Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling.
Oncogene
; 40(11): 1974-1987, 2021 03.
Article
in En
| MEDLINE
| ID: mdl-33603170
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
STAT3 Transcription Factor
/
Janus Kinase 2
/
SOXB1 Transcription Factors
/
Alpha7 Nicotinic Acetylcholine Receptor
/
Esophageal Squamous Cell Carcinoma
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Oncogene
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2021
Document type:
Article
Affiliation country:
China