title: AMP-activated protein kinase is dispensable for maintaining ATP levels and for survival following inhibition of glycolysis, but promotes tumour engraftment of Ras-transformed fibroblasts.
abstract: Lactic acid generated by highly glycolytic tumours is exported by the MonoCarboxylate Transporters, MCT1 and MCT4, to maintain pHi and energy homeostasis. We report that MCT1 inhibition combined with Mct4 gene disruption severely reduced glycolysis and tumour growth without affecting ATP levels. Because of the key role of the 5'-AMP-activated protein kinase (AMPK) in energy homeostasis, we hypothesized that targeting glycolysis (MCT-blockade) in AMPK-null (Ampk(-/-)) cells should kill tumour cells from 'ATP crisis'. We show that Ampk(-/-)-Ras-transformed mouse embryonic fibroblasts (MEFs) maintained ATP levels and viability when glycolysis was inhibited. In MCT-inhibited MEFs treated with OXPHOS inhibitors the ATP level and viability collapsed in both Ampk(+/+) and Ampk(-/-) cells. We therefore propose that the intracellular acidification resulting from lactic acid sequestration mimicks AMPK by blocking mTORC1, a major component of an ATP consuming pathway, thereby preventing 'ATP crisis'. Finally we showed that genetic disruption of Mct4 and/or Ampk dramatically reduced tumourigenicity in a xenograft mouse model suggesting a crucialrolefor these two actors in establishment of tumours in a nutrient-deprived environment. These findings demonstrated that blockade of lactate transport is an efficient anti-cancer strategy that highlights the potential in targeting Mct4 in a context of impaired AMPK activity.
authors.affiliation: Institute for Research on Cancer and Ageing of Nice (IRCAN), University of Nice-Sophia Antipolis, CNRS UMR INSERM, Centre Antoine Lacassagne, Nice, France.
authors.forename: Joffrey
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Institute for Research on Cancer and Ageing of Nice (IRCAN), University of Nice-Sophia Antipolis, CNRS UMR INSERM, Centre Antoine Lacassagne, Nice, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Roux
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Institute for Research on Cancer and Ageing of Nice (IRCAN), University of Nice-Sophia Antipolis, CNRS UMR INSERM, Centre Antoine Lacassagne, Nice, France.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Mazure
authors.affiliation: Institute for Research on Cancer and Ageing of Nice (IRCAN), University of Nice-Sophia Antipolis, CNRS UMR INSERM, Centre Antoine Lacassagne, Nice, France.|CNRS UMR8104, Paris, France.|Centre Scientifique de Monaco (CSM), Monaco.
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005347:Fibroblasts / Q000473:pathology*; D055786:Gene Knockout Techniques; D006019:Glycolysis / Q000502:physiology; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*
chemical_list: D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C406962:SLC16A4 protein, human; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases
keywords: AMPK; AMPK-null cells; ATP; cancer cell; glycolysis