Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells
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 chem...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-03-01
|
| Series: | FEBS Open Bio |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/2211-5463.13090 |
| _version_ | 1818414181882265600 |
|---|---|
| author | Liang Meng Deqiang Chen Gaopei Meng Li Lu Chenggang Han |
| author_facet | Liang Meng Deqiang Chen Gaopei Meng Li Lu Chenggang Han |
| author_sort | Liang Meng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T11:15:01Z |
| format | Article |
| id | doaj.art-8bb8b2ea531842aba6cbe9e6c553f430 |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-12-14T11:15:01Z |
| publishDate | 2021-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj.art-8bb8b2ea531842aba6cbe9e6c553f4302022-12-21T23:04:04ZengWileyFEBS Open Bio2211-54632021-03-0111392193110.1002/2211-5463.13090Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cellsLiang Meng0Deqiang Chen1Gaopei Meng2Li Lu3Chenggang Han4Department of Computer Tomography Cangzhou Central Hospital ChinaDepartment of Computer Tomography Cangzhou Central Hospital ChinaDepartment of Computer Tomography Cangzhou Central Hospital ChinaDepartment of Computer Tomography Cangzhou Central Hospital ChinaDepartment of Computer Tomography Cangzhou Central Hospital ChinaSunitinib (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.https://doi.org/10.1002/2211-5463.13090clear cell renal cell carcinomadesuccinylationisocitrate dehydrogenase 2Sirt5sunitinib |
| spellingShingle | Liang Meng Deqiang Chen Gaopei Meng Li Lu Chenggang Han Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells FEBS Open Bio clear cell renal cell carcinoma desuccinylation isocitrate dehydrogenase 2 Sirt5 sunitinib |
| title | Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells |
| title_full | Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells |
| title_fullStr | Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells |
| title_full_unstemmed | Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells |
| title_short | Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells |
| title_sort | dysregulation of the sirt5 idh2 axis contributes to sunitinib resistance in human renal cancer cells |
| topic | clear cell renal cell carcinoma desuccinylation isocitrate dehydrogenase 2 Sirt5 sunitinib |
| url | https://doi.org/10.1002/2211-5463.13090 |
| work_keys_str_mv | AT liangmeng dysregulationofthesirt5idh2axiscontributestosunitinibresistanceinhumanrenalcancercells AT deqiangchen dysregulationofthesirt5idh2axiscontributestosunitinibresistanceinhumanrenalcancercells AT gaopeimeng dysregulationofthesirt5idh2axiscontributestosunitinibresistanceinhumanrenalcancercells AT lilu dysregulationofthesirt5idh2axiscontributestosunitinibresistanceinhumanrenalcancercells AT chengganghan dysregulationofthesirt5idh2axiscontributestosunitinibresistanceinhumanrenalcancercells |