23 results on '"Emdad, Luni"'
Search Results
2. Abstract 3902: MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.
- Author
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Das, Swadesh K., primary, Kegelman, Timothy P., additional, Santhekadur, Prasanna K., additional, Dasgupta, Santanu, additional, Dent, Paul, additional, Grant, Steven, additional, Emdad, Luni, additional, Sarkar, Devanand, additional, Fisher, Paul B., additional, and Pellecchia, Maurizio, additional
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- 2013
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3. Astrocyte Elevated Gene-1 Interacts with Akt Isoform 2 to Control Glioma Growth, Survival, and Pathogenesis.
- Author
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Bin Hu, Emdad, Luni, Bacolod, Manny D., Kegelman, Timothy P., Xue-Ning Shen, Alzubi, Mohammad A., Das, Swadesh K., Sarkar, Devanand, and Fisher, Paul B.
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ONCOGENES , *METASTASIS , *GLIOMAS , *IMMUNOHISTOCHEMISTRY , *NEOVASCULARIZATION - Abstract
The oncogene astrocyte elevated gene-1 (AEG-1; MTDH) is highly expressed in glioblastoma multiforme (GBM) and many other types of cancer, where it activates multiple signaling pathways that drive proliferation, invasion, angiogenesis, chemoresistance, radioresistance, and metastasis. AEG-1 activates the Akt signaling pathway and Akt and c-Myc are positive regulators of AEG-1 transcription, generating a positive feedback loop between AEG-1 and Akt in regulating tumorigenesis. Here, we describe in GBM cells a direct interaction between an internal domain of AEG-1 and the PH domain of Akt2, a major driver in GBM. Expression and interaction of AEG-1 and Akt2 are elevated in GBM and contribute to tumor cell survival, proliferation, and invasion. Clinically, in silico gene expression and immunohistochemical analyses of patient specimens showed that AEG-1 and Akt2 expression correlated with GBM progression and reduced patient survival. AEG-1-Akt2 interaction prolonged stabilization of Akt2 phosphorylation at S474, regulating downstream signaling cascades that enable cell proliferation and survival. Disrupting AEG-1-Akt2 interaction by competitive binding of the Akt2-PH domain led to reduced cell viability and invasion. When combined with AEG-1 silencing, conditional expression of Akt2-PH markedly increased survival in an orthotopic mouse model of human GBM. Our study uncovers a novel molecular mechanism by which AEG-1 augments glioma progression and offers a rationale to block AEG-1-Akt2 signaling function as a novel GBM treatment. [ABSTRACT FROM AUTHOR]
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- 2014
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4. Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline.
- Author
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Quinn, Bridget A., Dash, Rupesh, Sarkar, Siddik, Azab, Belal, Bhoopathi, Praveen, Das, Swadesh K., Emdad, Luni, Wei, Jun, Pellecchia, Maurizio, Sarkar, Devanand, and Fisher, Paul B.
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PANCREATIC cancer treatment , *COMBINATION drug therapy , *CANCER chemotherapy , *MINOCYCLINE , *BIOCHEMICAL mechanism of action , *CELL-mediated cytotoxicity - Abstract
Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. [ABSTRACT FROM AUTHOR]
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- 2015
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5. Genetic Deletion of AEG-1 Prevents Hepatocarcinogenesis.
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Robertson, Chadia L., Srivastava, Jyoti, Siddiq, Ayesha, Gredler, Rachel, Emdad, Luni, Rajasekaran, Devaraja, Akiel, Maaged, Xue-Ning Shen, Chunqing Guo, Giashuddin, Shah, Xiang-Yang Wang, Ghosh, Shobha, Subler, Mark A., Windle, Jolene J., Fisher, Paul B., and Sarkar, Devanand
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LIVER cancer , *LIVER metastasis , *CARCINOGENS research , *CARCINOGENICITY , *NF-kappa B - Abstract
Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-κB in liver macrophages. Because AEG-1 is an essential component of NF-κB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1-deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of AKT, ERK, and β-catenin, compared with wild-type control animals. However, AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL6 production and STAT3 activation, two key mediators of HCC development, were also deficient along with other biologic and epigenetics findings in the tumor microenvironment, confirming that AEG-1 supports an NF-κB-mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-κB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development. [ABSTRACT FROM AUTHOR]
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- 2014
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6. Pancreatic Cancer--Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine--Polycytidylic Acid.
