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Sirt5/IDH2 轴的失调导致人肾癌细胞对舒尼替尼产生耐药性。

Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells.

机构信息

Department of Computer Tomography, Cangzhou Central Hospital, China.

出版信息

FEBS Open Bio. 2021 Mar;11(3):921-931. doi: 10.1002/2211-5463.13090. Epub 2021 Feb 8.

DOI:10.1002/2211-5463.13090
PMID:33455080
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7931237/
Abstract

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.

摘要

舒尼替尼（Sunitinib，Sun）是一种血管内皮生长因子受体的酪氨酸激酶抑制剂，是治疗晚期透明细胞肾细胞癌（RCC）的标准一线治疗药物，但不可避免会产生耐药性。活性氧的产生与化疗敏感性有关，但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 Sun 耐药的机制。我们报告说，Sun 耐药细胞表现出凋亡减少、细胞活力增加、活性氧产生增加和线粒体功能紊乱。此外，慢性 Sun 处理导致 Sirt5/异柠檬酸脱氢酶 2（IDH2）表达水平上调。Sirt5/IDH2 的敲低会损害线粒体功能，并部分减弱 Sun 耐药性。最后，Sirt5 的上调通过调节 K413 的琥珀酰化来增强 IDH2 的表达，并促进蛋白质稳定性。总之，Sirt5/IDH2 的失调部分通过影响抗氧化能力导致 RCC 细胞对 Sun 的耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bfb/7931237/ddc2f1131c96/FEB4-11-921-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bfb/7931237/ddc2f1131c96/FEB4-11-921-g005.jpg

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