Abstract 4288: Race specific differences in G-protein decoupling from CCR9 in prostate cancer cells contribute to the differences in docetaxel response

Current treatment approaches have failed to reduce racial disparity in treatment outcome of prostate cancer (PCa) primarily due to the race-specific difference in the biology of PCa. Therefore, identification of race-specific molecular differences is needed to address the disparity in treatment outcome. In this study, we have determined the race-specific differences in CCR9 signaling. Phospho-proteomic profile of key pro-survival molecules following CCL25 treatment in African American (AA) and European American (EA) PCa cells was determined using antibody microarray and validated by western blot analyses. Coupling and decoupling of G-protein(s) with CCR9 in response to CCL25, which determines downstream signaling of CCR9 was ascertained by immunoprecipitation assay (IPA). Cell viability and apoptosis in response to a taxane drug docetaxel (DTX), with/without CCL25 stimulation and CCR9-blockade, were examined using MTT and flow cytometry, respectively. Levels of pro-apoptotic proteins were determined by western blot analyses. Our data show differential G-protein(s) decoupling from CCR9 in AA and EA cells. CCR9-activation dissociated G_αi2/3/G_αq/ G_α13/G_β1γ7 –proteins in AA cells compared to G_αs/G_β2γ9 and G_α13/G_αs/G _β1/β3γ7 in EA cells, respectively, contribute to different molecular mechanisms supporting cell survival in cell lines derived from two races. Race-specific G-protein signaling in PCa cells, following CCL25 stimulation, is reflected into hyper-activation of molecules involved in PI3K/Akt and MEK/Erk1/2 signaling, which are associated with PCa aggressiveness in AA cells compared to EA counterparts. Further, activation of CCR9-CCL25 axis significantly influences the therapeutic response of PCa cells against DTX, which is highly compromised in AA cells compared to EA cells following CCL25 stimulation. However, this protective effect of CCL25 was abrogated after CCR9 blockade. Inhibition of MEK/Erk1/2 axis significantly improved DTX-induced cell death in AA cells, suggesting the importance of this axis in reducing drug response. Further, stimulation with CCL25, exclusively downregulated cleaved caspase-7, 8 and Bim in response to DTX in AA cells. In all, differential decoupling of G-proteins from CCR9 controls the downstream signaling and therefore determines disparity associated with PCa outcome and offer novel race-specific therapeutic targets for PCa.

Citation Format: Neeraj Kapur, Hina Mir, Shailesh Singh. Race specific differences in G-protein decoupling from CCR9 in prostate cancer cells contribute to the differences in docetaxel response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4288.