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Differential effects of AMPK agonists on cell growth and metabolism

Oncogene volume 34, pages 3627–3639 (2015)Cite this article

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Abstract

As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK dependence of six commonly used AMPK agonists (metformin, phenformin, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), 2-deoxy-D-glucose (2DG), salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity. Finally, contrary to the view of AMPK activity being tumor suppressive, we find that A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the antigrowth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution not only regarding the type of AMPK agonist proposed for cancer treatment but also the context in which they are used.

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Acknowledgements

We acknowledge Douglas Elder and Nicole Beauchemin, and members of the Jones Laboratory for critical reading of this manuscript. EEV, PPC and TG were funded by the McGill Integrated Cancer Research Training Program (MICRTP) and JB was funded by Fonds de researche Santé Québec. This work was supported by grants to RGJ from the Canadian Institute Health Research (CIHR) (MOP-93799), Canadian Cancer Society (2010-700586) and Terry Fox Research Foundation (TEF-116128). This work is dedicated to the memory of Rosalind Goodman.

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Authors and Affiliations

  1. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

    E E Vincent, P P Coelho, J Blagih, T Griss & R G Jones

  2. Department of Physiology, McGill University, Montreal, Quebec, Canada

    E E Vincent, P P Coelho, J Blagih, T Griss & R G Jones

  3. Inserm, U1016, Institut Cochin, Paris, France

    B Viollet

  4. CNRS, UMR 8104, Paris, France

    B Viollet

  5. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    B Viollet

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  1. E E Vincent
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  4. T Griss
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Correspondence to R G Jones.

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Vincent, E., Coelho, P., Blagih, J. et al. Differential effects of AMPK agonists on cell growth and metabolism. Oncogene 34, 3627–3639 (2015). https://doi.org/10.1038/onc.2014.301

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