Lung carcinoma signaling pathways activated by smoking

Abstract

Lung cancer is the leading cause of cancer death in men and women worldwide, with over a million deaths annually. Tobacco smoke is the major etiologic risk factor for lung cancer in current or previous smokers and has been strongly related to certain types of lung cancer, such as small cell lung carcinoma and squamous cell lung carcinoma. In recent years, there has been an increased incidence of lung adenocarcinoma. This change is strongly associated with changes in smoking behavior and cigarette design. Carcinogens present in tobacco products and their intermediate metabolites can activate multiple signaling pathways that contribute to lung cancer carcinogenesis. In this review, we summarize the smoking-activated signaling pathways involved in lung cancer.

Figure 1.. β-AR–mediated signaling pathways in lung cancers.

Binding of nicotine-derived nitrosoaminoketone (NNK) to β-adrenergic receptors (β-AR) on pulmonary epithelial cells results in cAMP/PKA activation. Protein kinase A (PKA) causes arachidonic acid (AA) release by activating phospholipase-A2, leading to increased DNA synthesis. Epidermal growth factor receptor (EGFR) and PI3K/Akt pathways may be activated as downstream of β-AR to promote cell proliferation and inhibit cell apoptosis.

Figure 2.. Subunit α7 of nicotinic acetylcholine receptors (α7 nAChR)-mediated signaling pathways in small cell lung cancers.

In fetal pulmonary neuroendocrine cells and small cell carcinoma cells, binding of NNK to α7 nAChR on the cell membrane results in Ca²⁺ influx and serotonin release, which activates protein kinase C (PKC) and the downstream Raf-1 mitogen–activated protein kinase/MAPK kinase cascade, leading to DNA synthesis and cell proliferation.

Figure 3.. nAChR-mediated signaling in lung squamous cell carcinomas and adenocarcinomas.

nAChR-mediated mitogen-activated protein kinase (MAPK) activation in squamous cell carcinoma and adenocarcinoma is mediated by the scaffolding protein β-arrestin, which binds to and recruits Src to the receptors and stimulates the Raf/MAPK pathway. MAPK activation functions with the PI3K/Akt and the EGFR/Raf/MAPK signaling pathways, both activated by Ca²⁺ influx through nAChRs, to induce phosphorylation and activation of transcription factors, further regulate downstream gene transcription and protein expression, provoke cell proliferation, anti-apoptosis, tumor invasion, and therapy resistance.