AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells.

Abstract

AMP-activated protein kinase (AMPK), a biologic 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 downregulated in hepatocellular carcinoma (HCC). Clinicopathologic analysis revealed that underexpression 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 Thr344, promoting p53 acetylation and apoptosis of HCC cells. Taken together, our findings suggest that underexpression of AMPK is frequently observed in HCC, and that inactivation of AMPK promotes hepatocarcinogenesis by destabilizing p53 in a SIRT1-dependent manner.

• Authors: Chi-Wai Lee, Leo Lap-Yan Wong, Edith Yuk-Ting Tse, Heong-Fai Liu, Veronica Yee-Law Leong, Joyce Man-Fong Lee, D Grahame Hardie, Irene Oi-Lin Ng, Yick-Pang Ching
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 17 Pg. 4394-404 (Sep 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22728651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Protein Kinase Inhibitors
• Tumor Suppressor Protein p53
• AMP-Activated Protein Kinases
• Sirtuin 1

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Acetylation
• Apoptosis (genetics)
• Carcinoma, Hepatocellular (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (genetics, metabolism)
• Male
• Phosphorylation
• Protein Binding
• Protein Kinase Inhibitors (pharmacology)
• Sirtuin 1 (genetics, metabolism)
• Transcriptional Activation
• Tumor Suppressor Protein p53 (genetics, metabolism)