title: Differential effects of AMPK agonists on cell growth and metabolism.
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.
authors.affiliation: 1] Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada [2] Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: E E
authors.initials: EE
authors.lastname: Vincent
authors.affiliation: 1] Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada [2] Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: P P
authors.initials: PP
authors.lastname: Coelho
authors.affiliation: 1] Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada [2] Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Blagih
authors.affiliation: 1] Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada [2] Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Griss
authors.affiliation: 1] Inserm, U1016, Institut Cochin, Paris, France [2] CNRS, UMR 8104, Paris, France [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Viollet
authors.affiliation: 1] Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada [2] Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: R G
authors.initials: RG
authors.lastname: Jones
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010629:Phenformin / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology*; D012265:Ribonucleotides / Q000494:pharmacology; D012980:Sodium Salicylate / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D011753:Pyrones; D012265:Ribonucleotides; D013876:Thiophenes; D019344:Lactic Acid; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D010629:Phenformin; D000263:Adenylate Kinase; C031143:AICA ribonucleotide; D005947:Glucose; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile; D012980:Sodium Salicylate