Abstract 775: Targeting the transcriptional coactivator LEDGF/p75 to overcome chemoresistance in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer death among men in the US, with African American men presenting a disproportionately high incidence and mortality. Reducing this mortality disparity requires developing novel strategies for overcoming prostate tumor chemoresistance. Currently, chemotherapy with Docetaxel (DTX), the standard of care for advanced PCa, is limited because most patients treated with the drug ultimately develop chemoresistance and succumb to the disease. Circumventing this resistance is therefore essential for increasing the effectiveness of DTX and other anti-PCa drugs. Our group has established previously that lens ephitelium-derived growth factor p75 (LEDGF/p75), a stress survival oncoprotein, is overexpressed in human prostate tumors, and that its overexpression in PCa cell models promotes resistance to DTX via inhibition of lysosomal cell death. The present study was designed to evaluate if overexpression of LEDGF/p75 in PCa cells also promotes resistance to other chemotheurapeutic drugs, and if its depletion sensitizes chemoresistant PCa cells to drug-induced cell death. First, we treated PC-3 cells (with and without stable LEDGF/p75 overexpression) with increasing concentrations of DTX, paclitaxel, doxorubicin, and TRAIL for up to 48 hrs. We then assessed cell viability by MTT assays and morphological examination. LEDGF/p75 overexpressing PC-3 cells showed higher viability than parental PC-3 cells in response to DTX, paclitaxel, and doxorubicin. However, LEDGF/p75 did not protect against TRAIL-induced cell death, indicating selectivity in the ability of this stress oncoprotein to induce chemoresistance. We also observed by immunoblotting and quantitative PCR that metastatic PCa cell lines selected for DTX resistance, designated PC3-DR and DU-145DR, naturally express high levels of endogenous LEDGF/p75 relative to their sensitive parental cell lines. To assess the contribution of elevated LEDGF/p75 expression to DTX resistance in these two cell lines, we knocked down this protein with a specific small inhibitory RNA (si-p75). Immunoblots showed that si-p75 depleted cells of LEDGF/p75. Cell viability significantly decreased in both PC3-DR and DU-145DR cell lines in response to combined treatment with DTX and si-p75, relative to scrambled siRNA control. Our preliminary results suggest that LEDGF/p75 overexpression promotes chemoresistance in cellular models of advanced PCa, and that its inhibition increases sensitization to DTX. These promising results have implications for the development of novel theraupetic strategies for chemoresistant PCa. Further studies are in progress to determine the spectrum of anti-PCa drugs antagonized by LEDGF/p75, and if depletion of this protein sensitizes PCa cells to a wide variety of antitumor drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 775. doi:1538-7445.AM2012-775