Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo 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 β1-subunit, 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 (<1.0 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 μM) and eliminated in mouse embryonic fibroblasts (MEFs) deficient in AMPK β1. 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. 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.
Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1.
Andrew J
AJ
O'Brien
Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1.
Linda A
LA
Villani
Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1.
Lindsay A
LA
Broadfield
Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1.
Vanessa P
VP
Houde
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.
Sandra
S
Galic
Oncology, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1 Translational Oncogenomic, Regina Elena Cancer Institute, Rome 00144, Italy.
Giovanni
G
Blandino
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.
Bruce E
BE
Kemp
Oncology, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1.
Theodoros
T
Tsakiridis
Oncology, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1.
Paola
P
Muti
Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1 Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1 gsteinberg@mcmaster.ca.
Gregory R
GR
Steinberg
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000819:agonists / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004622:Embryo, Mammalian / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000819:agonists / Q000494:pharmacology*; D050155:Lipogenesis; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008687:Metformin / Q000819:agonists / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012980:Sodium Salicylate / Q000819:agonists / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D012980:Sodium Salicylate
3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase; acetyl-CoA carboxylase (ACC); aspirin; cholesterol; fatty acids; mammalian target of rapamycin (mTOR); proliferation