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Interaction of SENP6 with PINK1 Promotes Temozolomide Resistance in Neuroglioma Cells via Inducing the Mitophagy

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Abstract

Temozolomide resistance is a major cause of recurrence and poor prognosis in neuroglioma. Recently, growing evidence has suggested that mitophagy is involved in drug resistance in various tumor types. However, the role and molecular mechanisms of mitophagy in temozolomide resistance in glioma remain unclear. In this study, mitophagy levels in temozolomide-resistant and -sensitive cell lines were evaluated. The mechanisms underlying the regulation of mitophagy were explored through RNA sequencing, and the roles of differentially expressed genes in mitophagy and temozolomide resistance were investigated. We found that mitophagy promotes temozolomide resistance in glioma. Specifically, small ubiquitin-like modifier specific protease 6 (SENP6) promoted temozolomide resistance in glioma by inducing mitophagy. Protein-protein interactions between SENP6 and the mitophagy executive protein PTEN-induced kinase 1 (PINK1) resulted in a reduction in small ubiquitin-like modifier 2 (SUMO2)ylation of PINK1, thereby enhancing mitophagy. Our study demonstrates that by inducing mitophagy, the interaction of SENP6 with PINK1 promotes temozolomide resistance in glioblastoma. Therefore, targeting SENP6 or directly regulating mitophagy could be a potential and novel therapeutic target for reversing temozolomide resistance in glioma.

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Funding

This work was supported by the Scientific Research Project of Hainan Health and Family Planning Industry (no. 18A200175), the Key Research and Development Projects of Sichuan Science and Technology (2022YFS0221, 2022YFS0074, 2022YFS0156 and 2022YFS0378), and the Sichuan Provincial People’s Hospital Hospital Young Talent Fund (2021QN08).

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Authors and Affiliations

  1. School of Medicine of University of Electronic Science and Technology of China, 611730, Chengdu, People’s Republic of China

    Y. W. Wang

  2. Department of Thoracic Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, 610031, Chengdu, People’s Republic of China

    K. G. Jia & Y. Y. Wang

  3. Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, 570100, Haikou, Hainan Province, People’s Republic of China

    H. J. Xing, C. S. Zeng, L. Chen, Q. J. Su & C. Chen

  4. Department of Pharmacy, The Second Affiliated Hospital of Hainan Medical University, 570100, Haikou, Hainan Province, People’s Republic of China

    Y. Pan

  5. Department of Oncology, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, Guangdong Province, People’s Republic of China

    W. T. Shen

  6. Department of Neurology, Danzhou People’s Hospital, Danzhou, 571700, Hainan Province, People’s Republic of China

    J. Chen

  7. Department of Assisted Reproductive Medicine, Sichuan Provincial Academy of Medical Sciences and Sichuan Provincial People’s Hospital, 611730, Chengdu, People’s Republic of China

    Q. Cao

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  1. Y. W. Wang
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  2. K. G. Jia
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  10. C. Chen
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  11. Q. Cao
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  12. Y. Y. Wang
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Contributions

Youyu Wang, Qi Cao and Cong Chen designed the study. Yawei Wang, Kegang Jia, Huaijie Xing, Yun Pan and Weitao Shen carried out the experiments and acquired the data. Yawei Wang, Kegang Jia, Chaosheng Zeng, Lin Chen and Qingjie Su conducted the data analysis. Youyu Wang, Qi Cao, Jing Chen and Cong Chen drafted and revised the manuscript.

Y.W. Wang, K.G. Jia, H.J. Xing—contributed equally to this work.

Corresponding authors

Correspondence to C. Chen, Q. Cao or Y. Y. Wang.

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COMPLIANCE WITH ETHICAL STANDARDS

The experimental protocol was performed according to the National Institutes of Health Guide for the Care and Use of Laboratory. Animal-related experiments were conducted in accordance with the Hainan Medical College Guidelines for the care and use of laboratory animals. Animal protocols were approved by Animal Ethics Committee of the Second Affiliated Hospital of Hainan Medical College at Haikou, Hainan province (No. LW2022032, issued on Febulary 1st, 2022).

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The authors declare that they have no conflicts of interest.

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Wang, Y.W., Jia, K.G., Xing, H.J. et al. Interaction of SENP6 with PINK1 Promotes Temozolomide Resistance in Neuroglioma Cells via Inducing the Mitophagy. Mol Biol 57, 1228–1238 (2023). https://doi.org/10.1134/S0026893324010175

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