Oncotarget

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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

Joffrey Pelletier, Danièle Roux, Benoit Viollet, Nathalie M. Mazure and Jacques Pouysségur _

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Oncotarget. 2015; 6:11833-11847. https://doi.org/10.18632/oncotarget.3738

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Abstract

Joffrey Pelletier1, Danièle Roux1, Benoit Viollet2,3,4, Nathalie M. Mazure1,* and Jacques Pouysségur1,3,5,*

1 Institute for Research on Cancer and Ageing of Nice (IRCAN), University of Nice-Sophia Antipolis, CNRS UMR INSERM, Centre Antoine Lacassagne, Nice, France

2 INSERM U1016, Institut Cochin, Paris, France

3 CNRS UMR8104, Paris, France

4 Université Paris Descartes, Sorbonne Paris Cité, Paris, France

5 Centre Scientifique de Monaco (CSM), Monaco

* These authors have contributed equally to this work

Correspondence to:

Jacques Pouysségur, email:

Nathalie Mazure, email:

Keywords: AMPK, AMPK-null cells, ATP, cancer cell, glycolysis

Received: January 19, 2015 Accepted: March 04, 2015 Published: March 30, 2015

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.


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