Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A₂α via AKT in prostate cancer cells.

Aberrant increase in pAKT, due to a gain-of-function mutation of PI3K or loss-of-function mutation or deletion of PTEN, occurs in prostate cancer and is associated with poor patient prognosis. Cytosolic phospholipase A₂α (cPLA₂α) is a lipid modifying enzyme by catalyzing the hydrolysis of membrane arachidonic acid. Arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. We examined whether AKT plays a role in promoting cPLA₂α action in prostate cancer cells. We found a concordant increase in pAKT and cPLA₂α levels in prostate tissue of prostate epithelial-specific PTEN-knockout but not PTEN-wide type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA₂α expression in PTEN-mutated or deleted prostate cancer cells. An increase in AKT by Myr-AKT elevated cPLA₂α protein levels, which could be diminished by inhibition of AKT phosphorylation without noticeable change in total AKT levels. pAKT levels had no influence on cPLA₂α at mRNA levels but reduced cPLA₂α protein degradation. Anti-AKT antibody co-immunoprecipitated cPLA₂α and vice versa. Hence, AKT plays a role in enhancing cPLA₂α protein stability in PTEN-null prostate cancer cells, revealing a link between oncogenic pathway and lipid metabolism.