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  3. STAT3β disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma

STAT3β disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma

  • Cancer Lett. 2021 Dec 1;522:171-183. doi: 10.1016/j.canlet.2021.09.035.
Zhen-Yuan Zheng 1,  Ping-Lian Yang 2,  Rong-Yao Li 1,  Lu-Xin Liu 1,  Xiu-E Xu 2,  Lian-Di Liao 2,  Xiang Li 2,  Man-Yu Chu 2,  Liu Peng 1,  Qing-Feng Huang 2,  Jing-Hua Heng 2,  Shao-Hong Wang 3,  Zhi-Yong Wu 3,  Zhi-Jie Chang 4,  En-Min Li 5,  Li-Yan Xu 6
Affiliations

Affiliations

  • 1 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, 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, 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 University Medical College, Shantou, 515041, Guangdong, China.
  • 3 Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, 515041, Guangdong, China.
  • 4 School of Medicine, Tsinghua University, Beijing, China.
  • 5 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China. Electronic address: [email protected].
  • 6 The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, 515041, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, 515041, Guangdong, China. Electronic address: [email protected].
PMID: 34571081 DOI: 10.1016/j.canlet.2021.09.035
Abstract

The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3β (STAT3β), a splice variant of STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3β contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent Pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3β was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of Caspase-3 and GSDME, and induced cell Pyroptosis. STAT3β blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3β and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3β sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing Pyroptosis, which demonstrates the prognostic significance of STAT3β in ESCC therapy.

Keywords

Chemosensitivity; Esophageal squamous cell carcinoma; Mitochondria; Pyroptosis; STAT3β.

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  • HY-D0985A
    98.70%, Mitochondrial Membrane Potential Fluorescent Dye