生物
表型
胰腺癌
癌症研究
平衡(能力)
干细胞
细胞生物学
癌症
神经科学
遗传学
基因
作者
Patricia Sancho,Emma Burgos‐Ramos,Alejandra Tavera-Tapia,Tony Bou Kheir,Petra Jagušt,Matthieu Schoenhals,David Barneda,Katherine Sellers,Ramón Campos‐Olivas,Osvaldo Graña‐Castro,Catarina R. Viera,Mariia Yuneva,Bruno Sáinz,Christopher Heeschen
出处
期刊:Cell Metabolism
[Cell Press]
日期:2015-09-12
卷期号:22 (4): 590-605
被引量:649
标识
DOI:10.1016/j.cmet.2015.08.015
摘要
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.
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