Suppression of Androgen Receptor Transactivation by Akt Kinase
Abstract
Data suggest androgen/androgen receptor (AR) may be involved in proliferation of prostate cancer, but opposite roles of in inhibition of cell growth and apoptosis are documented. The detailed mechanism of how androgen/AR functions in apoptosis, remains unclear. Serine/threonine kinase (Akt) plays a role in promoting cell survival through anti-apoptotic effects. Akt was found active in prostate cancer LNCaP cells and plays an essential role for survival. Our preliminary data demonstrated that Akt phosphorylates AR at Ser2l0 and Ser790. Mutation at Ser2l0 results in reversion of Akt-mediated suppression of AR transactivation. Activation of phosphatidylinositol-3-OH kinase/Akt pathway results in the suppression of AR target genes. Our hypothesis is that Akt may control androgen/AR-induced apoptosis by phosphorylating and inhibiting AR. In this past year our Akt studies have led into study of the PTEN pathway. We have shown 1) via P13K/Akt-dependent pathway, PTEN regulates AR activity in high passage LNCaP cells and suppresses AR activity in the early passage LNCP cells, 2) P13K/Akt pathway promoted AR ubiquitylation, leading to AR degradation, and 3) restoration of AR function or P13KIAkt pathway rescues cells from PTEN-induced apoptosis. Our project's success may enhance our understanding of cross-talk between Akt and androgen/AR pathway on prostate cancer progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2004
- Accession Number
- ADA423309
Entities
People
- Chanshang Chang
Organizations
- University of Rochester