, Tumor, Cell Proliferation, Female, Mice, Neoplasms pathology, Receptors, G-Protein-Coupled genetics, Antigens, CD physiology, Apoptosis, MicroRNAs physiology, Neoplasms therapy, RNA Editing, Receptors, G-Protein-Coupled physiology
- Abstract
Both miRNAs and A-to-I RNA editing, a widespread nucleotide modification mechanism, have recently emerged as key players in cancer pathophysiology. However, the functional impact of RNA editing of miRNAs in cancer remains largely unexplored. Here, we focused on an ADAR2-catalyzed RNA editing site within the miR-379-5p seed region. This site was under-edited in tumors relative to normal tissues, with a high editing level being correlated with better patient survival times across cancer types. We demonstrated that in contrast to wild-type miRNA, edited miR-379-5p inhibited cell proliferation and promoted apoptosis in diverse tumor contexts in vitro, which was due to the ability of edited but not wild-type miR-379-5p to target CD97. Importantly, through nanoliposomal delivery, edited miR-379-5p mimics significantly inhibited tumor growth and extended survival of mice. Our study indicates a role of RNA editing in diversifying miRNA function during cancer progression and highlights the translational potential of edited miRNAs as a new class of cancer therapeutics.
- Published
- 2019
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3. ATP11B mediates platinum resistance in ovarian cancer.
- Author
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Moreno-Smith M, Halder JB, Meltzer PS, Gonda TA, Mangala LS, Rupaimoole R, Lu C, Nagaraja AS, Gharpure KM, Kang Y, Rodriguez-Aguayo C, Vivas-Mejia PE, Zand B, Schmandt R, Wang H, Langley RR, Jennings NB, Ivan C, Coffin JE, Armaiz GN, Bottsford-Miller J, Kim SB, Halleck MS, Hendrix MJ, Bornman W, Bar-Eli M, Lee JS, Siddik ZH, Lopez-Berestein G, and Sood AK
- Published
- 2018
- Full Text
- View/download PDF
4. Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance.
- Author
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Leung CS, Yeung TL, Yip KP, Wong KK, Ho SY, Mangala LS, Sood AK, Lopez-Berestein G, Sheng J, Wong ST, Birrer MJ, and Mok SC
- Subjects
- Animals, Cell Line, Tumor, Cell Movement, Disease Progression, Endothelial Cells metabolism, Female, Fibrosis, Focal Adhesions, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Mice, Microcirculation, Neovascularization, Pathologic, Permeability, RNA, Small Interfering metabolism, Signal Transduction, Treatment Outcome, Up-Regulation, Cancer-Associated Fibroblasts metabolism, Cytoskeletal Proteins metabolism, Drug Resistance, Neoplasm, LIM Domain Proteins metabolism, Ovarian Neoplasms drug therapy, Ovarian Neoplasms metabolism
- Abstract
The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs.
- Published
- 2018
- Full Text
- View/download PDF
5. JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.
- Author
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Wang S, Liang K, Hu Q, Li P, Song J, Yang Y, Yao J, Mangala LS, Li C, Yang W, Park PK, Hawke DH, Zhou J, Zhou Y, Xia W, Hung MC, Marks JR, Gallick GE, Lopez-Berestein G, Flores ER, Sood AK, Huang S, Yu D, Yang L, and Lin C
- Subjects
- Animals, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms secondary, Breast Neoplasms genetics, Breast Neoplasms pathology, Female, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Janus Kinase 2 genetics, MCF-7 Cells, Mice, Mice, Nude, NIH 3T3 Cells, Neoplasm Metastasis, Neoplasm Proteins genetics, RNA, Long Noncoding genetics, RNA, Neoplasm genetics, Signal Transduction genetics, Tumor Microenvironment genetics, U937 Cells, Brain Neoplasms metabolism, Breast Neoplasms metabolism, Janus Kinase 2 metabolism, Neoplasm Proteins metabolism, RNA, Long Noncoding metabolism, RNA, Neoplasm metabolism
- Abstract
Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M- and IL-6-triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease.
- Published
- 2017
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6. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal.
