Beta Catenin in Prostate Cancer Apoptosis

During the past funding period, we performed TRAIL-TZD-mediated apoptotic studies in androgen dependent (LNCaP and 22RV1) and androgen independent (DU145 and PC3) prostate cancer cells. These revealed that the apoptotic response is maximal in the androgen responsive cells and LNCaP cells produced the best response. Extensive dose course studies revealed that 50 microM TZD and 100ng/ml TRAIL combination can produce maximal apoptosis in cells plated at high density. This apoptotic response is also associated with increased B-catenin cleavage, indicating its potential role. To confirm this, B-catenin mutants (D/A) have been created, which will be utilized to confirm whether they represent the caspase resistant B-catenin mutants and to understand their role in apoptosis. TRAIL-TZD studies also revealed that pretreatment with a pharmacological inhibitor of GSK3B (AR-A014418) can sensitize cells potently to TRAIL-induced apoptosis in the absence of TZD. These suggested that the inhibition of GSK3B activity might be the major mechanism by which TZD sensitizes prostate cancer cells towards TRAIL. GSK3B might thus represent a novel target for developing prostate cancer therapeutics. The in vivo xenograft studies are currently being planned to be performed in nude mice due to a very low tumor take and slow tumor growth in the SCID mice. Once completed these are expected to provide critical information regarding the efficacy of TRAIL-TZD and TRAIL-GSK3B inhibitor combination in regulating prostate tumor growth. ; The original document contains color images.