AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer.
AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
Motoshima
Hiroyuki
H
Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 8554, Japan. hmoto@gpo.kumamoto-u.ac.jp
Goldstein
Barry J
BJ
Igata
Motoyuki
M
Araki
Eiichi
E
D055372:AMP-Activated Protein Kinases; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008297:Male; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism*
D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases