Nicotine-Mediated Cell Proliferation and Tumor Progression in Smoking-Related Cancers

Abstract

Tobacco smoke contains multiple classes of established carcinogens including benzo(a)pyrenes, polycyclic aromatic hydrocarbons, and tobacco specific nitrosamines. Most of these compounds exert their genotoxic effects by forming DNA adducts and generation of reactive oxygen species, causing mutations in vital genes like K-Ras and p53. In addition, tobacco specific nitrosamines can activate nicotinic acetylcholine receptors (nAChRs) and to a certain extent β-Adrenergic receptors (β-ARs), promoting cell proliferation. Further, it has been demonstrated that nicotine, the major addictive component of tobacco smoke, can induce cell cycle progression, angiogenesis, and metastasis of lung and pancreatic cancers. These effects occur mainly through the α7-nAChRs, with possible contribution from the β-ARs and/or epidermal growth factor receptors (EGFRs). This review article will discuss the molecular mechanisms by which nicotine and its oncogenic derivatives such as NNK (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNN (N-nitrosonornicotine) induce cell cycle progression and promote tumor growth. A variety of signaling cascades are induced by nicotine through nAChRs, including the MAPK/ERK pathway, PI3K/AKT pathway and JAK/STAT signaling. In addition, studies have shown that nAChR activation induces Src kinase in a β-arrestin-1 dependent manner, leading to the inactivation of Rb protein and resulting in the expression of E2F1-regulated proliferative genes. Such nAChR-mediated signaling events enhance the proliferation of cells and render them resistant to apoptosis induced by various agents. These observations highlight the role of nAChRs in promoting the growth and metastasis of tumors and raise the possibility of targeting them for cancer therapy.

Pathogenic mechanisms of lung adenocarcinoma in smokers and non-smokers determined by gene expression interrogation

“…Notably, all of these upregulated DEGs encode essential regulators that dictate cell cycle control and progression, indicating that smoking induces cell hyperproliferation that contributes to the pathogenesis of lung adenocarcinoma. Indeed, numerous previous studies have established a strong association between cigarette smoking and cell proliferation in various types of malignancies, including lung cancer (37)(38)(39)(40)(41)(42). The mitogenic effect is largely mediated by nicotine and its derivatives (the major components of cigarettes) through multiple distinct molecular mechanisms (39).…”

“…Indeed, numerous previous studies have established a strong association between cigarette smoking and cell proliferation in various types of malignancies, including lung cancer (37)(38)(39)(40)(41)(42). The mitogenic effect is largely mediated by nicotine and its derivatives (the major components of cigarettes) through multiple distinct molecular mechanisms (39). For example, it has been demonstrated that smoking induces production of oxygen radicals that cause generation of cleaved transmembrane amphiregulin, which is subsequently detected by EGFR, thereby resulting in aberrant proliferation of lung epithelial cells (37).…”

“…Their potent carcinogenic capability is primarily mediated by imposing genotoxic stress and damage in host cells. For example, formation of DNA adducts is frequently induced, which results in loss-of-function mutation in tumor suppressor genes, such as p53 (39,(45)(46)(47)(48). p53 is a well-established master regulator for the DNA repair response, cell cycle checkpoint and apoptosis, and numerous studies have implicated a long-standing association between the high incidence of its perturbed expression or function and the development of various types of cancer (49,50).…”

A Debate: Can We Recommend Electronic Cigarettes to Our Patients? Opinion 1

“…It is also a powerful neurotoxin. Additionally, it indirectly affects the growth of neoplasms because it negatively influences the p53 gene, which hinders uncontrollable development of neoplastic cells [24]. Therefore, harmful effect of nicotine smoke on health is incomparably greater than that of e-cigarette aerosol.…”

Impact of Smoking on Clinical Outcomes of Open Arthrolysis for Post-Traumatic Elbow Stiffness

“…Nowadays, hazards from smoking are one of the most serious public health problems in the world, which is closely related to tumors [6], cardiovascular disease [7], cerebrovascular diseases [8], respiratory diseases [9], and so on. 100 million people died from smoking in the 20th century, according to WHO in 2008, and one billion people in the 21st century are expected to die from tobacco use [10].…”