Abstract
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.
Highlights
Membrane phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) provides the anchor site for PH-domain-containing proteins including protein kinaseB (AKT) [1]
Blocking Cytosolic phospholipase A2α (cPLA2α) with a gene silencing or pharmacological approach retards proliferation of prostate cancer cells in vitro or in vivo [23]. Since both phosphorylated AKT (pAKT) and cPLA2α levels are implicated in the prostate cancer, and an understanding of the integration of biochemical pathways involved in cancer progression is a key to the development of improved pharmacological treatment strategies for cancer [27, 28], we aimed to examine the relationship between the oncogenic protein and the lipid modifying enzyme
This study has revealed a previously-unrecognized concordant change between pAKT and lipid modifying enzyme cPLA2α protein levels in phosphatase and tensin homolog (PTEN)-knockout mouse prostate cancer tissues
Summary
Membrane phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) provides the anchor site for PH-domain-containing proteins including protein kinaseB (AKT) [1]. Due to close proximity to PH-domaincontaining kinases, AKT is activated by phosphorylation on cell membrane [2]. Phosphorylates a variety of target proteins, leading to an increase in cell survival and proliferation [2]. The homeostasis of PIP3 levels are maintained through phosphoinositide-3-kinase (PI3K) and phosphatase and tensin homolog (PTEN). 30-60% prostate cancer cases have either gain-of-function-mutation in PI3K or loss-of-function-mutation or deletion in PTEN [4]. About 45% of prostate cancer cases have increased levels of pAKT, which correlates with the disease severity [5, 6]. The loss of PTEN or increase in pAKT at Ser473 has been used to predict advanced prostate cancer that will fail to respond to treatment [7,8,9]
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