STAT3 beta disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma
STAT3 beta disrupted mitochondrial electron transport chain enhances chemosensitivity by inducing pyroptosis in esophageal squamous cell carcinoma
复制标题
STAT3β破坏线粒体电子传递链通过诱导食管鳞状细胞癌焦亡来增强化疗敏感性
DOI：
10.1016/j.canlet.2021.09.035
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发表时间：
2021
期刊：
影响因子：
9.7
通讯作者：
Xu Li-Yan
中科院分区：
文献类型：
--
作者：
Zheng Zhen-Yuan;Yang Ping-Lian;Li Rong-Yao;Liu Lu-Xin;Xu Xiu-E;Liao Lian-Di;Li Xiang;Chu Man-Yu;Peng Liu;Huang Qing-Feng;Heng Jing-Hua;Wang Shao-Hong;Wu Zhi-Yong;Chang Zhi-Jie;Li En-Min;Xu Li-Yan
顺铂治疗食管鳞状细胞癌（ESCC）的临床疗效不理想。信号转导子和转录激活子3β（STAT 3 β）是STAT 3的剪接变异体，可抑制STAT 3 α的活性，增强食管鳞癌的化疗敏感性。然而，潜在的分子机制仍然知之甚少。在此，我们发现STAT 3 β的高表达有助于顺铂敏感性，并增强暴露于顺铂后ESCC细胞中Gasdermin E（GSDME）依赖性的焦亡。从机制上讲，STAT 3 β位于线粒体中，其高表达破坏了电子传递链的活性，导致顺铂处理细胞中ROS的增加。而高浓度的ROS则可激活caspase-3和GSDME，诱导细胞凋亡。STAT 3 β通过与ERK 1/2相互作用，阻断线粒体内STAT 3 α S727的磷酸化，破坏电子传递链，诱导GSDME活化。在临床上，STAT 3 β和GSDME的高表达与ESCC患者更好的总生存期和无病生存期密切相关。总之，我们的研究揭示了STAT 3 β通过破坏线粒体电子传递链和增强细胞凋亡而使ESCC细胞对顺铂敏感，这证明了STAT 3 β在ESCC治疗中的预后意义。
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.