Downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1

Xiangyu Tan; Xueqian Wang; Xueyao Liao; Xin Wang; Zhichao Jiang; Wenjia Liang; Chen Cao; Danni Gong; Zheng Hu; Xun Tian

doi:10.1016/j.isci.2023.107315

Downregulation of VPS13C promotes cisplatin resistance in cervical cancer by upregulating GSTP1

iScience. 2023 Jul 10;26(8):107315. doi: 10.1016/j.isci.2023.107315. eCollection 2023 Aug 18.

Authors

Xiangyu Tan^{1

2}, Xueqian Wang^{1

2}, Xueyao Liao³, Xin Wang^{1

2}, Zhichao Jiang³, Wenjia Liang³, Chen Cao³, Danni Gong³, Zheng Hu^{4

5

6

7}, Xun Tian^{1

3

2}

Affiliations

¹ Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
² National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430110, China.
³ Department of Obstetrics and Gynecology, Academician Expert Workstation, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China.
⁴ Department of Gynecologic Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
⁵ Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071 Hubei, China.
⁶ Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan 430071 Hubei, China.
⁷ Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071 Hubei, China.

Abstract

Cisplatin resistance remains a major obstacle limiting the effectiveness of chemotherapy in cervical cancer. However, the underlying mechanism of cisplatin resistance is still unclear. In this study, we demonstrate that vacuolar protein sorting 13 homolog C (VPS13C) deficiency promotes cisplatin resistance in cervical cancer. Moreover, through an RNA sequencing screen, VPS13C deficiency was identified as negatively correlated with the high expression of glutathione S-transferase pi gene (GSTP1). Mechanistically, loss of VPS13C contributes to cisplatin resistance by influencing the expression of GSTP1 and inhibiting the downstream c-Jun N-terminal kinase (JNK) pathway. In addition, targeting GSTP1 with the inhibitor NBDHEX effectively rescued the cisplatin resistance induced by VPS13C deficiency. Overall, our findings provide insights into the underlying mechanisms of VPS13C in cisplatin resistance and identify VPS13C as a promising candidate for the treatment of chemoresistance in cervical cancer.

Keywords: Cancer; Molecular biology; Transcriptomics.