Cisplatin-induced pyroptosis is mediated via the CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME axis in esophageal cancer

Rong-Yao Li; Zhen-Yuan Zheng; Zhi-Mao Li; Jing-Hua Heng; Ya-Qi Zheng; Dan-Xia Deng; Xiu-E Xu; Lian-Di Liao; Wan Lin; Hong-Yao Xu; He-Cheng Huang; En-Min Li; Li-Yan Xu

doi:10.1016/j.cbi.2022.109967

Cisplatin-induced pyroptosis is mediated via the CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME axis in esophageal cancer

Chem Biol Interact. 2022 Jul 1:361:109967. doi: 10.1016/j.cbi.2022.109967. Epub 2022 May 5.

Authors

Rong-Yao Li¹, Zhen-Yuan Zheng², Zhi-Mao Li³, Jing-Hua Heng³, Ya-Qi Zheng³, Dan-Xia Deng³, Xiu-E Xu³, Lian-Di Liao³, Wan Lin⁴, Hong-Yao Xu⁵, He-Cheng Huang⁵, En-Min Li⁶, Li-Yan Xu⁷

Affiliations

¹ The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China.
² The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China.
³ Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, Guangdong, China.
⁴ Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China.
⁵ Department of Radiation Oncology, Shantou Central Hospital, Shantou, 515041, China.
⁶ The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China. Electronic address: nmli@stu.edu.cn.
⁷ Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Center, Shantou University Medical College, Shantou, 515041, Guangdong, China. Electronic address: lyxu@stu.edu.cn.

PMID: 35525317
DOI: 10.1016/j.cbi.2022.109967

Abstract

Esophageal cancer is the seventh most common cancer globally. Chemotherapy resistance remains a significant challenge in the treatment of esophageal cancer patients. Cisplatin can damage tumor cells by inducing pyroptosis. However, the underlying molecular mechanisms remain unclear. In this work, we aim to investigate pyroptosis-dependent molecular mechanisms underlying cisplatin sensitivity and find potential biomarkers to predict response to cisplatin-based chemotherapy for esophageal cancer patients. Pyroptosis-associated proteins were screened via proteomics for esophageal cancer (n = 124) and bioinformatics analysis. We observed that high calpain-1 (CAPN1) and calpain-2 (CAPN2) expression were associated with favorable clinical outcomes and prolonged survival in esophageal cancer patients. We employed immunohistochemistry to evaluate the expression of CAPN1 and CAPN2 in pretreatment tumor biopsies from 108 patients with esophageal cancer who received concurrent chemoradiotherapy (CCRT). These results suggested that esophageal cancer patients with high expression of both CAPN1 and CAPN2 are likely to experience a complete response to CCRT and have significantly better survival. Western blotting, LDH release, calpain activity and cell viability assays indicated that cisplatin could activate calpain activity, while calpain inhibition or knockout suppressed cisplatin-induced pyroptosis. Mechanistically, we uncovered a novel mechanism whereby cisplatin induced pyroptosis via activation of a CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME signaling axis in esophageal cancer cells. Collectively, this study is the first to explore the effects of calpain on cisplatin-induced pyroptosis in esophageal cancer cells. Further, our findings also imply that the combination of CAPN1 and CAPN2 could be considered as a promising biomarker of cisplatin sensitivity and prognosis in patients with esophageal cancer, providing a possibility to guide individualized treatment.

Keywords: CAPN1; CAPN2; Cisplatin sensitivity; Esophageal cancer; Prognostic model; Pyroptosis.

MeSH terms

Calpain / metabolism
Caspase 3 / metabolism
Caspase 9 / metabolism
Cisplatin* / metabolism
Cisplatin* / pharmacology
Cisplatin* / therapeutic use
Esophageal Neoplasms* / drug therapy
Esophageal Neoplasms* / metabolism
Humans
Pyroptosis
bcl-2-Associated X Protein / metabolism

Substances

bcl-2-Associated X Protein
Calpain
Caspase 3
Caspase 9
CAPN1 protein, human
CAPN2 protein, human
Cisplatin