摘要
蛋白激酶B(AKT) 磷酸化(PAKT)的异常增加,由于磷脂酰肌醇3-激酶(PI3K)突变功能增强或突变功能丧失或磷酸酶和张力蛋白同源物(PTEN) 缺失,是前列腺癌及预后不良相关的一种常见的突变。胞浆磷脂酶A2α (cPLA2α)是一种脂质修饰酶,通过来自膜磷脂的花生四烯酸催化水解。所释放的花生四烯酸及其代谢产物有助于前列腺癌细胞的存活和增殖。本文总结pAKT和cPLA2α在前列腺癌细胞中的关系。与PTEN基因的野生型小鼠相比,前列腺上皮细胞特异型PTEN基因剔除小鼠的前列腺组织中cPLA2α和pAKT水平增加。PTEN的表达恢复或PI3K的活性抑制降低了PTEN突变或前列腺癌细胞消除过程中cPLA2α的表达。AKT磷酸化水平升高,cPLA2α蛋白水平减少,同时AKT磷酸化作用抑制减少。在mRNA水平上,pAKT对cPLA2α表达无影响,但在蛋白质水平上,通过保护其免受降解使cPLA2α稳定。相反地,cPLA2α表达感应导致PTEN基因突变中pAKT水平增加或前列腺癌细胞消除,而cPLA2α表达沉默或药物阻断cPLA2α作用降低了pAKT水平。花生四烯酸可减缓基因沉默或药物阻断cPLA2α作用而导致 pAKT水平的降低。花生四烯酸是通过抑制花生四烯酸的代谢产物而产生对pAKT水平的刺激作用。这些研究揭示了致癌途径和脂质代谢之间的联系,同时也为治疗前列腺癌提供了潜在的分子靶点。
关键词: AKT
Current Cancer Drug Targets
Title:AKT and cytosolic phospholipase A2α form a positive loop in prostate cancer cells
Volume: 15 Issue: 9
Author(s): Sheng Hua, Soma Vignarajan, Mu Yao, Chanlu Xie, Paul Sved and Qihan Dong
Affiliation:
关键词: AKT
摘要: 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.
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Cite this article as:
Sheng Hua, Soma Vignarajan, Mu Yao, Chanlu Xie, Paul Sved and Qihan Dong , AKT and cytosolic phospholipase A2α form a positive loop in prostate cancer cells, Current Cancer Drug Targets 2015; 15 (9) . https://dx.doi.org/10.2174/1568009615666150706103234
DOI https://dx.doi.org/10.2174/1568009615666150706103234 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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