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

Lu Wang,Yuping Chen,Zhimeng Yao,Yusheng Lin,Yi Guo,Liang Du,Hao Zhang,Shuhong Wang,Jianlin Zhu,Fuyou Zhou,Kyla Geary,Sai-Ching Jim Yeung,Shegan Gao,Xiao Xiong,Yunlong Pan,Dianzheng Zhang

doi:10.1038/s41388-021-01682-z

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.

Highlights

To determine if nicotine played any role in tumors other than lung cancer, we first conducted gene set enrichment analysis (GSEA) and revealed that in human esophageal squamous cell carcinoma (ESCC) the cancer-initiating cells (CIC) signature was highly correlated with cigarette smoking (Fig. 1a)
Since it has been reported that metformin is capable of increasing DNA hypermethylation [25,26,27] and we have previously demonstrated that metformin possesses antineoplastic property toward ESCC [21, 28, 29], we decided to explore (1) if metformin can inhibit nicotine-induced CIC traits, (2) whether nicotine upregulates cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) in ESCC cells by altering promoter DNA methylation of CHRNA7 gene, and if so, (3) whether metformin can downregulate CHRNA7 by counteracting nicotinemediated hypomethylation
Our studies reveal that CHRNA7, a nicotine-enhanced receptor, confers high oncogenic potential by inducing CIC properties and serves as a predictor of poor prognostic in ESCC

Summary

Introduction

10 Department of Emergency Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting. Both tobacco consumption and nicotine-based e-cigarettes [1,2,3]. CHRNA7 and CHRNA9 have been reported to be capable of inducing cancer stem cell-like cells (CSC) or cancer-initiating cells (CIC) [16,17,18]. Targeting these nAChRs could potentially inhibit nicotine-induced tumor initiation

Methods

Results

Conclusion