Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1 Expression

Abstract

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27 Kip1 cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27 Kip1 . To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27 Kip1 expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27Kip1 expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.

Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

“…We conclude that these findings may be of medical importance, as a number of the components in the PI3-kinase pathway have been demonstrated to be dysregulated in human cancers (52)(53)(54). Therefore, based upon the observation that overexpression of an integral component in the PI3-kinase pathway, PKB, had no effect on sulindac sulfide-induced cell death, whereas the effects of sulindac were dramatically blunted, we propose that treatment with the former may be an effective adjuvant therapy.…”

Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients

“…Since the activation of Akt promotes cell cycle progression by modulating the expression (Brennan et al, 1997;Muise-Helmericks et al, 1998) and stabilization of cyclin D1 (Graff et al, 2000) and the SPF is an indicator of the proliferative state of the cells, the negative association between pAkt and SPF was unexpected. Nevertheless, an increase in cyclin D1 does not always lead to cell cycle progression (Hiyama et al, 1997;Mitsuuchi et al, 2000), and in some cases the expression of cyclin D1 has been associated with low proliferative rate in clinical material (Nielsen et al, 1999).…”

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

“…71 The Akt-mediated reduction of free p27 Kip1 protein levels is associated with growth acceleration of prostate xenograft tumors. 72 Phosphorylation and inhibition of GSK3b by Akt abolishes phosphorylation of cytoplasmic signaling molecule b-catenin, causing its stabilization and nuclear translocation, where it associates with T-cell factor (TCF)/lymphocyte enhancing-binding factor-1 (LEF-1) to induce the transcription of several genes, including cyclin D1, that promote cell cycle progression through hyperphosphorylation and inactivation of the retinoblastoma (Rb) tumor-suppressor protein. 73 Phosphorylation of MDM2 promotes its translocation to the nucleus where it binds and inhibits p53 activities towards cell cycle regulation.…”