Abstract 135: Apoptotic cell death triggering in the prostate carcinoma cell line PC3 by the anoikis effector Bit1

Abstract

Abstract Highly aggressive cancer cells often are associated with resistance to caspase-dependent apoptosis, due, in part to loss in function or mutation in caspase effectors. Such apoptotic defects in caspase signaling pathway may provide a selective growth advantage for tumor cells and potentiate their aggressiveness and resistance to chemotherapeutic agents. Here, we test the responsiveness of the highly aggressive prostate cancer cell line PC3 cells to the apoptotic function of the novel, caspase-independent anoikis effector Bcl2 inhibitor of transcription (Bit1). Overexpression of the cytoplasmic localized Bit1 in PC3 cells results in significant induction of apoptosis as evidenced by the increased levels of histone-DNA fragments. Furthermore, PC3 cells transfected with the mitochondrial localized Bit1 exhibit significant apoptosis following loss of cell attachment as compared to vector treated cells, and such induction of anoikis is associated with increased levels of Bit1 in the cytosol. In contrast, both the control and Bit1 transfected PC3 cells show the same level of spontaneous apoptosis when grown attached to a culture dish. We also tested whether Bit1 alters the chemoresistant phenotype of PC3 cells. Consistent with the induction of anoikis sensitivity, overexpression of mitochondrial Bit1 also renders PC3 cells more sensitive to etoposide-induced apoptosis. Interestingly, the Bit1-mediated apoptosis in PC3 cells is correlated with increased NFkappa B activity as evidenced by increased nuclear translocation and transcription factor activity of the p65 subunit. Taken together, these findings indicate that activation of the caspase-independent Bit1 apoptotic pathway may serve as a preferred alternate approach in triggering apoptosis in aggressive prostate cancer cells. Bit1 may thus serve as a future therapeutic target for the treatment and alleviation of the chemoresistance characteristic of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 135.