Cancer Res.:AMPK调节p53抑制肝细胞癌
2012-06-26 bo 本站原创
6月22日,Cancer Research 杂志报道了AMP活化的蛋白激酶(AMPK)自身在肝细胞癌中发挥抑癌功能的机制研究。 AMP活化的蛋白激酶(AMPK),一个细胞能量状态的生物感应器,已被证明在已知的肿瘤抑制基因的上游和下游发挥作用。然而,是否AMPK本身起着肿瘤抑制因子的作用仍不清楚。 该研究发现, AMPK的α2催化亚基异构体在肝细胞癌(HCC)中显著下调。临床分析表明,AMPK-
6月22日,Cancer Research 杂志报道了AMP活化的蛋白激酶(AMPK)自身在肝细胞癌中发挥抑癌功能的机制研究。
AMP活化的蛋白激酶(AMPK),一个细胞能量状态的生物感应器,已被证明在已知的肿瘤抑制基因的上游和下游发挥作用。然而,是否AMPK本身起着肿瘤抑制因子的作用仍不清楚。
该研究发现, AMPK的α2催化亚基异构体在肝细胞癌(HCC)中显著下调。临床分析表明,AMPK-α2下调在统计学上与未分化的细胞表型及病人的预后不佳有关。无论在体外和体内实验中,肝癌细胞的AMPK-α2丧失,使它们比对照细胞更具有成瘤性。
其机理是, AMPK的异位表达在肝癌细胞中增强了p53的乙酰化和稳定。 p53去乙酰化酶SIRT1 的Thr-344位点可被AMPK所磷酸化,这造成SIRT1失活,从而促进p53的乙酰化和肝癌细胞的凋亡。
总之,该研究结果表明,肝细胞癌中经常存在AMPK表达下调,AMPK失活通过SIRT1依赖的方式引发P53不稳定进而促进肝癌。
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
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.
作者:bo
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#肝细胞#
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#Res.:#
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#细胞癌#
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#p53#
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