Accession Number:

ADA609572

Title:

Beta Catenin in Prostate Cancer Apoptosis

Descriptive Note:

Final rept. 1 Apr 2010-31 Mar 2014

Corporate Author:

LOYOLA UNIV MAYWOOD IL

Personal Author(s):

Report Date:

2014-04-01

Pagination or Media Count:

36.0

Abstract:

During this funding period, we performed TRAIL-TZD-mediated apoptotic studies in androgen dependent LNCaP and 22RV1 and androgen independent DU145 and PC3 prostate cancer cells and the response was maximal in the LNCaP cells with 50 M TZD and 100ngml TRAIL combination. This apoptotic response is also associated with increased -catenin cleavage, indicating its potential role. Knockdown of -catenin expression and overexpression of -catenin modulated TRAIL-TZD-induced apoptosis. Studies with the cleaved -catenin protein revealed that this cleaved fragment losses interaction with TCF4, while retaining strong interaction with E-cadherin and -catenin. These indicated i a potential mechanism by which TRAIL-TZD antagonizes -cateninTCF4-induced transcription and ii suggested that E-cadherin and -catenin interaction might be critical for apoptosis induction. Based on Mass Spec data various myc -catenin DA mutants were created but they were unable to significantly antagonize -catenin cleavage and apoptosis. Studies also showed that GSK3 inhibition promotes TRAIL-induced apoptosis and TRAIL-TZD significantly reduces expression of GSK3 and increases pGSK3 Ser9 levels. In addition, this apoptosis pathway seems to involve AMPK, since AMPK-dominant negative DN overexpression significantly attenuates TRAIL-TZD-induced apoptosis and -catenin cleavage. The C42 and C42B cells showed significant apoptosis with TRAIL-TZD in vitro and C42 cells formed in vivo xenografts in nude mice. Treatment with TRAIL-TZD in vivo however, didn t show any significant effect on prostate tumor regression.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE