AKT and cytosolic phospholipase A 2 α form a positive loop in prostate cancer cells

Aberrant increase in protein kinase B (AKT) phosphorylation (pAKT), due to a gain-offunction mutation of phosphatidylinositol-3-kinase (PI3K) or loss-of-function mutation or deletion of phosphatase and tensin homolog (PTEN), is a common alteration in prostate cancer and associated with poor prognosis. Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) is a lipid modifying enzyme that catalyzes the hydrolysis of arachidonic acid from membrane phospholipid. The released arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. In this mini-review, we summarize the relationship between pAKT and cPLA(2)alpha in prostate cancer cells. There was a concordant increase in pAKT and cPLA(2)alpha levels in prostate tissue of prostate epithelial-specific PTEN-knockout mice compared to PTEN-wild type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA(2)alpha expression in PTEN-mutated or deleted prostate cancer cells. An increase in AKT phosphorylation elevated, whereas inhibition of AKT phosphorylation diminished, cPLA(2)alpha protein levels. pAKT had no influence on cPLA(2)alpha expression at mRNA levels but stabilized cPLA(2)alpha at protein levels by protecting it from degradation. Conversely, an induction of cPLA(2)alpha expression led to an increase in pAKT levels in PTEN-mutated or deleted prostate cancer cells while silencing of cPLA(2)alpha expression or pharmacological blocking of cPLA(2)alpha action decreased pAKT levels. The diminishment of pAKT by either genetic silencing or pharmacological blocking of cPLA(2)alpha was mitigated by the addition of arachidonic acid. The stimulatory effect of arachidonic acid on pAKT levels was lessened by inhibiting the production of arachidonic acid metabolites. These studies have revealed a link between an oncogenic pathway and lipid metabolism and provided potential molecular targets for treating prostate cancer.