Abstract 892: The stress oncoprotein LEDGF/P75 promotes selective resistance to multiple chemotherapeutic drugs in prostate cencer cells.

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer related deaths among men in the United States, with African American men presenting more aggressive tumors and increased mortality compared to other ethnic groups. Eliminating these disparities will require an interdiplinary effort that combines improved access to healthcare and health education, combined with innovative approaches to circumvent therapy resistance. The lens epithelium-derived growth factor p75 (LEDGF/p75) is a stress survival transcription co-activator that transactivates stress protective genes to promote resistance to microenvironmental stressors such as oxidative stress and chemotherapy. Previously, our group established that LEDGF/p75 is overexpressed in PCa cells and clinical tumors and that it promotes resistance to docetaxel (DTX) treatment, the standard of chemotheraoy for metastatic PCa. The present study was designed to determine the effects of LEDGF/p75 overexpression and knockdown on cell viability in different PCa cellular models exposed to various chemotherapeutic drugs used in the treatment of advanced PCa. We also evaluated if exposure to DTX and the other drugs increased expression of LEDGF/p75 in PCa cells. For these studies, we used different cell lines with LEDGF/p75 overexpression and siRNA-mediated knockdown, as well as DTX resistant cell lines with elevated levels of this protein. PCa cells were treated with increasing concentrations of the chemotherapeutic drugs DTX, Doxorubicin (DOXO), Paclitaxel (PTX), and TRAIL for up to 96 hours. Loss of cell viability was assessed by viability assays and morphological microscopic examination. Our preliminary results suggested that elevated expression of LEDGF/p75 promotes selective resistance to chemotherapeutic drugs, particularly to DTX, DOXO, and PTX, but not to TRAIL. This selectivity seems to be related to the ability of LEDGF/p75 to protect against stress-induced lysosomal cell death but not against TRAIL-induced classical death receptor mediated apoptosis. Knockdown of LEDGF/p75 sensitized PCa cells to the chemotherapeutic drugs. In addition, increased cellular stress induced by exposure to DTX treatment resulted in increased expression of LEDGF/p75 in a cell-type dependent manner. These results have implications for the development of novel therapeutic strategies for the treatment of PCa based on targeting LEDGF/p75 and its target genes for the sensitization of tumor cells to chemotherapeutic agents. Citation Format: Leslimar Rios-Colon, Anamika Basu, Catherine Elix, Carlos A. Casiano, Marino De León. The stress oncoprotein LEDGF/P75 promotes selective resistance to multiple chemotherapeutic drugs in prostate cencer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 892. doi:10.1158/1538-7445.AM2013-892