title: AKT and cytosolic phospholipase A2α form a positive loop in prostate cancer cells.
abstract: Aberrant increase in protein kinase B (AKT) phosphorylation (pAKT), due to a gain-of-function 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 A2α (cPLA2α) is a lipid modifying enzyme by catalyzing 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 cPLA2α in prostate cancer cells. There was a concordant increase in pAKT and cPLA2α 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 cPLA2α expression in PTEN-mutated or deleted prostate cancer cells. An increase in AKT phosphorylation elevated, whereas inhibition of AKT phosphorylation diminished, cPLA2α protein levels. pAKT had no influence on cPLA2α expression at mRNA levels but stabilized cPLA2α at protein levels by protecting it from degradation. Conversely, an induction of cPLA2α expression led to an increase in pAKT levels in PTEN-mutated or deleted prostate cancer cells, while silencing of cPLA2α expression or pharmacological blocking cPLA2α action decreased pAKT levels. The diminishment of pAKT by either genetic silencing or pharmacological blocking of cPLA2α 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 oncogenic pathway and lipid metabolism and provided potential molecular targets for treating prostate cancer.
authors.forename: Sheng
authors.initials: S
authors.lastname: Hua
authors.forename: Soma
authors.initials: S
authors.lastname: Vignarajan
authors.forename: Mu
authors.initials: M
authors.lastname: Yao
authors.forename: Chanlu
authors.initials: C
authors.lastname: Xie
authors.forename: Paul
authors.initials: P
authors.lastname: Sved
authors.affiliation: School of Science and Health, The University of Western Sydney, Penrith South, NSW 2751, Australia. q.dong@uws.edu.au.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D054513:Group IV Phospholipases A2 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D051057:Proto-Oncogene Proteins c-akt; D054513:Group IV Phospholipases A2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human