Beta Catenin in Prostate Cancer Apoptosis
Abstract
During the past funding period, we have focused on mapping the cleaved B-catenin protein following TRAIL-TZD treatment and have determined that this cleaved fragment losses interaction with TCF4, while retaining strong interaction with E-cadherin and a-catenin. These indicated (i) a potential mechanism by which TRAIL-TZD antagonizes B-catenin/TCF4-induced transcription and (ii) suggested that the interaction with E-cadherin and a-catenin might be critical for apoptosis induction. To understand these we have recently created six myc-B-catenin (D/A) mutants (and more are underway) to conclusively map the cleavage site on B-catenin and to understand its role on apoptosis induction. Our recent results with B-catenin knockdown and overexpression in AR-positive LNCaP cells suggested that B-catenin might be promoting a pro-survival axis in these as opposed to AR-negative cells. Studies with two different GSK3 inhibitors (AR-A014418 and BIO) showed that GSK3 inhibition promotes TRAIL-induced apoptosis in AR-negative DU145 cells and TRAIL-TZD significantly reduces expression of GSK3 , GSK3 and Cyclin dependent kinases (CDKs). In addition, this apoptosis pathway seems to involve AMPK, since AMPK-dominant negative (DN) mutant overexpression significantly attenuates TRAIL-TZD-induced apoptosis. The C42 and C42B cells showed significant apoptosis with TRAIL-TZD in vitro and will be utilized in the in vivo xenograft studies to provide critical information regarding the efficacy of TRAIL-TZD and TRAIL-GSK3 inhibitor combination in regulating prostate tumor growth.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2013
- Accession Number
- ADA580101
Entities
People
- Basabi Rana
Organizations
- Loyola University New Orleans