Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27(Kip1) expression

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/pro tein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be i nvolved in human prostate cancer progression. me now show that ART activati on and activity are markedly increased in androgen-independent, prostate-sp ecific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cel ls show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for inc reased phosphorylation of the AKT target protein, BAD. Furthermore, express ion of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, con sistent with the notion that AKT directly inhibits AFX/Forkhead-mediated tr anscription of p27(Kip1). To assess directly the impact of increased AKT ac tivity on prostate cancer progression, an activated hAKT1 mutant was overex pressed in LNCaP cells, resulting in a B-fold increase in xenograft tumor g rowth. Like LNAI cells, these transfectants showed dramatically reduced p27 1(Kip1) expression. Together, these data implicate increased AKT activity i n prostate tumor progression and androgen independence and suggest that dim inished p27(Kip1) expression, which has been repeatedly associated with pro state cancer progression, may be a consequence of increased AKT activity.