MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.

Autor:	Sancho P; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: p.sancho@qmul.ac.uk., Burgos-Ramos E; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain., Tavera A; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain., Bou Kheir T; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Jagust P; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Schoenhals M; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Barneda D; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Sellers K; The Francis Crick Institute, Mill Hill Laboratories, The Ridgeway, London NW7 1AA, UK., Campos-Olivas R; Spectroscopy and NMR Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain., Graña O; Bioinformatics Unit and Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain., Viera CR; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain., Yuneva M; The Francis Crick Institute, Mill Hill Laboratories, The Ridgeway, London NW7 1AA, UK., Sainz B Jr; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain., Heeschen C; Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. Electronic address: c.heeschen@qmul.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2015 Oct 06; Vol. 22 (4), pp. 590-605. Date of Electronic Publication: 2015 Sep 10.
DOI:	10.1016/j.cmet.2015.08.015
Abstrakt:	The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer. (Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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