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Bhoopathi, Praveen, Quinn, Bridget A., Qin Gui, Xue-Ning Shen, Grossman, Steven R., Das, Swadesh K., Sarkar, Devanand, Fisher, Paul B., and Emdad, Luni
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CELL death , *CANCER cells , *PANCREATIC cancer , *KILLER cells , *IMMUNOCOMPETENT cells - Abstract
Polyinosine--polycytidylic acid [pIC] is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and natural killer cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells (PDAC) but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC]PEI) in PDAC and investigated its mechanism of action. [pIC]PEI stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC]PEI repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I, and NOXA. Phosphorylation of AKT was inhibited by [pIC]PEI in PDAC, and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC]PEI inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC]PEI as an immunochemotherapy to treat pancreatic cancer. [ABSTRACT FROM AUTHOR]
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- 2014
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7. AEG-1 Regulates Retinoid X Receptor and Inhibits Retinoid Signaling.
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Srivastava, Jyoti, Robertson, Chadia L., Rajasekaran, Devaraja, Gredler, Rachel, Siddiq, Ayesha, Emdad, Luni, Mukhopadhyay, Nitai D., Ghosh, Shobha, Hylemon, Phillip B., Gil, Gregorio, Shah, Khalid, Bhere, Deepak, Subler, Mark A., Windle, Jolene J., Fisher, Paul B., and Sarkar, Devanand
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RETINOID X receptors , *LIVER cancer , *CANCER genetics , *REGULATION of cell growth , *ANIMAL models of cancer , *GENETICS - Abstract
Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)-mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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8. Novel Mechanism of MDA-7/IL-24 Cancer-Specific Apoptosis through SARI Induction.
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Dash, Rupesh, Bhoopathi, Praveen, Das, Swadesh K., Sarkar, Siddik, Emdad, Luni, Dasgupta, Santanu, Sarkar, Devanand, and Fisher, Paul B.
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CANCER cell differentiation , *MELANOMA , *INTERLEUKINS , *INTERFERONS , *DNA damage - Abstract
Subtraction hybridization combined with induction of cancer cell terminal differentiation in human melanoma cells identified melanoma differentiation--associated gene-7/interleukin-24 (mda-7/IL-24) and SARI (suppressor of AP-1, induced by IFN) that display potent antitumor activity. These genes are not constitutively expressed in cancer cells and forced expression of mda-7/IL-24 (Ad.mda-7) or SARI (Ad.SARI) promotes cancer-specific cell death. Ectopic expression of mda-7/IL-24 induces SARI mRNA and protein in a panel of different cancer cells, leading to cell death, without harming corresponding normal cells. Simultaneous inhibition of K-ras downstream extracellular signal-regulated kinase 1/2 signaling in pancreatic cancer cells reverses the translational block of MDA-7/IL-24 and induces SARI expression and cell death. Using SARI-antisense-based approaches, we demonstrate that SARI expression is necessary for mda-7/IL-24 antitumor effects. Secreted MDA-7/IL-24 protein induces antitumor "bystander" effects by promoting its own expression. Recombinant MDA-7/IL-24 (His-MDA-7) induces SARI expression, supporting the involvement of SARI in the MDA-7/IL-24-driven autocrine loop, culminating in antitumor effects. Moreover, His-MDA-7, after binding to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL- 20R2), induces intracellular signaling by phosphorylation of p38 MAPK, leading to transcription of a family of growth arrest and DNA damage inducible (GADD) genes, culminating in apoptosis. Inhibition of p38 MAPK fails to induce SARI following Ad.mda-7 infection. These findings reveal the significance of the mda-7/IL-24-SARI axis in cancer-specific killing and provide a potential strategy for treating both local and metastatic disease. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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9. MDA-9/Syntenin and IGFBP-2 Promote Angiogenesis in Human Melanoma.
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Das, Swadesh K., Bhutia, Sujit K., Azab, Belal, Kegelman, Timothy P., Peachy, Leyla, Santhekadur, Prasanna K., Dasgupta, Santanu, Dash, Rupesh, Dent, Paul, Grant, Steven, Emdad, Luni, Pellecchia, Maurizio, Sarkar, Devanand, and Fisher, Paul B.
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MELANOMA treatment , *CELL differentiation , *CANCER invasiveness , *CANCER treatment , *CANCER cells - Abstract
Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chorioallantoic membrane (CAM) assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/ syntenin in which MDA-9/syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces hypoxia inducible factor 1-α (HIF-1α). The HIF-1α activates transcription of insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (nonautonomous). [ABSTRACT FROM AUTHOR]
- Published
- 2013
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10. Oncogene AEG-1 Promotes Glioma-Induced Neurodegeneration by Increasing Glutamate Excitotoxicity.
