title: LEDGF/p75 Overexpression Attenuates Oxidative Stress-Induced Necrosis and Upregulates the Oxidoreductase ERP57/PDIA3/GRP58 in Prostate Cancer.
abstract: Prostate cancer (PCa) mortality is driven by highly aggressive tumors characterized by metastasis and resistance to therapy, and this aggressiveness is mediated by numerous factors, including activation of stress survival pathways in the pro-inflammatory tumor microenvironment. LEDGF/p75, also known as the DFS70 autoantigen, is a stress transcription co-activator implicated in cancer, HIV-AIDS, and autoimmunity. This protein is targeted by autoantibodies in certain subsets of patients with PCa and inflammatory conditions, as well as in some apparently healthy individuals. LEDGF/p75 is overexpressed in PCa and other cancers, and promotes resistance to chemotherapy-induced cell death via the transactivation of survival proteins. We report in this study that overexpression of LEDGF/p75 in PCa cells attenuates oxidative stress-induced necrosis but not staurosporine-induced apoptosis. This finding was consistent with the observation that while LEDGF/p75 was robustly cleaved in apoptotic cells into a p65 fragment that lacks stress survival activity, it remained relatively intact in necrotic cells. Overexpression of LEDGF/p75 in PCa cells led to the upregulation of transcript and protein levels of the thiol-oxidoreductase ERp57 (also known as GRP58 and PDIA3), whereas its depletion led to ERp57 transcript downregulation. Chromatin immunoprecipitation and transcription reporter assays showed LEDGF/p75 binding to and transactivating the ERp57 promoter, respectively. Immunohistochemical analysis revealed significantly elevated co-expression of these two proteins in clinical prostate tumor tissues. Our results suggest that LEDGF/p75 is not an inhibitor of apoptosis but rather an antagonist of oxidative stress-induced necrosis, and that its overexpression in PCa leads to ERp57 upregulation. These findings are of significance in clarifying the role of the LEDGF/p75 stress survival pathway in PCa.
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Anamika
authors.initials: A
authors.lastname: Basu
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Christina K
authors.initials: CK
authors.lastname: Cajigas-Du Ross
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Leslimar
authors.initials: L
authors.lastname: Rios-Colon
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Mediavilla-Varela
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Tracy R
authors.initials: TR
authors.lastname: Daniels-Wells
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Lai Sum
authors.initials: LS
authors.lastname: Leoh
authors.affiliation: Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Heather
authors.initials: H
authors.lastname: Rojas
authors.affiliation: Novartis Pharmaceutical Oncology, East Hanover, New Jersey 08807, United States of America.
authors.forename: Hiya
authors.initials: H
authors.lastname: Banerjee
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Shannalee R
authors.initials: SR
authors.lastname: Martinez
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Stephanny
authors.initials: S
authors.lastname: Acevedo-Martinez
authors.affiliation: Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.|Department of Medicine, Loma Linda University School of Medicine, Loma Linda, California 92350, United States of America.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Casiano
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009336:Necrosis / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human