Journal
BIOCHEMICAL JOURNAL
Volume 469, Issue -, Pages 177-187Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20150122
Keywords
3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase; aspirin; cholesterol; fatty acids; mammalian target of rapamycin (mTOR); acetyl-CoA carboxylase (ACC); proliferation
Categories
Funding
- Canadian Institutes of Health Research [MOP-11480]
- Canadian Cancer Society [20001191]
- Australian Research Council [DP130104548]
- National Health and Medical Research Council [APP1085460]
- Victorian Government
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Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers of the colon, lung and prostate and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) by binding at the A-769662 drug binding site on the AMPK beta 1-subunit, amechanism that is distinct from metformin which disrupts the adenylate charge of the cell. A hallmark of many cancers is high rates of fatty acid synthesis and AMPK inhibits this pathway through phosphorylation of acetyl-CoA carboxylase (ACC). It is currently unknown whether targeting the AMPK-ACC-lipogenic pathway using salicylate and/or metformin may be effective for inhibiting cancer cell survival. Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations achievable following the ingestion of aspirin (<1.0 mM); effects not observed in prostate (PNT1A) and lung (MRC-5) epithelial cell lines. Salicylate concentrations of 1 mM increased the phosphorylation of ACC and suppressed de novo lipogenesis and these effects were enhanced with the addition of clinical concentrations of metformin (100 mu M) and eliminated in mouse embryonic fibroblasts (MEFs) deficient in AMPK beta 1. Supplementation of media with fatty acids and/or cholesterol reverses the suppressive effects of salicylate and metformin on cell survival indicating the inhibition of de novo lipogenesis is probably important. Preclinical studies evaluating the use of salicylate based drugs alone and in combination with metformin to inhibit de novo lipogenesis and the survival of prostate and lung cancers are warranted.
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