RE: Omega-6 fatty acids fuel prostate cancer growth

February 21, 2006

>>>Omega-6 fatty acids fuel prostate cancer growth

Cancer Research 66, 1427-1433, February 1, 2006]

Cell, Tumor, and Stem Cell Biology

Arachidonic Acid Activates Phosphatidylinositol 3-Kinase Signaling and Induces

Gene Expression in Prostate Cancer

Millie -Fulford1,2,3, Chai-Fei Li2, Jim Boonyaratanakornkit1,3 and Sina

Sayyah2

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 -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@... .

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 {omega}-6 fatty acid, induced 11 genes that

are regulated by nuclear factor-{kappa}B (NF-{kappa}. We verified gene

induction by {omega}-6 fatty acid, including COX-2, I{kappa}B{alpha},

NF-{kappa}B, GM-CSF, IL-1ß, CXCL-1, TNF-{alpha}, IL-6, LTA, IL-8, PPAR{gamma},

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 {omega}-6 fatty acid addition. Thirty minutes after

fatty acid addition, we found a significant 3-fold increase in translocation of

NF-{kappa}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-{kappa}B translocation to the nucleus. (Cancer Res

2006; 66(3): 1427-33)

February 21, 2006