Contribution of LEDGF/p75 to Prostate Cancer Chemoresistance
Prostate cancer (PCa) is the second leading cause of male cancer death in the United States, and is considered a health disparity because of its disproportionate incidence and mortality in African American (AA) males. A major challenge in PCa treatment is its recurrence into hormone refractory prostate cancer (HRPC). Docetaxel is the standard of care for first line chemotherapy to HRPC. Unfortunately, most patients ultimately manifest resistance to DTX and succumb to the disease. Circumventing DTX resistance in HRPC will require better understanding of the mechanisms by which this drug kills prostate tumor cells, and the genes that promote this resistance. We investigated the mechanism underlying DTX-induced death and observed that it involved the concomitant activation of caspase and lysosomal pathways. We also investigated the role of the stress response protein and transcription co-activator lens epithelium derived growth factor p75 (LEDGF/p75) in HRPC resistance to DTX. Our studies show that LEDGF/p75 overexpression attenuates DTX-induced lysosomal destabilization and cell death in a cellular model of HRPC, implicating this stress protein in DTX resistance in virto. However, LEDGF/p75 did not protect against cell death induced by the classical apoptosis inducers TRAIL and staurosporine. This selectivity might be related to LEDGF/p75’s ability to protect cells against insults that induce ROS generation, since we observed that DTX but not TRAIL and staurosporine generated ROS. To better understand the mechanism by which LEDGF/p75 confers its chemoresistant phenotype, a protein expression profile was performed in PCa cells stably overexpressing LEDGF/p75. A marked increase in the expression of the thiol-oxidoreductase ERp57 was observed in overexpressing cells. Transactivation of ERp57 by LEDGF/p75 was confirmed using transcription reporter assays, providing evidence that ERp57 might be a target gene of LEDGF/p75. However, there was incomplete correlation in the expression patterns of LEDGF/p75 and ERp57 in PCa cell lines and tissues. These findings suggest that LEDGD/p75 might contribute to cellular resistance to drugs or insults that induce cell death associated with ROS generation. If proven to contribute to DTX resistance in an in vivo model, LEDGF/p75 and its target genes could be attractive targets for novel therapeutic strategies in the treatment of HRPC.
Microbiology, Molecular Genetics, Prostatic Neoplasms -- genetics; Prostatic Neoplasms -- microbiology; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents -- pharmacology; Intercellular Signaling Peptides and Proteins; Cell Line, Tumor; Cell Aging -- drug effects; Apoptosis -- drug effects; Cysteine Proteinase Inhibitors; Immunoblotting
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