Sunitinib (Sun), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, is the standard first‐line treatment against advanced clear cell renal cell carcinoma (RCC), but resistance to therapy is inevitable. Reactive oxygen species production is associated with sensitivity to chemotherapy, but the underlying mechanisms are not completely understood. Here, we investigated the mechanisms contributing to Sun resistance using the RCC cell lines ACHN and 786‐O. We report that Sun‐resistant cells exhibited reduced apoptosis, increased cell viability, increased reactive oxygen species production and disrupted mitochondrial function. Furthermore, chronic Sun treatment resulted in an up‐regulation of Sirt5/isocitrate dehydrogenase 2 (IDH2) expression levels. Knockdown of Sirt5/IDH2 impaired mitochondrial function and partially attenuated Sun resistance. Finally, up‐regulation of Sirt5 enhanced the expression of IDH2 via modulation of succinylation at K413 and promoted protein stability. In conclusion, dysregulation of Sirt5/IDH2 partially contributes to Sun resistance in RCC cells by affecting antioxidant capacity.

中文翻译：

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Sirt5/IDH2 轴的失调导致人肾癌细胞对舒尼替尼的耐药性

舒尼替尼 (Sun) 是一种血管内皮生长因子受体的酪氨酸激酶抑制剂，是晚期透明细胞肾细胞癌 (RCC) 的标准一线治疗药物，但耐药性不可避免。活性氧的产生与对化疗的敏感性有关，但其潜在机制尚不完全清楚。在这里，我们使用 RCC 细胞系 ACHN 和 786-O 研究了导致抗晒的机制。我们报告说，耐晒细胞表现出细胞凋亡减少、细胞活力增加、活性氧产生增加和线粒体功能破坏。此外，长期 Sun 治疗导致 Sirt5/异柠檬酸脱氢酶 2 (IDH2) 表达水平上调。敲除 Sirt5/IDH2 会损害线粒体功能并部分减弱太阳抗性。最后，Sirt5 的上调通过调节 K413 的琥珀酰化增强了 IDH2 的表达，并促进了蛋白质的稳定性。总之，Sirt5/IDH2 的失调通过影响抗氧化能力部分促成了肾细胞癌细胞的耐晒性。