1. ¹Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA
2. ²Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

Correspondence: Dr FA Fitzpatrick, Department of Medicinal Chemistry and Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA. E-mail: frank.fitzpatrick@hci.utah.edu

Received 16 November 2006; Revised 25 January 2007; Accepted 1 February 2007; Published online 19 March 2007.

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-3 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.