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首页> 外文期刊>Cell metabolism >MYC/PGC-1 alpha Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells
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MYC/PGC-1 alpha Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells

机译：MYC / PGC-1 alpha平衡决定胰腺癌干细胞的代谢表型和可塑性

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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, trans-latedintoenergy crisisandapoptosis. However, resistantCSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1 alpha 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.
机译：抗糖尿病药物二甲双胍靶向胰腺癌干细胞（CSC），但不靶向其分化后代（非CSC），后者可能与独特的代谢表型有关。在这里，我们最终证明，尽管非CSC具有高度的糖酵解作用，但CSC依赖于氧化代谢（OXPHOS），而其代谢可塑性非常有限。因此，例如通过二甲双胍的线粒体抑制，转化为能量危机和细胞凋亡。然而，由于其中间的糖酵解/呼吸表型，抗性CSC克隆最终在二甲双胍治疗期间出现。从机理上讲，MYC的抑制和随后PGC-1α的增加被确定为CSC的OXPHOS依赖性的关键决定因素，而在抗性CSC克隆中已被取消。有趣的是，未观察到线粒体ROS诱导剂甲萘醌的抗药性，并且通过MYC的遗传/药理抑制作用也可以预防/逆转二甲双胍的抗药性。因此，胰腺CSCs的特定代谢特征可修改为治疗干预措施，并可为开发更有效的疗法来对抗这种致死性癌症提供基础。

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