Tan Xiangyu, Wang Xueqian, Liao Xueyao, Wang Xin, Jiang Zhichao, Liang Wenjia, Cao Chen, Gong Danni, Hu Zheng, Tian Xun
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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.
iScience. 2023 Jul 10;26(8):107315. doi: 10.1016/j.isci.2023.107315. eCollection 2023 Aug 18.
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.
顺铂耐药仍然是限制宫颈癌化疗疗效的主要障碍。然而，顺铂耐药的潜在机制仍不清楚。在本研究中，我们证明了液泡蛋白分选13同源物C（VPS13C）缺陷促进宫颈癌的顺铂耐药。此外，通过RNA测序筛选，发现VPS13C缺陷与谷胱甘肽S-转移酶pi基因（GSTP1）的高表达呈负相关。机制上，VPS13C的缺失通过影响GSTP1的表达并抑制下游c-Jun氨基末端激酶（JNK）途径导致顺铂耐药。此外，用抑制剂NBDHEX靶向GSTP1可有效挽救由VPS13C缺陷诱导的顺铂耐药。总体而言，我们的研究结果为VPS13C在顺铂耐药中的潜在机制提供了见解，并确定VPS13C是治疗宫颈癌化疗耐药的一个有前景的候选靶点。