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Lee, Seok-Geun, Kim, Keetae, Kegelman, Timothy P., Dash, Rupesh, Das, Swadesh K., Choi, Jung Kyoung, Emdad, Luni, Howlett, Eric L., Jeon, Hyun Yong, Su, Zhao Zhong, Yoo, Byoung Kwon, Sarkar, Devanand, Kim, Sung-Hoon, Kang, Dong-Chul, and Fisher, Paul B.
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TUMOR growth , *GLIOMAS , *ASTROCYTES , *CANCER cells , *GLIOBLASTOMA multiforme - Abstract
Aggressive tumor growth, diffuse tissue invasion, and neurodegeneration are hallmarks of malignant glioma. Although glutamate excitotoxicity is considered to play a key role in glioma-induced neurodegeneration, the mechanism(s) controlling this process is poorly understood. Astrocyte elevated gene-1 (AEG-1 ) is an oncogene that is overexpressed in several types of human cancers, including more than 90% of brain tumors. In addition, AEG-1 promotes gliomagenesis, particularly in the context of tumor growth and invasion, 2 primary characteristics of glioma. In the present study, we investigated the contribution of AEG-1 to glioma-induced neurodegeneration. Pearson correlation coefficient analysis in normal brain tissues and samples from glioma patients indicated a strong negative correlation between expression of AEG-1 and a primary glutamate transporter of astrocytes EAAT2. Gain- and loss-of-function studies in normal primary human fetal astrocytes and T98G glioblastoma multiforme cells revealed that AEG-1 repressed EAAT2 expression at a transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the promoter. In addition, AEG- EAAT2 1--mediated EAAT2 repression caused a reduction of glutamate uptake by glial cells, resulting in induction of neuronal cell death. These findings were also confirmed in samples from glioma patients showing that AEG-1 expression negatively correlated with NeuN expression. Taken together, our findings suggest that AEG-1 contributes to glioma-induced neurodegeneration, a hallmark of this fatal tumor, through regulation of EAAT2 expression. [ABSTRACT FROM AUTHOR]
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- 2011
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11. Editor's Note: mda-9 /Syntenin: A Positive Regulator of Melanoma Metastasis.
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Boukerche H, Su ZZ, Emdad L, Baril P, Balme B, Thomas L, Randolph A, Valerie K, Sarkar D, and Fisher PB
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- 2019
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12. The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion.
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Das SK, Pradhan AK, Bhoopathi P, Talukdar S, Shen XN, Sarkar D, Emdad L, and Fisher PB
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- Animals, Carcinogenesis genetics, Carcinogenesis pathology, Cell Differentiation genetics, Cell Line, Tumor, Cell Movement genetics, Gene Expression Regulation, Neoplastic genetics, Humans, Interleukin-6 genetics, Interleukin-8 genetics, Male, Matrix Metalloproteinase 2 genetics, Matrix Metalloproteinase 9 genetics, Melanoma genetics, Melanoma pathology, Neoplasm Invasiveness pathology, Prostatic Neoplasms pathology, Receptor, IGF Type 1, Signal Transduction genetics, Vascular Endothelial Growth Factor A genetics, Neoplasm Invasiveness genetics, Prostatic Neoplasms genetics, Receptors, Somatomedin genetics, STAT3 Transcription Factor genetics, Syntenins genetics
- Abstract
Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin -manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers. Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852-63. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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13. mda-7/IL-24 Mediates Cancer Cell-Specific Death via Regulation of miR-221 and the Beclin-1 Axis.
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Pradhan AK, Talukdar S, Bhoopathi P, Shen XN, Emdad L, Das SK, Sarkar D, and Fisher PB
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- Animals, Beclin-1 genetics, Cell Line, Tumor, Female, Humans, Mice, Neoplasms drug therapy, Reactive Oxygen Species metabolism, Sirolimus pharmacology, Apoptosis, Beclin-1 physiology, Interleukins physiology, MicroRNAs physiology, Neoplasms pathology
- Abstract
Melanoma differentiation-associated gene-7/IL-24 ( mda-7/IL-24 ) displays broad-spectrum anticancer activity in vitro, in vivo in preclinical animal models, and in a phase I/II clinical trial in patients with advanced cancers without harming normal cells or tissues. Here we demonstrate that mda-7/IL-24 regulates a specific subset of miRNAs, including cancer-associated miR-221. Either ectopic expression of mda-7/IL-24 or treatment with recombinant His-MDA-7 protein resulted in downregulation of miR-221 and upregulation of p27 and PUMA in a panel of cancer cells, culminating in cell death. Mda-7/IL-24 -induced cancer cell death was dependent on reactive oxygen species induction and was rescued by overexpression of miR-221. Beclin-1 was identified as a new transcriptional target of miR-221, and mda-7/IL-24 regulated autophagy through a miR-221/beclin-1 feedback loop. In a human breast cancer xenograft model, miR-221-overexpressing MDA-MB-231 clones were more aggressive and resistant to mda-7/IL-24 -mediated cell death than parental clones. This is the first demonstration that mda-7/IL-24 directly regulates miRNA expression in cancer cells and highlights the novelty of the mda-7/IL-24 -miR-221-beclin-1 loop in mediating cancer cell-specific death. Cancer Res; 77(4); 949-59. ©2016 AACR ., (©2016 American Association for Cancer Research.)
