α7 nicotinic acetylcholine receptors in lung cancer (Review)

Abstract

Abstract. Lung cancer has one of the highest mortality rates among malignancies globally, and smoking has been documented as the main cause of lung cancer. Nicotinic acetylcholine receptors (nAChRs) were initially identified as notable regulators of the nervous system. In addition to their function in the brain, accumulating evidence indicates that nAChRs perform a host of diverse functions in almost all non-neuronal mammalian cells. The homomeric α7nAChR, a subtype of nAChRs, is responsible for the proliferative, pro-angiogenic and pro-metastatic effects of nicotine in lung cancer. Provided the association of cigarette smoking with several disease types such as cardiovascular disease, the α7nAChR-mediated signaling pathway has been implicated in the pathophysiology of lung cancer. Currently, strategies that target the α7nAChR including α7nAChR antagonists are considered to be potentially useful anticancer drugs for therapeutic purposes. Thus, the present review assesses current understanding of the function and underlying molecular mechanisms of α7nAChR in lung cancer and evaluates how targeting α7nAChR may result in novel therapeutic methods. IntroductionLung cancer is one of the most commonly occurring carcinoma types globally and has limited treatment options for advanced-stage disease (1). Lung cancer is a heterogeneous disease comprised of two main pathological types: Non-small-cell lung cancer (NSCLC) which accounts for 70-80% of all lung cancer cases and small-cell lung cancer (SCLC) which accounts for ~20% of all lung cancer cases (2). NSCLCs may be divided into three subtypes: Squamous-cell carcinoma (25-30% of all lung cancer cases), adenocarcinoma (~40% of all lung cancer cases) and large-cell carcinoma (10-15% of all lung cancer cases) (3). SCLC is the second most prevalent form of lung cancer, with a 5-year survival rate of <7% (4). Cigarette smoking is considered to be the main risk factor for lung cancer, and ~90% of all cases are associated with exposure to smoking and second-hand smoking (5). Other contributory factors include residential radon, occupational hazards including exposure to asbestos, arsenic and polycyclic aromatic hydrocarbons, radiation, coal smoke, indoor emission of fuel burning, outdoor pollution, previous non-malignant lung diseases in addition to a family history of tumors (6,7). Squamous-cell, large-cell and SCLC are the most commonly identified types of lung cancer present in smokers (8,9). In contrast, adenocarcinoma is the lung cancer type most commonly identified in non-smokers (10).Cigarette smoke is a mixture of thousands of chemical compounds, a number of which have potent carcinogenic potential including polycyclic aromatic hydrocarbons, nicotine and the nicotine-derived nitrosamines 4-(methylnitrosamino)-1-(3-pyrydyl)-1-butanone (NNK) and N-nitrosonornicotine (11). The most harmful and addictive component is nicotine (11). These carcinogens and their metabolites may induce the formation of DNA adducts which result in mutations of a number of key cancer suppressor...

Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System

“…Lung cancer cells endogenously express α7 nAChR, and their activation on these cells leads to stimulation of proliferation [29]. Because acylcholines demonstrated the ability to inhibit nAChR, we hypothesized that they could inhibit proliferation of a lung cancer cell line A549.…”

Emerging Role of Lymphocyte Antigen-6 Family of Genes in Cancer and Immune Cells

“…In colorectal cancer, the activation of α7nAChR in tumor macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway (64). α7nAChR has been considered an important drug target for the inhibition of lung cancer (65). On a cautionary note, α7nAChR is such an important neurotransmitter receptor in the CNS and muscle, that targeting nicotinic signaling directly via α7nAChR may cause multiple unwanted side effects.…”

Nicotinic-nAChR signaling mediates drug resistance in lung cancer

“…Genome-wide association studies have indicated a strong link between nicotine/nAChRs and lung cancer risk [34,38]. Nicotine might lead to suppressed apoptosis and cisplatin resistance via α5nAChR/AKT signaling [112].…”

“…Targeting nAChRs signaling pathways can significantly attenuate nicotine-associated drug resistance. Several α7nAChR antagonists are potential anticancer drugs [38]. Collectively, studies have suggested that nAChR-induced antiapoptotic effects may play notable roles in drug resistance in lung cancer.…”

“…Activation of nicotine-nAChR signaling promotes cancer progression [18]. Upregulation of α7nAChR in lung cancer cells involved in the nicotine-induced tumor progression [38]. Homomeric α7nAChR was implicated as the primary receptor facilitating nicotine-and NNK-mediated cell proliferation [21].…”