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Arachidonic Acid Activates Phosphatidylinositol 3-Kinase Signaling and Induces Gene Expression in Prostate Cancer

¹ Department of Veterans Affairs Medical Center; ² Northern California Institute for Research and Education; and ³ University of California, San Francisco, California

Requests for reprints: Millie Hughes-Fulford, Laboratory of Cell Growth (151F), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. Phone: 415-750-6940; Fax: 415-750-6667; E-mail: milliehf{at}aol.com.

Essential fatty acids are not only energy-rich molecules; they are also an important component of the membrane bilayer and recently have been implicated in induction of fatty acid synthase and other genes. Using gene chip analysis, we have found that arachidonic acid, an -6 fatty acid, induced 11 genes that are regulated by nuclear factor-B (NF-B). We verified gene induction by -6 fatty acid, including COX-2, IB, NF-B, GM-CSF, IL-1ß, CXCL-1, TNF-, IL-6, LTA, IL-8, PPAR, and ICAM-1, using quantitative reverse transcription-PCR. Prostaglandin E₂ (PGE₂) synthesis was increased within 5 minutes of addition of arachidonic acid. Analysis of upstream signal transduction showed that within 5 minutes of fatty acid addition, phosphatidylinositol 3-kinase (PI3K) was significantly activated followed by activation of Akt at 30 minutes. Extracellular signal-regulated kinase 1 and 2, p38 and stress-activated protein kinase/c-Jun-NH₂-kinase were not phosphorylated after -6 fatty acid addition. Thirty minutes after fatty acid addition, we found a significant 3-fold increase in translocation of NF-B transcription factor to the nucleus. Addition of a nonsteroidal anti-inflammatory drug (NSAID) caused a decrease in COX-2 protein synthesis, PGE₂ synthesis, as well as inhibition of PI3K activation. We have previously shown that NSAIDs cause an inhibition of arachidonic acid–induced proliferation; here, we have shown that arachidonic acid–induced proliferation is also blocked (P < 0.001) by PI3K inhibitor LY294002. LY294002 also significantly inhibited the arachidonic acid–induced gene expression of COX-2, IL-1ß, GM-CSF, and ICAM1. Taken together, the data suggest that arachidonic acid via conversion to PGE₂ plays an important role in stimulation of growth-related genes and proliferation via PI3K signaling and NF-B translocation to the nucleus. (Cancer Res 2006; 66(3): 1427-33)

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