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- 2017
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14. Astrocyte Elevated Gene-1 Regulates β-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal.
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Hu B, Emdad L, Kegelman TP, Shen XN, Das SK, Sarkar D, and Fisher PB
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- Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Adhesion Molecules genetics, Cell Line, Tumor, Glioblastoma genetics, Glioblastoma metabolism, Humans, Membrane Proteins, RNA-Binding Proteins, Signal Transduction, Tumor Cells, Cultured, beta Catenin genetics, Brain Neoplasms pathology, Cell Adhesion Molecules metabolism, Glioblastoma pathology, Neoplastic Stem Cells pathology, beta Catenin metabolism
- Abstract
Glioblastoma multiforme is a common malignant brain tumor that portends extremely poor patient survival. Recent studies reveal that glioma stem-like cells (GSC) are responsible for glioblastoma multiforme escape from chemo-radiotherapy and mediators of tumor relapse. Previous studies suggest that AEG-1 (MTDH), an oncogene upregulated in most types of cancers, including glioblastoma multiforme, plays a focal role linking multiple signaling pathways in tumorigenesis. We now report a crucial role of AEG-1 in glioma stem cell biology. Primary glioblastoma multiforme cells were isolated from tumor specimens and cultured as neurospheres. Using the surface marker CD133, negative and positive cells were separated as nonstem and stem populations by cell sorting. Tissue samples and low passage cells were characterized and compared with normal controls. Functional biological assays were performed to measure stemness, self-renewal, differentiation, adhesion, protein-protein interactions, and cell signaling. AEG-1 was upregulated in all glioblastoma multiforme neurospheres compared with normal neural stem cells. Expression of AEG-1 was strongly associated with stem cell markers CD133 and SOX2. AEG-1 facilitated β-catenin translocation into the nucleus by forming a complex with LEF1 and β-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3β signaling axis, AEG-1 controlled phosphorylation levels of β-catenin that stabilized the protein., Implications: This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225-33. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2017
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15. mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM.
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Bhoopathi P, Lee N, Pradhan AK, Shen XN, Das SK, Sarkar D, Emdad L, and Fisher PB
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- Adenoviridae isolation & purification, Animals, Caspases physiology, Cell Line, Tumor, Cell Proliferation, Histones physiology, Humans, Mice, Neuroblastoma virology, Apoptosis, Apoptosis Inducing Factor physiology, Ataxia Telangiectasia Mutated Proteins physiology, Interleukins physiology, Neuroblastoma pathology
- Abstract
Advanced stages of neuroblastoma, the most common extracranial malignant solid tumor of the central nervous system in infants and children, are refractive to therapy. Ectopic expression of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) promotes broad-spectrum antitumor activity in vitro, in vivo in preclinical animal models, and in a phase I clinical trial in patients with advanced cancers without harming normal cells. mda-7/IL-24 exerts cancer-specific toxicity (apoptosis or toxic autophagy) by promoting endoplasmic reticulum stress and modulating multiple signal transduction pathways regulating cancer cell growth, invasion, metastasis, survival, and angiogenesis. To enhance cancer-selective expression and targeted anticancer activity of mda-7/IL-24, we created a tropism-modified cancer terminator virus (Ad.5/3-CTV), which selectively replicates in cancer cells producing robust expression of mda-7/IL-24 We now show that Ad.5/3-CTV induces profound neuroblastoma antiproliferative activity and apoptosis in a caspase-3/9-independent manner, both in vitro and in vivo in a tumor xenograft model. Ad.5/3-CTV promotes these effects through a unique pathway involving apoptosis-inducing factor (AIF) translocation into the nucleus. Inhibiting AIF rescued neuroblastoma cells from Ad.5/3-CTV-induced cell death, whereas pan-caspase inhibition failed to promote survival. Ad.5/3-CTV infection of neuroblastoma cells increased ATM phosphorylation instigating nuclear translocation and increased γ-H2AX, triggering nuclear translocation and intensified expression of AIF. These results were validated further using two ATM small-molecule inhibitors that attenuated PARP cleavage by inhibiting γ-H2AX, which in turn inhibited AIF changes in Ad.5/3-CTV-infected neuroblastoma cells. Taken together, we elucidate a novel pathway for mda-7/IL-24-induced caspase-independent apoptosis in neuroblastoma cells mediated through modulation of AIF, ATM, and γ-H2AX. Cancer Res; 76(12); 3572-82. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
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16. Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis.
