Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells.
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays important roles for prostate cancer cell survival, and the androgen receptor (AR) plays essential roles for prostate cancer cell proliferation. How these two signals cooperate to control cell growth and death, however, remains unclear and debated. Here we provide the first linkage by the identification of Forkhead transcription factor FOXO3a, the PI3K/Akt downstream substrate, as a positive regulator for the induction of AR gene expression. Both Western blot and real time PCR assays demonstrate that FOXO3a can induce AR expression at the protein and mRNA levels, and gel shift and chromatin immunoprecipitation assays further demonstrate that FOXO3a can induce 5' AR promoter activity via binding to the consensus DNA-binding sequence in the AR 5' promoter -1290 to -1297 (5'-TTGTTTCA-3'). Under normal growth conditions, blocking PI3K/Akt signals by LY294002 causes LNCaP cell arrest in G1 phase rather than apoptosis. However, further blocking of AR functions by AR small interfering RNA leads to dramatic LNCaP cell death, suggesting that AR may play important protective roles when the PI3K/Akt signal pathway is blocked by LY294002. Together, our data provide the first model to explain how PI3K/Akt and AR can cooperate to control LNCaP cell growth and death under normal conditions.