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Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells

Oncogene volume 24, pages 3574–3582 (2005)Cite this article

Abstract

Activation of AKT and overexpression of fatty acid synthase (FAS) are frequently observed in human ovarian cancer. To explore a possible connection between AKT and FAS, immunohistochemical 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 experiments 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, we 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 intraperitoneally with SKOV3 cells were treated with C75. Growth of SKOV3 xenografts was markedly inhibited by C75. Analysis of the levels of phospho-AKT and FAS in C75-treated tumors revealed concordant downregulation of phospho-AKT and FAS. Collectively, our findings are consistent with a working model in which AKT activation regulates FAS expression, at least in part, whereas FAS activity modulates AKT activation.

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Abbreviations

FAS:

fatty acid synthase

PI3K:

phosphatidylinositol 3-OH kinase

SCID:

severe combined immunodeficient

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Acknowledgements

We thank Dr AJP Klein-Szanto for immunohistochemical analysis and H Wang for statistical analysis. This work was supported by National Cancer Institute Grants CA83638 (SPORE in Ovarian Cancer), CA77429, and CA06927, and by an appropriation from the Commonwealth of Pennsylvania. The following Fox Chase Cancer Center shared facilities were used in the course of this work: Cell Culture Facility, Biosample and Tissue Procurement Core, and Laboratory Animal Facility. HQ Wang is supported by a Board of Directors Postdoctoral Fellowship at Fox Chase Cancer Center and by an NIH Institutional Training Grant CA-09035-28. FASgen did not contribute reagents or support for these studies. However, we acknowledge that under a licensing agreement between FASgen and the Johns Hopkins University, FPK is entitled to a share of royalty received by the University on products that may be developed from FAS technology. FPK owns FASgen stock, which is subject to certain restrictions under University policy. The Johns Hopkins University, in accordance with its conflict of interest policies, is managing the terms of this arrangement.

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  1. Human Genetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA

    Hui Qin Wang, Deborah A Altomare, Kristine L Skele, Poulikos I Poulikakos, Antonio Di Cristofano & Joseph R Testa

  2. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA

    Francis P Kuhajda

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  1. Hui Qin Wang
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Correspondence to Joseph R Testa.

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Wang, H., Altomare, D., Skele, K. et al. Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene 24, 3574–3582 (2005). https://doi.org/10.1038/sj.onc.1208463

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