Novel Pathways and Mechanisms of Nicotine-Induced Oral Carcino-genesis

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 alpha 4132nAChR and alpha 7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to alpha 7nAChR 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 alpha 7nAChR and desensitizes cancer inhibitory alpha 4132nAChR. 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.

Automated summary

Nicotine and nicotine-derived Nitrosamines (NDNs) enhance carcinogenic effects by acting on nicotinic Acetylcholine Receptors (nAChRs), promoting proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Prolonged exposure to nicotine/NDN increases cancer-stimulatory alpha 7nAChR and decreases cancer inhibitory alpha 4 beta 2nAChR expression.