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Hu B, Emdad L, Bacolod MD, Kegelman TP, Shen XN, Alzubi MA, Das SK, Sarkar D, and Fisher PB
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- Animals, Cell Adhesion Molecules metabolism, Cell Line, Tumor, Cell Proliferation genetics, Cell Survival genetics, Gene Expression Regulation, Neoplastic, Glioblastoma metabolism, Glioblastoma pathology, Glioma metabolism, Glioma pathology, Humans, Membrane Proteins, Mice, Neovascularization, Pathologic genetics, Protein Interaction Maps genetics, Proto-Oncogene Proteins c-akt metabolism, RNA-Binding Proteins, Signal Transduction genetics, Cell Adhesion Molecules genetics, Glioblastoma genetics, Glioma genetics, Proto-Oncogene Proteins c-akt biosynthesis
- Abstract
The oncogene astrocyte elevated gene-1 (AEG-1; MTDH) is highly expressed in glioblastoma multiforme (GBM) and many other types of cancer, where it activates multiple signaling pathways that drive proliferation, invasion, angiogenesis, chemoresistance, radioresistance, and metastasis. AEG-1 activates the Akt signaling pathway and Akt and c-Myc are positive regulators of AEG-1 transcription, generating a positive feedback loop between AEG-1 and Akt in regulating tumorigenesis. Here, we describe in GBM cells a direct interaction between an internal domain of AEG-1 and the PH domain of Akt2, a major driver in GBM. Expression and interaction of AEG-1 and Akt2 are elevated in GBM and contribute to tumor cell survival, proliferation, and invasion. Clinically, in silico gene expression and immunohistochemical analyses of patient specimens showed that AEG-1 and Akt2 expression correlated with GBM progression and reduced patient survival. AEG-1-Akt2 interaction prolonged stabilization of Akt2 phosphorylation at S474, regulating downstream signaling cascades that enable cell proliferation and survival. Disrupting AEG-1-Akt2 interaction by competitive binding of the Akt2-PH domain led to reduced cell viability and invasion. When combined with AEG-1 silencing, conditional expression of Akt2-PH markedly increased survival in an orthotopic mouse model of human GBM. Our study uncovers a novel molecular mechanism by which AEG-1 augments glioma progression and offers a rationale to block AEG-1-Akt2 signaling function as a novel GBM treatment., (©2014 American Association for Cancer Research.)
- Published
- 2014
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17. Astrocyte elevated gene-1: far more than just a gene regulated in astrocytes.
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Sarkar D, Emdad L, Lee SG, Yoo BK, Su ZZ, and Fisher PB
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- Animals, Humans, Membrane Proteins, RNA-Binding Proteins, Astrocytes physiology, Cell Adhesion Molecules physiology, Neoplasms genetics
- Abstract
Since its original cloning by subtraction hybridization in 2002, it is now evident that Astrocyte elevated gene-1 (AEG-1) is a key contributor to the carcinogenic process in diverse organs. AEG-1 protein expression is elevated in advanced stages of many cancers, which correlates with poor survival. In specific cancers, such as breast and liver cancer, the AEG-1 gene itself is amplified, further supporting a seminal role in tumorigenesis. Overexpression and inhibition studies both in in vitro and in in vivo models reveal the importance of AEG-1 in regulating multiple physiologically and pathologically relevant processes including proliferation, invasion, metastasis, and gene expression. AEG-1 is a single-pass transmembrane protein with multiple nuclear localization signals and no known domains or motifs. Although pertinent roles of AEG-1 in the carcinogenic process are established, its potential function (promotion of metastasis only versus functioning as a bona fide oncogene) as well as localization (cell surface versus nucleus) remain areas requiring further clarification. The present review critically evaluates what is currently known about AEG-1 and provides new perspectives relative to this intriguing molecule that may provide a rational target for intervening in the cancer phenotype.
