Understanding phosphatidylinositol 3-kinase independent survival pathways in the prostate cancer model, LNCaP

Abstract

Constitutive activation of the PI3-K/Akt pathway is known to be the major survival pathway in LNCaP, a prostate cancer model which has a frameshift mutation in the PTEN gene resulting in a defective PTEN. Recent studies have shown that PI3-K/Akt independent survival pathway existed in LNCaP as apoptosis triggered by PI3-K inhibitors in serum-free condition can be blocked by the addition of growth factors such as serum, EGF and androgen. In this study, we show that the PI3-K/Akt independent survival pathway in LNCaP mediated by androgen requires the activity of androgen receptor (AR) and it is probably due to the up-regulation of the anti-apoptotic protein Bcl-xL through STAT3 activation. The increase in Bcl-xL induced by androgen could block apoptosis caused by inhibition of PI3-K probably by binding to pro-apoptotic counterpart Bak to oppose its killing activity. Thus STAT3 and Bcl-xL expression are critical for the androgen-mediated PI3-K independent cell survival.