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

• Published in: The Journal of biological chemistry 2000-08, Vol.275 (32), p.24500-24505
• Main Authors: Graff, Jeremy R., Konicek, Bruce W., McNulty, Ann M., Wang, Zejing, Houck, Keith, Allen, Sheryl, Paul, Jonathan D., Hbaiu, Ahed, Goode, Robin G., Sandusky, George E., Vessella, Robert L., Neubauer, Blake Lee
• Format: Article
• Language: English
• Subjects: Animals; bcl-Associated Death Protein; Carrier Proteins - metabolism; Cell Cycle Proteins; Cell Death; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; Enzyme Activation; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Male; Mice; Mice, Nude; Microtubule-Associated Proteins - genetics; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; Transcription, Genetic; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Suppressor Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M003145200

The PTENtumor 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 p27Kip1 cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27Kip1. 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 p27Kip1 expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27Kip1expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.