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- 2009
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18. Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1.
- Author
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Sarkar D, Park ES, Emdad L, Lee SG, Su ZZ, and Fisher PB
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- Brain Neoplasms metabolism, CREB-Binding Protein metabolism, Cell Line, Tumor, Cell Movement, Cell Nucleus metabolism, Glioma metabolism, Humans, Models, Biological, NF-kappa B genetics, Neoplasm Invasiveness, Promoter Regions, Genetic, Protein Binding, RNA-Binding Proteins, Transcription, Genetic, Cell Adhesion Molecules biosynthesis, Gene Expression Regulation, Neoplastic, Membrane Proteins biosynthesis, NF-kappa B metabolism
- Abstract
Malignant glioma is a consistently fatal brain cancer. The tumor invades the surrounding tissue, limiting complete surgical removal and thereby initiating recurrence. Identifying molecules critical for glioma invasion is essential to develop targeted, effective therapies. The expression of astrocyte elevated gene-1 (AEG-1) increases in malignant glioma and AEG-1 regulates in vitro invasion and migration of malignant glioma cells by activating the nuclear factor-kappaB (NF-kappaB) signaling pathway. The present studies elucidate the domains of AEG-1 important for mediating its function. Serial NH(2)-terminal and COOH-terminal deletion mutants were constructed and functional analysis revealed that the NH(2)-terminal 71 amino acids were essential for invasion, migration, and NF-kappaB-activating properties of AEG-1. The p65-interaction domain was identified between amino acids 101 to 205, indicating that p65 interaction alone is not sufficient to mediate AEG-1 function. Coimmunoprecipitation assays revealed that AEG-1 interacts with cyclic AMP-responsive element binding protein-binding protein (CBP), indicating that it might act as a bridging factor between NF-kappaB, CBP, and the basal transcription machinery. Chromatin immunoprecipitation assays showed that AEG-1 is associated with the NF-kappaB binding element in the interleukin-8 promoter. Thus, AEG-1 might function as a coactivator for NF-kappaB, consequently augmenting expression of genes necessary for invasion of glioma cells. In these contexts, AEG-1 represents a viable potential target for the therapy of malignant glioma.
- Published
- 2008
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19. mda-9/Syntenin regulates the metastatic phenotype in human melanoma cells by activating nuclear factor-kappaB.
- Author
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Boukerche H, Su ZZ, Emdad L, Sarkar D, and Fisher PB
- Subjects
- Adenoviridae genetics, Cell Adhesion physiology, Cell Growth Processes physiology, Cell Movement physiology, Enzyme Precursors metabolism, Focal Adhesion Kinase 1 metabolism, Gene Expression Regulation, Neoplastic, Genetic Vectors genetics, Humans, Matrix Metalloproteinase 14 biosynthesis, Matrix Metalloproteinase 14 genetics, Matrix Metalloproteinase 2 metabolism, Melanoma metabolism, NF-kappa B biosynthesis, NF-kappa B genetics, Neoplasm Metastasis, Phenotype, Syntenins antagonists & inhibitors, Syntenins genetics, Transcription Factor RelA metabolism, Transduction, Genetic, p38 Mitogen-Activated Protein Kinases metabolism, Melanoma genetics, Melanoma pathology, NF-kappa B metabolism, Syntenins biosynthesis
- Abstract
mda-9/Syntenin is a scaffolding PDZ domain-containing protein overexpressed in multiple human cancers that functions as a positive regulator of melanoma metastasis. Using a normal immortal human melanocyte cell line and weakly and highly metastatic human melanoma cell lines, we presently show that mda-9/syntenin initiates a signaling cascade that activates nuclear factor-kappaB (NF-kappaB) in human melanoma cells. As a consequence of elevated mda-9/syntenin expression, tumor cell growth and motility, fundamental components of tumor cell invasion and metastatic spread of melanoma cells, are enhanced through focal adhesion kinase (FAK)-induced and p38 mitogen-activated protein kinase (MAPK)-induced activation of NF-kappaB. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin, NF-kappaB, using an adenovirus expressing a mutant super-repressor of IkappaBalpha, or FAK, and using a dominant-negative mutant of FAK (FRNK), blocks melanoma cell migration, anchorage-independent growth, and invasion. Downstream signaling changes mediated by mda-9/syntenin, which include activation of FAK, p38 MAPK, and NF-kappaB, promote induction of membrane-type matrix metalloproteinase-1 that then activates pro-MMP-2-promoting migration and extracellular matrix invasion of melanoma cells. These results highlight the importance of mda-9/syntenin as a key component of melanoma metastasis providing a rational molecular target for potentially intervening in the metastatic process.
