RGD Reference Report - Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling. - Rat Genome Database

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Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling.

Authors: Wang, Lu  Du, Liang  Xiong, Xiao  Lin, Yusheng  Zhu, Jianlin  Yao, Zhimeng  Wang, Shuhong  Guo, Yi  Chen, Yuping  Geary, Kyla  Pan, Yunlong  Zhou, Fuyou  Gao, Shegan  Zhang, Dianzheng  Yeung, Sai-Ching Jim  Zhang, Hao 
Citation: Wang L, etal., Oncogene. 2021 Mar;40(11):1974-1987. doi: 10.1038/s41388-021-01682-z. Epub 2021 Feb 18.
RGD ID: 151667905
Pubmed: PMID:33603170   (View Abstract at PubMed)
PMCID: PMC7979537   (View Article at PubMed Central)
DOI: DOI:10.1038/s41388-021-01682-z   (Journal Full-text)

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 of CHRNA7. 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
esophagus squamous cell carcinoma disease_progressionIEP 151667905 RGD 
esophagus squamous cell carcinoma exacerbatesIDA 151667905 RGD 
esophagus squamous cell carcinoma disease_progressionISOCHRNA7 (Homo sapiens)151667905; 151667905 RGD 
esophagus squamous cell carcinoma exacerbatesISOCHRNA7 (Homo sapiens)151667905; 151667905 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Chrna7  (cholinergic receptor nicotinic alpha 7 subunit)

Genes (Mus musculus)
Chrna7  (cholinergic receptor, nicotinic, alpha polypeptide 7)

Genes (Homo sapiens)
CHRNA7  (cholinergic receptor nicotinic alpha 7 subunit)


Additional Information