Regulation of X-linked inhibitor of apoptosis protein by androgen deprivation therapy promotes castration-resistant prostate cancer progression

Introduction: Hormone-sensitive prostate cancer typically progresses to a castration-resistant stage after an average of 18–24 months of androgen deprivation therapy (ADT). The anti-apoptotic factor X-linked inhibitor of apoptosis protein (XIAP) is not only implicated in the development of prostate cancer but also plays a critical role in its progression to the castration-resistant state. Objective: This study aims to investigate the relationship between ADT and the regulation of XIAP. Methods: The protein expression levels of midline 1 (MID1), serine/threonine kinase proviral integration site for Moloney murine leukemia virus 2 (PIM2), protein phosphatase 2A (PP2A), eukaryotic translation initiation factor 4B (EIF4B), phosphorylated EIF4B, and XIAP were analyzed and compared among castration-naïve, hormone-sensitive, and castration-resistant prostate cancer (CRPC) tissues. The MID1 gene was manipulated in both androgen-dependent and androgen-independent prostate cancer cells to evaluate its effect on XIAP protein expression and the apoptosis rate of the prostate cancer cells. Results: XIAP protein expression and EIF4B phosphorylation levels were significantly increased in CRPC. In contrast, PIM2 and EIF4B protein expression levels remained similar before and after the development of castration resistance. MID1 protein expression level was significantly elevated, while PP2A expression was significantly reduced in CRPC tissues. Conclusion: ADT may lead to elevated MID1 and reduced PP2A protein expression levels, which indirectly enhance the phosphorylation activity of PIM2 on EIF4B, thereby increasing XIAP expression and reducing apoptosis in prostate cancer cells. This mechanism likely contributes to disease progression toward the castration-resistant stage.