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Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

Oncogene volume 26, pages 5784–5792 (2007)Cite this article

Abstract

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes are overexpressed during inflammation and multistage tumor progression in many neoplastic disorders including lung, breast and pancreatic cancers. Here we report that the tumor suppressor phosphatase and tensin homolog (PTEN) is oxidized and inactivated during arachidonic acid (AA) metabolism in pancreatic cancer cell lines expressing COX-2 or 5-LOX. Oxidation of PTEN decreases its phosphatase activity, favoring increased phosphatidylinositol 3,4,5-triphosphate production, activation of Akt and phosphorylation of downstream Akt targets including GSK-3β and S6K. These effects are recapitulated with pancreatic phospholipase A2, which hydrolyses the release of membrane-bound AA. Interference with PTEN's physiological antagonism of signals from growth factors, insulin and oncogenes may confer risk for hypertrophic or neoplastic diseases associated with chronic inflammation or unwarranted oxidative metabolism of essential fatty acids.

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Acknowledgements

Matt Firpo and Jill Coursen provided cell lines. This work was supported by USPHS Grant PO1 CA73992 Project 5 and the Huntsman Cancer Institute Directors Translational Research Initiative. TMC is supported by a MCRTP fellowship T32 CA093247. FAF holds the Dee Glen and Ida Smith Chair for Cancer Research.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA

    T M Covey & F A Fitzpatrick

  2. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    K Edes

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  1. T M Covey
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  2. K Edes
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  3. F A Fitzpatrick
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Correspondence to F A Fitzpatrick.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Covey, T., Edes, K. & Fitzpatrick, F. Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor. Oncogene 26, 5784–5792 (2007). https://doi.org/10.1038/sj.onc.1210391

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