- Author
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Haemmerle M, Bottsford-Miller J, Pradeep S, Taylor ML, Choi HJ, Hansen JM, Dalton HJ, Stone RL, Cho MS, Nick AM, Nagaraja AS, Gutschner T, Gharpure KM, Mangala LS, Rupaimoole R, Han HD, Zand B, Armaiz-Pena GN, Wu SY, Pecot CV, Burns AR, Lopez-Berestein G, Afshar-Kharghan V, and Sood AK
- Subjects
- Adenosine Diphosphate metabolism, Animals, Antibodies, Neoplasm pharmacology, Bevacizumab pharmacology, Blood Platelets pathology, Cell Hypoxia drug effects, Cell Hypoxia genetics, Cell Line, Tumor, Female, Focal Adhesion Kinase 1 antagonists & inhibitors, Focal Adhesion Kinase 1 genetics, Humans, Indazoles, Mice, Mice, Knockout, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neovascularization, Pathologic enzymology, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Ovarian Neoplasms enzymology, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Pyrimidines pharmacology, Sulfonamides pharmacology, Tumor Microenvironment genetics, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Focal Adhesion Kinase 1 metabolism, Neoplasm Proteins metabolism, Neovascularization, Pathologic drug therapy, Ovarian Neoplasms drug therapy, Tumor Microenvironment drug effects
- Abstract
Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.
- Published
- 2016
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7. ATP11B mediates platinum resistance in ovarian cancer.
- Author
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Moreno-Smith M, Halder JB, Meltzer PS, Gonda TA, Mangala LS, Rupaimoole R, Lu C, Nagaraja AS, Gharpure KM, Kang Y, Rodriguez-Aguayo C, Vivas-Mejia PE, Zand B, Schmandt R, Wang H, Langley RR, Jennings NB, Ivan C, Coffin JE, Armaiz GN, Bottsford-Miller J, Kim SB, Halleck MS, Hendrix MJ, Bornman W, Bar-Eli M, Lee JS, Siddik ZH, Lopez-Berestein G, and Sood AK
- Subjects
- ATP-Binding Cassette Transporters genetics, Adenosine Triphosphatases genetics, Animals, Antineoplastic Agents pharmacology, Carcinoma drug therapy, Carcinoma genetics, Carcinoma metabolism, Cell Line, Tumor, Cell Membrane metabolism, Female, Fluorescent Dyes pharmacology, Gene Silencing, Golgi Apparatus metabolism, Humans, Membrane Transport Proteins genetics, Mice, Middle Aged, Ovarian Neoplasms metabolism, Qa-SNARE Proteins metabolism, R-SNARE Proteins metabolism, RNA, Small Interfering metabolism, ATP-Binding Cassette Transporters physiology, Adenosine Triphosphatases physiology, Cisplatin pharmacology, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Membrane Transport Proteins physiology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics
- Abstract
Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.
- Published
- 2013
- Full Text
- View/download PDF
8. An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic.
- Author
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Fernández A, Sanguino A, Peng Z, Ozturk E, Chen J, Crespo A, Wulf S, Shavrin A, Qin C, Ma J, Trent J, Lin Y, Han HD, Mangala LS, Bankson JA, Gelovani J, Samarel A, Bornmann W, Sood AK, and Lopez-Berestein G
- Subjects
- Animals, Benzamides, Cardiotoxins chemistry, Cardiotoxins pharmacology, Drug Screening Assays, Antitumor, Fusion Proteins, bcr-abl, Heart Diseases chemically induced, Heart Diseases enzymology, Humans, Imatinib Mesylate, K562 Cells, MAP Kinase Kinase 4 metabolism, Neoplasms, Experimental drug therapy, Neoplasms, Experimental enzymology, Piperazines adverse effects, Piperazines chemistry, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors chemistry, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Pyrimidines adverse effects, Pyrimidines chemistry, Rats, Rats, Sprague-Dawley, Gastrointestinal Stromal Tumors drug therapy, Gastrointestinal Stromal Tumors enzymology, MAP Kinase Kinase 4 antagonists & inhibitors, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-kit metabolism, Pyrimidines pharmacology
- Abstract
Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity.
- Published
- 2007
- Full Text
- View/download PDF
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