Abstract
Abstract : Cell death and survival signaling pathways are important for the cellular response against ionizing radiation (IR) and chemotherapy in prostate cancer (PCa). IR and Apo2L/TRAIL, are widely used as therapeutics for PCa, however cellular resistance developed over the time may hinder their effectiveness. In this study we have investigated the response of Apo2L/TRAIL and IR in PCa cell lines. PC3 cells were more sensitive to Apo2L/TRAIL-mediated cell death as compared to LNCaP-derived C4-2. The cell death observed showed both apoptotic and non-apoptotic characteristics, suggesting that autophagy might also contribute to cytotoxicity. We therefore further investigated the role of autophagy in the IR and Apo2/TRAIL response in PCa. Following Apo2L/TRAIL treatment of PC3 cells, microtubule-associated protein 1 light chain LC3, a classical marker for autophagy showed enhanced autophagosomal staining. In contrast, LC3 failed to associate with autophagosomes in C4-2 cells. Moreover, ATG7 levels were lower in C4-2 in comparison to PC3 cells. Furthermore, the ATG5-12 complex protein levels were decreased in PC3 cells while remaining unchanged in C4-2 cells. Sub-cellular fractionation revealed decreased ATG5 levels in the membrane fraction upon Apo2L/TRAIL and IR in PC3 cells. In C4-2 cells ATG5 was enriched in the soluble fraction upon IR while it decreased in both fractions upon Apo2L/TRAIL treatment. Real time PCR data showed differential expression of various autophagy related genes in PC3 and C4-2 cells. More cell death was observed in PC3 cells upon Apo2L/TRAIL treatment and was inhibited by inhibiting autophagy by 3-MA and/or by using pan-caspase inhibitor z-VAD, suggesting that autophagy induced by Apo2L/TRAIL results in caspase dependent cell death in PC3 cells. On the other hand, C4-2 cells did not show any cell death following Apo2L/TRAIL treatment, and inhibiting autophagy increased Apo2L/TRAIL-induced cell death in C4-2 cells.
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