- Published
- 2007
- Full Text
- View/download PDF
20. BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis.
- Author
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Gupta P, Walter MR, Su ZZ, Lebedeva IV, Emdad L, Randolph A, Valerie K, Sarkar D, and Fisher PB
- Subjects
- Adenoviridae genetics, Apoptosis, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Cell Survival, DNA Mutational Analysis, DNA Primers, DNA, Neoplasm genetics, Endoplasmic Reticulum Chaperone BiP, Epithelial Cells physiology, Female, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, Male, Mutagenesis, Nucleic Acid Conformation, Prostate cytology, Recombination, Genetic, Sequence Deletion, Heat-Shock Proteins genetics, Interleukins genetics, Molecular Chaperones genetics
- Abstract
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that induces cancer-selective growth suppression and apoptosis in a wide spectrum of human cancers in cell culture and animal models. Additionally, recent clinical trials confirm safety and document significant clinical activity of mda-7/IL-24 in patients with diverse solid cancers and melanomas. Despite intensive study the molecular basis of tumor-cell selectivity of mda-7/IL-24 is not well characterized. Using deletion analysis, a specific mutant of MDA-7/IL-24, M4, consisting of amino acids 104 to 206, is described that retains the cancer-specific growth-suppressive and apoptosis-inducing properties of the full-length protein. Employing rationally designed mutational analysis, we show that MDA-7/IL-24 and M4 physically interact with BiP/GRP78 through their C and F helices, localize in the endoplasmic reticulum, and activate p38 MAPK and GADD gene expression, culminating in cancer-selective apoptosis. These studies provide novel mechanistic insights into the discriminating antitumor activity of MDA-7/IL-24 by elucidating BiP/GRP78 as a defined intracellular target of action and present an unparalleled opportunity to develop improved therapeutic versions of this cancer-specific apoptosis-inducing cytokine.
- Published
- 2006
- Full Text
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21. Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis.
- Author
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Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K, and Fisher PB
- Subjects
- Adenoviridae genetics, Amino Acid Sequence, Carrier Proteins antagonists & inhibitors, Carrier Proteins biosynthesis, Carrier Proteins genetics, Cell Adhesion physiology, Cell Adhesion Molecules, Cell Growth Processes physiology, Disease Progression, HeLa Cells, Humans, I-kappa B Proteins metabolism, Interleukin-8 biosynthesis, Interleukin-8 genetics, Membrane Proteins antagonists & inhibitors, Membrane Proteins biosynthesis, Membrane Proteins genetics, Molecular Sequence Data, NF-KappaB Inhibitor alpha, NF-kappa B antagonists & inhibitors, NF-kappa B p50 Subunit metabolism, Protein Binding, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA-Binding Proteins, Transcription Factor RelA metabolism, Transfection, Up-Regulation, Carrier Proteins physiology, Membrane Proteins physiology, NF-kappa B metabolism
- Abstract
Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor kappaB (NF-kappaB), a TNF-alpha downstream signaling component, is associated with several human illnesses, including cancer, and NF-kappaB controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-kappaB. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-kappaB. The NF-kappaB activation induced by AEG-1 corresponded with degradation of IkappaBalpha and nuclear translocation of p65 that resulted in the induction of NF-kappaB downstream genes. Infection with an adenovirus expressing the mt32IkappaBalpha superrepressor (Ad.IkappaBalpha-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-alpha treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-kappaB. Our findings suggest that activation of NF-kappaB by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype.
- Published
- 2006
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22. mda-9/Syntenin: a positive regulator of melanoma metastasis.
