CST1 Promotes Chemoresistance in Esophageal Squamous Cell Carcinoma Cells by Inducing Mitophagy

Min Hou, Long Cheng, Qing-mei Huang, Hong-mei Zhan, Ting-ting Jia, Jing Wen, Jing Lei, Ya-kun Zhang, Yan Gui

Article ID: 7436
Vol 37, Issue 7, 2023
DOI: https://doi.org/10.23812/j.biol.regul.homeost.agents.20233707.381
Received: 8 August 2023; Accepted: 8 August 2023; Available online: 8 August 2023; Issue release: 8 August 2023

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is the main type of esophageal cancer. Due to the limited diagnosis and treatment for advanced ESCC, the mortality rate is high. Studies have shown that cystatin SN (CST1, cysteine proteinase inhibitor 1) plays an important role in the development of many cancers, but its role in ESCC remains unclear. The purpose of this study was to investigate the expression and clinical value of CST1 in ESCC, and the influence of CST1 on the development and drug resistance of ESCC. Methods: Cancer tissues (ESCC group) and adjacent normal esophageal epithelial tissues (normal group) was collected from patients with ESCC. Based on the sensitivity of patients to cisplatin (also known as DDP, cis-Diamminedichloroplatinum(II)), ESCC tissues were divided into the sensitive group and resistance group. Subsequently, the expression of CST1 in different tissue group was observed by quantitative real-time polymerase chain reaction (qRT-PCR). Cisplatin-resistant ESCC cells (EC9706/DDP cells) were established by continuous exposure to cisplatin in vitro. Next, knockdown (si-CST1) or over-expression (CST1) was carried out in EC9706/DDP cells. Besides, a mitophagy inhibitor (Mdivi-1) was employed to treat EC9706/DDP cells. Later, qRT-PCR was conducted to observe the efficiency of over-expression or knockdown of CST1. Colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were responsible to examining the proliferation ability of EC9706/DDP cells, and western blot to test the expression of mitophagy inhibitor-related proteins. Results: Compared to the normal group, CST1 expression was significantly up-regulated in ESCC tissues (p < 0.01). Also, the resistance group exhibited notably increased CST1 expression relative to that in the sensitive group (p < 0.01). MTT results indicated successful establishment of cisplatin-resistant EC9706 cells. Over-expression of CST1 not only remarkably up-regulated the proliferation ability and drug resistance in EC9706/DDP cells (p < 0.01), but also activated mitophagy (p < 0.01). However, knocking down CST1 showed the opposite result. In addition, over-expression of CST1 could reverse the effect of Mdivi-1. Conclusion: CST1 is significantly highly expressed in ESCC patients developing resistance to cisplatin. Additionally, CST1 can increase chemoresistance in EC9706 cells through inducing mitophagy.


Keywords

esophageal squamous cell carcinoma (ESCC);chemoresistance;mitophagy;cystatin SN


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