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Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells {Less than}i{Greater than}ex vivo{Less than}/i{Greater than} through inhibition of {Less than}i{Greater than}de novo{Less than}/i{Greater than} lipogenesis

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 β1subunit, a mechanism, 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 (<1.0mM); effects not observed in prostate (PNT1A) and lung (MRC-5) epithelial cell lines. Salicylate concentrations of 1mM increased the phosphorylation of ACC and suppressed de novo lipogenesis and these effects were enhanced with the addition of clinical concentrations of metformin (100 mM) and eliminated in mouse embryonic fibroblasts (MEFs) deficient in AMPK b1. 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 likely important. Pre-clinical 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.

Authors:   O'Brien A; Villani L; Broadfield L; Houde V; Galic S; Blandino G; Kemp B; Tsakaridis T; Muti P; Steinberg G
Journal:   Biochemical Journal
Year:   2015
DOI:   10.1042/BJ20150122
Publication date:   05-May-2015
Facts, background information, dossiers
  • metformin
  • phosphorylation
  • lung cancer
  • cholesterol
  • cell lines
  • cancer
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