Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling.
Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling.
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通过直接靶向 CHRNA7 抑制 JAK2/STAT3/SOX2 信号传导，重新利用右美沙芬和二甲双胍治疗尼古丁诱导的癌症
DOI：
10.1038/s41388-021-01682-z
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Wang L;Du L;Xiong X;Lin Y;Zhu J;Yao Z;Wang S;Guo Y;Chen Y;Geary K;Pan Y;Zhou F;Gao S;Zhang D;Yeung SJ;Zhang H
吸烟是许多癌症类型中最具影响力的生活方式相关风险因素之一，包括食管鳞状细胞癌（ESCC）。作为烟草和电子烟的主要成分，尼古丁不仅是导致吸烟成瘾的原因，也是一种致癌物质。在这里，我们报告说，尼古丁增强食管鳞癌恶性肿瘤和肿瘤启动能力，通过与胆碱能受体烟碱α 7亚基（CHRNA 7），随后激活JAK 2/STAT 3信号通路。我们发现CHRNA 7异常表达可以作为ESCC患者的独立预后因素。在多种ESCC小鼠模型中，美沙芬和二甲双胍协同抑制尼古丁增强的癌症起始细胞（CIC）特性并抑制ESCC进展。从机制上讲，美沙芬非竞争性抑制尼古丁与CHRNA 7的结合，而二甲双胍通过拮抗尼古丁诱导的CHRNA 7启动子DNA低甲基化下调CHRNA 7表达。由于美沙芬和二甲双胍是FDA批准的两种安全药物，不良副作用最小，因此这些药物的组合具有很高的潜力，可作为尼古丁促进的ESCC以及其他尼古丁敏感性癌症类型的预防和/或治疗策略。
Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation ofCHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.
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二甲双胍通过下调 Stat3 信号促进食管鳞状细胞癌自噬和凋亡
影响因子：
9
作者：
通讯作者：
--
影响因子：
29.4
作者：
Nimmakayala RK;Seshacharyulu P;Lakshmanan I;Rachagani S;Chugh S;Karmakar S;Rauth S;Vengoji R;Atri P;Talmon GA;Lele SM;Smith LM;Thapa I;Bastola D;Ouellette MM;Batra SK;Ponnusamy MP
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Ponnusamy MP
影响因子：
2.2
作者：
Martin, Elodie;Morel, Veronique;Pickering, Gisele
通讯作者：
Pickering, Gisele
影响因子：
8.8
作者：
Sang, CN;Booher, S;Max, MB
通讯作者：
Max, MB
影响因子：
120.7
作者：
Cummings, Jeffrey L.;Lyketsos, Constantine G.;Siffert, Joao
通讯作者：
Siffert, Joao