Abstract B76: Circumventing chemoresistance as a strategy to reduce the mortality disparities associated with advanced prostate cancer.

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer death among men in the U.S., with African American men presenting a disproportionately high incidence and mortality from this disease. Although these disparities result from the combination of multiple factors (socioeconomic, health care, lifestyle, biological, etc.), there is growing consensus that PCa in African-American men is in general more aggressive than in other ethnic groups. Reducing PCa mortality disparities will therefore require novel strategies for the effective treatment of advanced, aggressive tumors characterized by chemotherapy resistance. 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 emerging anti-PCa drugs, and reducing the high mortality associated with advanced PCa. We established previously that lens epithelium-derived growth factor p75 (LEDGF/p75), a stress survival oncoprotein, is overexpressed in clinical prostate tumors, and that its overexpression in PCa cell models promotes resistance to DTX treatment via inhibition of lysosomal cell death. In the present study we evaluated if overexpression of LEDGF/p75 in PCa cells also promotes resistance to other chemotherapeutic drugs, and if its depletion sensitizes chemoresistant PCa cells to drug-induced cell death. We treated PC-3 cells (with and without stable LEDGF/p75 overexpression) with increasing concentrations of the anti-cancer drugs 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 control cells in response to DTX and doxorubicin. However, LEDGF/p75 did not protect against paclitaxel and TRAIL, indicating selectivity in its ability to promote 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 determine if the elevated expression of LEDGF/p75 in these two cell lines contribute to DTX resistance, we knocked down this protein with a specific small inhibitory RNA (si-p75). Cell viability significantly decreased in both cell lines in response to combined treatment with DTX and si-p75, relative to siRNA controls. We also observed that these chemoresistant PCa cell lines express high levels of proteins associated with inflammation and cellular response to oxidative stress, such as IL-6, IL-6R, Hsp27, PRDX6, and cytoglobin, and that the levels of these proteins decreased upon LEDGF/p75 knockdown. Our preliminary results suggest that LEDGF/p75 overexpression promotes selective chemoresistance in cellular models of advanced PCa, and that its inhibition increases sensitization to DTX associated with downregulation of inflammation/oxidative stress-related genes. These promising results have implications for the development of novel therapeutic strategies for chemoresistant PCa. Studies are in progress to assess the expression levels of LEDGF/p75 in sera and prostate tissues from African-American and Caucasian PCa patients, and correlate these levels with advanced disease and chemotherapy resistance in these patients. Citation Format: Leslimar Rios-Colon, Anamika Basu, Christina Cajigas, Catherine Elix, Carlos A. Casiano. Circumventing chemoresistance as a strategy to reduce the mortality disparities associated with advanced prostate cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B76.