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Wang Hui Qin , Altomare Deborah A , Skele Kristine L , Poulikakos Poulikos I , Kuhajda Francis P , Di Cristofano Antonio , Testa Joseph R
Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells
Oncogene. 2005 ;24(22) :3574-3582
PMID: AN 2005:431132   
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Abstract
Activation of AKT and overexpression of fatty acid synthase (FAS) are frequently obsd. in human ovarian cancer. To explore a possible connection between AKT and FAS, immunohistochem. analyses were conducted on an ovarian cancer tissue microarray, which revealed a significant correlation between phosphorylated AKT (phospho-AKT) and expression of FAS. To investigate the relationship between phospho-AKT and FAS in vitro, a variety of expts. employing a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor (LY294002), inducible PTEN expression in PTEN-null cells, or AKT1 siRNA demonstrated that phosphatidylinositol-3 kinase (PI3K)/AKT signaling modulates FAS expression. In contrast, inhibition of FAS activity by the drug C75 resulted in downregulation of phospho-AKT and increased cell death. To explore the functional relationship between phospho-AKT and FAS, the authors used SKOV3, C200, and OVCAR10 ovarian carcinoma cells, which have constitutively active AKT, and OVCAR5 cells, which have very low basal phospho-AKT levels. Treatment with LY294002 abolished AKT activity and potentiated apoptosis induced by FAS inhibitors cerulenin or C75 only in cells with constitutively active AKT, suggesting that constitutive activation of AKT protects against FAS inhibitor-induced cell death. Furthermore, inhibition of FAS activity by cerulenin or C75 resulted in downregulation of phospho-AKT, which preceded the induction of apoptosis. To investigate the relationship between phospho-AKT and FAS in vivo, severe combined immunodeficient mice injected i.p. with SKOV3 cells were treated with C75. Growth of SKOV3 xenografts was markedly inhibited by C75. Anal. of the levels of phospho-AKT and FAS in C75-treated tumors revealed concordant downregulation of phospho-AKT and FAS. Collectively, the authors' findings are consistent with a working model in which AKT activation regulates FAS expression, at least in part, whereas FAS activity modulates AKT activation. [on SciFinder (R)]
Notes
CAN 143:23954 14-1 Mammalian Pathological Biochemistry Human Genetics Program,Fox Chase Cancer Center,Philadelphia,PA,USA. Journal 0950-9232 written in English. 9045-77-6 (Fatty acid synthase); 148640-14-6 (AKT kinase) Role: BSU (Biological study, unclassified), BIOL (Biological study) (pos. feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells)