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.
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