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Review Article

Novel Pathways and Mechanisms of Nicotine-Induced Oral Carcinogenesis

Author(s): Mohit Sharma , Smitha S. Shetty and Raghu A. Radhakrishnan *

Volume 17, Issue 1, 2022

Published on: 06 August, 2021

Page: [66 - 79] Pages: 14

DOI: 10.2174/1574892816666210806161312

Price: $65

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Abstract

Background: Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine- derived Nitrosamines (NDNs).

Methods: A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis.

Results: Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade, promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR.

Conclusion: Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.

Keywords: Oral cancer, carcinogen, nicotine, nitrosamines, smokeless, tobacco.

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