STAT3β disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in
Zhen-Yuan Zheng1, Ping-Lian Yang2, Rong-Yao Li1
1The 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.
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.
Insights
Signal transducer and activator of transcription 3β (STAT3β) enhances cisplatin sensitivity in esophageal squamous cell carcinoma (ESCC) by promoting pyroptosis. High STAT3β expression correlates with better patient survival, offering prognostic value.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Mechanisms
Background:
- Cisplatin efficacy is limited in esophageal squamous cell carcinoma (ESCC).
- Signal transducer and activator of transcription 3β (STAT3β), a STAT3 splice variant, modulates STAT3α activity and chemosensitivity.
- The precise molecular mechanisms by which STAT3β influences ESCC chemosensitivity are not fully elucidated.
Purpose of the Study:
- To investigate the role of STAT3β in enhancing cisplatin sensitivity in ESCC.
- To elucidate the molecular mechanisms underlying STAT3β-mediated chemosensitization.
- To assess the clinical significance of STAT3β and Gasdermin E (GSDME) expression in ESCC patient outcomes.
Main Methods:
- Cellular and molecular biology techniques to study STAT3β localization and function.
- Assessment of mitochondrial electron transport chain activity and reactive oxygen species (ROS) production.
- Analysis of caspase-3 and GSDME activation, and pyroptosis induction.
- Correlation analysis of STAT3β and GSDME expression with clinical survival data in ESCC patients.
Main Results:
- High STAT3β expression enhances cisplatin sensitivity and promotes GSDME-dependent pyroptosis in ESCC cells.
- STAT3β localizes to mitochondria, disrupting the electron transport chain and increasing ROS levels upon cisplatin treatment.
- STAT3β inhibits STAT3α phosphorylation at S727 by interacting with ERK1/2, leading to GSDME activation and pyroptosis.
- Elevated STAT3β and GSDME expression is significantly associated with improved overall and disease-free survival in ESCC patients.
Conclusions:
- STAT3β sensitizes ESCC to cisplatin by disrupting mitochondrial function and inducing pyroptosis.
- The STAT3β/ERK1/2/STAT3α pathway is crucial for GSDME-mediated pyroptosis.
- STAT3β and GSDME serve as valuable prognostic biomarkers for ESCC therapy.
