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
- Others:
- Institut de Recherche sur le Cancer et le Vieillissement (IRCAN) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
- Laboratoire des sciences et matériaux pour l'électronique et d'automatique (LASMEA) ; Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)
- Institut Cochin (IC UM3 (UMR 8104 / U1016)) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Hypoxie tumorale et métabolisme ; Biologie Médicale ; Centre Scientifique de Monaco (CSM)-Centre Scientifique de Monaco (CSM)
- This research was supported by grants from the Fondation ARC, Fondation de France, the ANR, the INCA, la Ligue Nationale Contre le Cancer (JP, équipe Labellisée LNCC), METOXIA (FP7-EU programs), MRT and Canceropôle PACA.
Description
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 crucial role for 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.
Abstract
International audience
Additional details
- URL
- https://www.hal.inserm.fr/inserm-01171368
- URN
- urn:oai:HAL:inserm-01171368v1
- Origin repository
- UNICA