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.
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Research Article|
July 06 2015
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
Andrew J. O’Brien;
Andrew J. O’Brien
*Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1
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Linda A. Villani;
Linda A. Villani
*Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1
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Lindsay A. Broadfield;
Lindsay A. Broadfield
*Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1
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Vanessa P. Houde;
Vanessa P. Houde
*Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1
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Sandra Galic;
Sandra Galic
†St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia
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Giovanni Blandino;
Giovanni Blandino
‡Oncology, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1
§Translational Oncogenomic, Regina Elena Cancer Institute, Rome 00144, Italy
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Bruce E. Kemp;
Bruce E. Kemp
†St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia
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Theodoros Tsakiridis;
Theodoros Tsakiridis
‡Oncology, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1
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Paola Muti;
Paola Muti
‡Oncology, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1
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Gregory R. Steinberg
Gregory R. Steinberg
1
*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
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 27 2015
Revision Received:
April 22 2015
Accepted:
May 05 2015
Accepted Manuscript online:
May 05 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2015 Authors; published by Portland Press Limited
2015
Biochem J (2015) 469 (2): 177–187.
Article history
Received:
January 27 2015
Revision Received:
April 22 2015
Accepted:
May 05 2015
Accepted Manuscript online:
May 05 2015
Citation
Andrew J. O’Brien, Linda A. Villani, Lindsay A. Broadfield, Vanessa P. Houde, Sandra Galic, Giovanni Blandino, Bruce E. Kemp, Theodoros Tsakiridis, Paola Muti, Gregory R. Steinberg; 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. Biochem J 15 July 2015; 469 (2): 177–187. doi: https://doi.org/10.1042/BJ20150122
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