Nicotine-induced Activation of Cholinergic Receptor Nicotinic Alpha 5 Subunit Mediates the Malignant Behaviours of Laryngeal Squamous Epithelial Cells by Interacting with RABL6

Overview

Journal Cell Death Discov

Date 2024 Jun 15

PMID 38879667

Authors

Yujie Shen

Qiang Huang

Xiaohui Yuan

Hongli Gong

Chengzhi Xu

Huaidong Du

Chi-Yao Hsueh

Liang Zhou

Affiliations

Soon will be listed here.

Abstract

Nicotine, a crucial constituent of tobacco smoke, can bind to and activate nicotinic acetylcholine receptors (nAChRs), thereby regulating various biological functions. However, the specific mechanisms through which nicotine mediates nAChRs to regulate the metastasis of laryngeal squamous cell carcinoma (LSCC) remain elusive. In this study, smoking status was found to be closely associated with metastasis in patients with LSCC. In addition, nicotine exposure potentiated the hematogenous and lymphatic metastatic capacity of LSCC cells. Nicotine activates membrane-bound CHRNA5, promoting cell migration and invasion, EMT and cell-ECM adhesion in LSCC. Furthermore, this study demonstrated that the Ras superfamily protein RABL6 directly interacted with CHRNA5, which preferentially binds to the RABL6-39-279aa region, and this interaction was enhanced by nicotine. Nicotine-mediated activation of CHRNA5 enhanced its interaction with RABL6, triggering the JAK2/STAT3 signalling pathway and eventually augmenting the metastatic potential of LSCC cells. This study reveals a novel mechanism through which nicotine-mediated CHRNA5-RABL6 interaction promotes the metastasis of LSCC. The findings of this study may help to develop effective strategies for improving the outcome of patients with LSCC in clinical settings.

Citing Articles

Selective degradation-inducing probes for studying cereblon (CRBN) biology.

Powell C, Du G, Bushman J, He Z, Zhang T, Fischer E RSC Med Chem. 2021; 12(8):1381-1390.

PMID: 34458741 PMC: 8372211. DOI: 10.1039/d0md00382d.

References

Jethwa A, Khariwala S . Tobacco-related carcinogenesis in head and neck cancer. Cancer Metastasis Rev. 2017; 36(3):411-423. PMC: 5709040. DOI: 10.1007/s10555-017-9689-6. View

Jia L, Song Q, Zhou C, Li X, Pi L, Ma X . Dihydroartemisinin as a Putative STAT3 Inhibitor, Suppresses the Growth of Head and Neck Squamous Cell Carcinoma by Targeting Jak2/STAT3 Signaling. PLoS One. 2016; 11(1):e0147157. PMC: 4718674. DOI: 10.1371/journal.pone.0147157. View

Lian S, Li S, Zhu J, Xia Y, Do Jung Y . Nicotine stimulates IL-8 expression via ROS/NF-κB and ROS/MAPK/AP-1 axis in human gastric cancer cells. Toxicology. 2021; 466:153062. DOI: 10.1016/j.tox.2021.153062. View

Lin C, Lee H, Kuei C, Lin H, Lu L, Lee F . Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma. J Clin Med. 2019; 8(9). PMC: 6780171. DOI: 10.3390/jcm8091454. View

Feng Y, Yan S, Huang Y, Huang Q, Wang F, Lei Y . High expression of RABL6 promotes cell proliferation and predicts poor prognosis in esophageal squamous cell carcinoma. BMC Cancer. 2020; 20(1):602. PMC: 7325041. DOI: 10.1186/s12885-020-07068-w. View

Ayele T, Muche Z, Teklemariam A, Kassie A, Abebe E . Role of JAK2/STAT3 Signaling Pathway in the Tumorigenesis, Chemotherapy Resistance, and Treatment of Solid Tumors: A Systemic Review. J Inflamm Res. 2022; 15:1349-1364. PMC: 8887966. DOI: 10.2147/JIR.S353489. View

Hecht S, Hatsukami D . Smokeless tobacco and cigarette smoking: chemical mechanisms and cancer prevention. Nat Rev Cancer. 2022; 22(3):143-155. PMC: 9308447. DOI: 10.1038/s41568-021-00423-4. View

Wu C, Zhou L, Gong H, Du H, Tian J, Sun S . Establishment and characterization of a novel HPV-negative laryngeal squamous cell carcinoma cell line, FD-LSC-1, with missense and nonsense mutations of TP53 in the DNA-binding domain. Cancer Lett. 2013; 342(1):92-103. DOI: 10.1016/j.canlet.2013.08.041. View

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

10.

Russo P, Cardinale A, Margaritora S, Cesario A . Nicotinic receptor and tobacco-related cancer. Life Sci. 2012; 91(21-22):1087-92. DOI: 10.1016/j.lfs.2012.05.003. View

11.

Wittenberg R, Wolfman S, De Biasi M, Dani J . Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction. Neuropharmacology. 2020; 177:108256. PMC: 7554201. DOI: 10.1016/j.neuropharm.2020.108256. View

12.

Umesalma S, Kaemmer C, Kohlmeyer J, Letney B, Schab A, Reilly J . RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth. J Clin Invest. 2019; 129(4):1641-1653. PMC: 6436899. DOI: 10.1172/JCI123049. View

13.

Dang N, Meng X, Qin G, An Y, Zhang Q, Cheng X . α5-nAChR modulates melanoma growth through the Notch1 signaling pathway. J Cell Physiol. 2020; 235(11):7816-7826. DOI: 10.1002/jcp.29435. View

14.

Fu Y, Ci H, Du W, Dong Q, Jia H . CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity. Pharmaceutics. 2022; 14(2). PMC: 8877699. DOI: 10.3390/pharmaceutics14020275. View

15.

Xu P, Xu X, Wu X, Zhang L, Meng L, Chen Z . CircTMC5 promotes gastric cancer progression and metastasis by targeting miR-361-3p/RABL6. Gastric Cancer. 2021; 25(1):64-82. DOI: 10.1007/s10120-021-01220-6. View

16.

Hurst R, Rollema H, Bertrand D . Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol Ther. 2012; 137(1):22-54. DOI: 10.1016/j.pharmthera.2012.08.012. View

17.

Qi J, Xue W, Zhang Y, Qu C, Lu B, Yin Y . Cholinergic α5 nicotinic receptor is involved in the proliferation and invasion of human prostate cancer cells. Oncol Rep. 2019; 43(1):159-168. PMC: 6908936. DOI: 10.3892/or.2019.7411. View

18.

Chow L . Head and Neck Cancer. N Engl J Med. 2020; 382(1):60-72. DOI: 10.1056/NEJMra1715715. View

19.

Zhang H, Zhang G, Zhang J, Xiao M, Cui S, Wu S . Transcription factor SP1 and oncoprotein PPP1R13L regulate nicotine-induced epithelial-mesenchymal transition in lung adenocarcinoma via a feedback loop. Biochem Pharmacol. 2022; 206:115344. DOI: 10.1016/j.bcp.2022.115344. View

20.

Tyagi A, Wu S, Sharma S, Wu K, Zhao D, Deshpande R . Exosomal miR-4466 from nicotine-activated neutrophils promotes tumor cell stemness and metabolism in lung cancer metastasis. Oncogene. 2022; 41(22):3079-3092. PMC: 9135627. DOI: 10.1038/s41388-022-02322-w. View