Suppression Versus Induction of Androgen Receptor Functions by the Phosphatidylinositol 3-Kinase/Akt Pathway in Prostate Cancer LNCaP Cells with Different Passage Numbers

Hui-Kuan Lin,Yen-Ta Chen,Chawnshang Chang,Yueh-Chiang Hu,Hong-Yo Kang,Saleh Altuwaijri,Lin Yang

doi:10.1074/jbc.m300676200

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway controls several important biological functions, such as cell growth regulation, apoptosis, and migration. However, the way in which PI3K/Akt controls androgen receptor (AR)-mediated prostate cancer cell growth remains unclear and controversial. Here, we demonstrate that the PI3K/Akt pathway regulates AR activity in a cell passage number-dependent manner. Specifically, PI3K/Akt pathway can suppress AR activity in androgen-dependent LNCaP cells with low passage numbers. In contrast, it can also enhance AR activity in LNCaP cells with high passage numbers. Furthermore, we also demonstrate that insulin-like growth factor-1 can activate the PI3K/Akt pathway that results in the phosphorylation of AR at Ser210 and Ser790. The consequence of these events may then change the stability of AR protein. Together, our results demonstrate that the PI3K/Akt pathway may have distinct mechanisms to modulate AR functions in various stages of prostate cancer cells and that a combined therapy of antiandrogens and anti-PI3K/Akt inhibitors may be worth considering as a future therapeutic approach to battle prostate cancer.

Highlights

Summary—On the basis of this study and our previous reports (3, 4) we propose a model for the PI3K/Akt pathway action on the regulation of AR activity in prostate cancer LNCaP cells (Fig. 4)
In low passage LNCaP cells, the basal activity of PI3K/Akt signaling is low and cells are strongly dependent on androgen signaling for growth and survival
In high passage LNCaP cells, the basal activity of the PI3K/Akt pathway is high and cells are less dependent on androgen signaling

Summary

Introduction

How the cell passage number affects PI3K/Akt modulation of AR activity remains unclear. It is possible that the variant basal Akt activity levels among cells of different passages may be a key factor contributing to this phenomenon. Different cell contexts may exist in LNCaP cells of different passage numbers contributing to the modulating effect of the PI3K/Akt pathway on AR activity. Because Mdm2 is a downstream effector of the PI3K/Akt pathway, it would be useful to determine whether the levels of Mdm2 in various passage numbers of LNCaP cells are significantly different.

Results

Conclusion