6月22日,,Cancer Research 雜志報(bào)道了AMP活化的蛋白激酶(AMPK)自身在肝細(xì)胞癌中發(fā)揮抑癌功能的機(jī)制研究。
AMP活化的蛋白激酶(AMPK),,一個(gè)細(xì)胞能量狀態(tài)的生物感應(yīng)器,,已被證明在已知的腫瘤抑制基因的上游和下游發(fā)揮作用。然而,,是否AMPK本身起著腫瘤抑制因子的作用仍不清楚,。
該研究發(fā)現(xiàn), AMPK的α2催化亞基異構(gòu)體在肝細(xì)胞癌(HCC)中顯著下調(diào),。臨床分析表明,,AMPK-α2下調(diào)在統(tǒng)計(jì)學(xué)上與未分化的細(xì)胞表型及病人的預(yù)后不佳有關(guān)。無論在體外和體內(nèi)實(shí)驗(yàn)中,,肝癌細(xì)胞的AMPK-α2喪失,,使它們比對(duì)照細(xì)胞更具有成瘤性。
其機(jī)理是,, AMPK的異位表達(dá)在肝癌細(xì)胞中增強(qiáng)了p53的乙?;头€(wěn)定,。 p53去乙酰化酶SIRT1 的Thr-344位點(diǎn)可被AMPK所磷酸化,,這造成SIRT1失活,,從而促進(jìn)p53的乙酰化和肝癌細(xì)胞的凋亡,。
總之,,該研究結(jié)果表明,肝細(xì)胞癌中經(jīng)常存在AMPK表達(dá)下調(diào),,AMPK失活通過SIRT1依賴的方式引發(fā)P53不穩(wěn)定進(jìn)而促進(jìn)肝癌,。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells
Chi Wai Lee1, Leo Lap-Yan Wong1, Edith Yuk-Ting Tse1, Heong Fai Liu1, Veronica Yee-Law Leong1, Joyce Man-Fong Lee2, Lee D. Grahame Hardie3, Irene Oi-Lin Ng4, and Yick-Pang Ching1,*
AMP-activated protein kinase (AMPK), a biological sensor for cellular energy status, has been shown to act upstream and downstream of known tumor suppressors. However, whether AMPK itself plays a tumor suppressor role in cancer remains unclear. Here, we found that the α2 catalytic subunit isoform of AMPK is significantly down-regulated in hepatocellular carcinoma (HCC). Clinicopathological analysis revealed that under-expression of AMPK-α2 was statistically associated with an undifferentiated cellular phenotype and poor patient prognosis. Loss of AMPK-α2 in HCC cells rendered them more tumorigenic than control cells both in vitro and in vivo. Mechanistically, ectopic expression of AMPK enhanced the acetylation and stability of p53 in HCC cells. The p53 deacetylase SIRT1 was phosphorylated and inactivated by AMPK at Thr-344, promoting p53 acetylation and apoptosis of HCC cells. Taken together, our findings suggest that under-expression of AMPK is frequently observed in HCC, and that inactivation of AMPK promotes hepatocarcinogenesis by destabilizing p53 in a SIRT1-dependent manner.