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 p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.
Authors	J R Graff, B W Konicek, A M McNulty, Z Wang, K Houck, S Allen, J D Paul, A Hbaiu, R G Goode, G E Sandusky, R L Vessella, B L Neubauer
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 32 Pg. 24500-5 (Aug 11 2000) ISSN: 0021-9258 [Print] United States
PMID	10827191 (Publication Type: Journal Article)
Chemical References	BAD protein, human Bad protein, mouse Carrier Proteins Cdkn1b protein, mouse Cell Cycle Proteins Microtubule-Associated Proteins Proto-Oncogene Proteins Tumor Suppressor Proteins bcl-Associated Death Protein Cyclin-Dependent Kinase Inhibitor p27 Protein-Tyrosine Kinases AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Topics	Animals 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, metabolism, 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 bcl-Associated Death Protein

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