Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells.
Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anti-cancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis. While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC. These effects of nicotine occur at concentrations of 1 microM or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.
Heusch
W L
WL
Division of Surgical Oncology, Oregon Health Sciences University, Portland 97201-3098, USA.
Maneckjee
R
R
D017209:Apoptosis / Q000187:drug effects*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008691:Methadone / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D009538:Nicotine; D019950:Mitogen-Activated Protein Kinase 1; D008691:Methadone