- Author
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Boukerche H, Su ZZ, Emdad L, Baril P, Balme B, Thomas L, Randolph A, Valerie K, Sarkar D, and Fisher PB
- Subjects
- Adenoviridae genetics, Animals, Cell Adhesion genetics, Cell Movement genetics, Focal Adhesion Protein-Tyrosine Kinases metabolism, Humans, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins genetics, JNK Mitogen-Activated Protein Kinases metabolism, Melanocytes metabolism, Melanocytes physiology, Melanoma genetics, Melanoma metabolism, Melanoma pathology, Membrane Proteins antagonists & inhibitors, Membrane Proteins biosynthesis, Membrane Proteins genetics, Neoplasm Invasiveness, Rats, Rats, Wistar, Syntenins, Transduction, Genetic, p38 Mitogen-Activated Protein Kinases metabolism, Intracellular Signaling Peptides and Proteins physiology, Melanoma secondary, Membrane Proteins physiology
- Abstract
Metastasis is a significant event in cancer progression and continues to pose the greatest challenge for a cancer cure. Defining genes that control metastasis in vivo may provide new targets for intervening in this process with profound therapeutic implications. Melanoma differentiation associated gene-9 (mda-9) was initially identified by subtraction hybridization as a novel gene displaying biphasic expression during terminal differentiation in human melanoma cells. Mda-9, also known as syntenin, is a PDZ-domain protein overexpressed in many types of human cancers, where it is believed to function in tumor progression. However, a functional role of mda-9/syntenin in tumor growth and metastasis and the signaling pathways involved in mediating these biological activities remain to be defined. Evidence is now provided, using weakly and highly metastatic isogenic melanoma variants, that mda-9/syntenin regulates metastasis. Expression of mda-9/syntenin correlates with advanced stages of melanoma progression. Regulating mda-9/syntenin expression using a replication-incompetent adenovirus expressing either sense or antisense mda-9/syntenin modifies the transformed phenotype and alters metastatic ability in immortal human melanocytes and metastatic melanoma cells in vitro and in vivo in newborn rats. A direct relationship is observed between mda-9/syntenin expression and increased phosphorylation of focal adhesion kinase, c-Jun-NH2-kinase, and p38. This study provides the first direct link between mda-9/syntenin expression and tumor cell dissemination in vivo and indicates that mda-9/syntenin expression activates specific signal transduction pathways, which may regulate melanoma tumor progression. Based on its ability to directly alter metastasis, mda-9/syntenin provides a promising new focus for melanoma cancer research with potential therapeutic applications for metastatic diseases.
- Published
- 2005
- Full Text
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23. Human polynucleotide phosphorylase (hPNPaseold-35): a potential link between aging and inflammation.
- Author
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Sarkar D, Lebedeva IV, Emdad L, Kang DC, Baldwin AS Jr, and Fisher PB
- Subjects
- Adenoviridae genetics, Cellular Senescence physiology, Chemokine CCL5 biosynthesis, Chemokine CCL5 genetics, Exoribonucleases biosynthesis, Exoribonucleases genetics, HeLa Cells, Humans, Inflammation enzymology, Inflammation genetics, Interleukin-6 biosynthesis, Interleukin-6 genetics, Interleukin-8 biosynthesis, Interleukin-8 genetics, Matrix Metalloproteinase 3 metabolism, NF-kappa B metabolism, RNA, Messenger biosynthesis, RNA, Messenger genetics, Reactive Oxygen Species metabolism, Exoribonucleases physiology
- Abstract
Chronic inflammation is a characteristic feature of aging, and the relationship between cellular senescence and inflammation, although extensively studied, is not well understood. An overlapping pathway screen identified human polynucleotide phosphorylase (hPNPase(old-35)), an evolutionary conserved 3',5'-exoribonuclease, as a gene up-regulated during both terminal differentiation and cellular senescence. Enhanced expression of hPNPase(old-35) via a replication-incompetent adenovirus (Ad.hPNPase(old-35)) in human melanoma cells and normal human melanocytes results in a characteristic senescence-like phenotype. Reactive oxygen species (ROS) play a key role in the induction of both in vitro and in vivo senescence. We now document that overexpression of hPNPase(old-35) results in increased production of ROS, leading to activation of the nuclear factor (NF)-kappaB pathway. Ad.hPNPase(old-35) infection promotes degradation of IkappaBalpha and nuclear translocation of NF-kappaB and markedly increases binding of the transcriptional activator p50/p65. The generation of ROS and activation of NF-kappaB by hPNPase(old-35) are prevented by treatment with a cell-permeable antioxidant, N-acetyl-l-cysteine. Infection with Ad.hPNPase(old-35) enhances the production of interleukin (IL)-6 and IL-8, two classical NF-kappaB-responsive cytokines, and this induction is inhibited by N-acetyl-l-cysteine. A cytokine array reveals that Ad.hPNPase(old-35) infection specifically induces the expression of proinflammatory cytokines, such as IL-6, IL-8, RANTES, and matrix metalloproteinase (MMP)-3. We hypothesize that hPNPase(old-35) might play a significant role in producing pathological changes associated with aging by generating proinflammatory cytokines via ROS and NF-kappaB. Understanding the relationship between hPNPase(old-35) and inflammation and aging provides a unique opportunity to mechanistically comprehend and potentially intervene in these physiologically important processes.
- Published
- 2004
- Full Text
- View/download PDF
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