Therapeutic inhibition of mitochondrial function induces cell death in starvation-resistant renal cell carcinomas.
Therapeutic inhibition of mitochondrial function induces cell death in starvation-resistant renal cell carcinomas.
复制标题
线粒体功能的治疗抑制可诱导饥饿肾细胞癌中的细胞死亡。
DOI：
10.1038/srep25669
复制
发表时间：
2016-05-09
影响因子：
4.6
通讯作者：
Yuasa T
中科院分区：
文献类型：
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作者：
Isono T;Chano T;Yonese J;Yuasa T
肾细胞癌（RCC）有两种类型的细胞碳代谢和细胞信号在营养缺乏的条件下，即饥饿抵抗和饥饿敏感的细胞。在这里，我们评估了这些细胞类型的线粒体特征，发现耐药型比敏感型具有更高的线粒体氧化磷酸化和糖酵解活性。这些更高的活性由储存的碳、脂质和碳水化合物来源以及由于抗性RCC细胞中持续的SOD2表达而导致的低水平的线粒体活性氧（ROS）支持。在转移性肾细胞癌病例中，SOD2的高表达与生存期显著缩短相关。我们发现，在耐饥饿的RCC细胞中，用药物etomoxir和burethane治疗显著降低了线粒体氧化磷酸化，并在葡萄糖剥夺条件下诱导细胞死亡。我们的数据表明，线粒体的抑制性靶向可能为对当前治疗有抗性的转移性RCC提供有效的治疗选择。
Renal cell carcinomas (RCC) have two types of cells for carbon metabolism and for cell signaling under nutrient-deprivation conditions, namely starvation-resistant and starvation-sensitive cells. Here, we evaluated the mitochondrial characteristics of these cell types and found that the resistant type possessed higher activities for both mitochondrial oxidative phosphorylation and glycolysis than the sensitive types. These higher activities were supported by the stored carbon, lipid and carbohydrate sources, and by a low level of mitochondrial reactive oxygen species (ROS) due to sustained SOD2 expression in the resistant RCC cells. In metastatic RCC cases, higher SOD2 expression was associated with a significantly shorter survival period. We found that treatment with the drugs etomoxir and buformin significantly reduced mitochondrial oxidative phosphorylation and induced cell death under glucose-deprivation conditions in starvation-resistant RCC cells. Our data suggest that inhibitory targeting of mitochondria might offer an effective therapeutic option for metastatic RCC that is resistant to current treatments.