SIRT3 aggravates metformin‐induced energy stress and apoptosis in ovarian cancer cells
SIRT3 aggravates metformin‐induced energy stress and apoptosis in ovarian cancer cells
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DOI：
10.1016/j.yexcr.2018.03.030
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发表时间：
2018-06
影响因子：
3.7
通讯作者：
Yao Wu;Weinan Gao;Ya-Nan Xue;Li-chao Zhang;Juanjuan Zhang;Sheng-Yao Lu;Xiao-Yu Yan;Huimei Yu;Jing Su;Liankun Sun
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文献类型：
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作者：
Yao Wu;Weinan Gao;Ya-Nan Xue;Li-chao Zhang;Juanjuan Zhang;Sheng-Yao Lu;Xiao-Yu Yan;Huimei Yu;Jing Su;Liankun Sun
越来越多的证据表明，线粒体呼吸链复合体I通过提供能量和维持线粒体功能参与了癌症的发生和进展。然而，复合体I在卵巢癌中的作用在很大程度上是未知的。在这项研究中，我们发现二甲双胍，被认为是复合物I的抑制剂，在人卵巢癌细胞中同时抑制细胞生长和诱导线粒体相关的凋亡。二甲双胍中断细胞能量代谢主要是通过对复合体I造成损伤而影响线粒体功能。此外，二甲双胍治疗增加了线粒体去乙酰化酶sirtuin 3 （SIRT3）的激活。我们证实SIRT3过表达加重了二甲双胍诱导的细胞凋亡、能量应激和线粒体功能障碍。此外，二甲双胍或SIRT3过表达治疗增加了amp活化蛋白激酶（AMPK）的激活，AMPK是细胞能量状态的主要传感器。AMPK通过增加糖酵解来补偿能量损失。通过降低培养基中的葡萄糖水平或使用糖酵解和AMPK抑制剂（2-脱氧葡萄糖，化合物C）来评估其影响。这些因子与二甲双胍的联合作用通过进一步下调ATP而增强了细胞毒性。我们的研究概述了SIRT3在人类卵巢癌细胞线粒体复合物I抑制剂的抗肿瘤作用中的重要作用。这种效应可能是通过诱导能量应激和细胞凋亡介导的。可以通过调节糖酵解来增强靶向线粒体的策略，从而进一步加重能量应激，从而增加抗肿瘤作用。
Increasing evidence suggests that mitochondrial respiratory chain complex I participates in carcinogenesis and cancer progression by providing energy and maintaining mitochondrial function. However, the role of complex I in ovarian cancer is largely unknown. In this study we showed that metformin, considered to be an inhibitor of complex I, simultaneously inhibited cell growth and induced mitochondrial-related apoptosis in human ovarian cancer cells. Metformin interrupted cellular energy metabolism mainly by causing damage to complex I that impacted mitochondrial function. Additionally, treatment with metformin increased the activation of sirtuin 3 (SIRT3), a mitochondrial deacetylase. We demonstrated that SIRT3 overexpression aggravated metformin-induced apoptosis, energy stress and mitochondrial dysfunction. Moreover, treatment with metformin or SIRT3 overexpression increased activation of AMP-activated protein kinase (AMPK), a major sensor of cellular energy status. AMPK compensated for energy loss by increasing glycolysis. The impact of this was assessed by reducing glucose levels in the media or by using inhibitors (2-deoxyglucose, Compound C) of glycolysis and AMPK. The combination of these factors with metformin intensified cytotoxicity through further downregulation of ATP. Our study outlines an important role for SIRT3 in the antitumor effect of mitochondrial complex I inhibitors in human ovarian cancer cells. This effect appears to be mediated by induction of energy stress and apoptosis. Strategies that target the mitochondria could be enhanced by modulating glycolysis to further aggravate energy stress that may increase the antitumor effect.