title: Mechanisms of growth-promoting and tumor-protecting effects of epithelial nicotinic acetylcholine receptors.
abstract: Although the role of nicotine as a carcinogen is debatable, it is widely accepted that it contributes to cancer by promoting growth and survival of mutated cell clones and protecting them from the chemo- and radiotherapy-induced apoptosis. On the cell membrane (cm), the nicotinic acetylcholine (ACh) receptors (nAChRs) implement upregulation of proliferative and survival genes. Nicotine also can permeate cells and activate mitochondrial (mt)-nAChRs coupled to inhibition of the mitochondrial permeability transition pore (mPTP) opening, thus preventing apoptosis. In this study, we sought to pin down principal mechanisms mediating the tumor-promoting activities of nicotine resulting from activation of cm- and mt-nAChRs in oral and lung cancer cells, SCC25 and SW900, respectively. Activated cm-nAChRs were found to form complexes with receptors for EGF and VEGEF via the α7 and β2 nAChR subunits, respectively, whereas activated mt-nAChRs physically associated with the intramitochondrial protein kinases PI3K and Src via the α7 and β4 subunits. This was associated with upregulated expression of cyclin D1/activation of ERK1/2 and inhibition of mPTP opening, respectively, as well as upregulated proliferation and resistance to H(2)O(2)-induced apoptosis. The molecular synergy between cm-nAChRs and growth factor receptors helps explain how one biological mediator, such as ACh, can modulate activity of the other, such as a growth factor, and vice versa. Establishment of functional coupling of mt-nAChRs to regulation of mPTP opening provides a novel mechanism of nicotine-dependent protection from cell death. Further elucidation of this novel mechanism of tumor-promoting activities of nicotine should have a strong translational impact, because extraneuronal nAChRs may provide a novel molecular target to prevent, reverse, or retard progression of both nicotine-related and unrelated cancers.
authors.affiliation: Department of Dermatology, University of California, Irvine, CA, USA.
authors.forename: Alex I
authors.initials: AI
authors.lastname: Chernyavsky
authors.affiliation: National Cancer Institute, Kiev, Ukraine.
authors.forename: Igor B
authors.initials: IB
authors.lastname: Shchepotin
authors.affiliation: Department of Dermatology, University of California, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, CA, USA; Cancer Center and Research Institute, University of California, Irvine, CA, USA. Electronic address: sgrando@uci.edu.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
mesh_terms: D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D009538:Nicotine / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D019061:src-Family Kinases
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009538:Nicotine; D019869:Phosphatidylinositol 3-Kinases; D012313:RNA; D017978:Receptors, Growth Factor; D011978:Receptors, Nicotinic; D019061:src-Family Kinases
keywords: Cytochrome c; EGF receptor; Head and neck squamous cell carcinoma cells; Intrinsic apoptosis; Lung carcinoma cells; Mitochondria; Nicotinic acetylcholine receptors; VEGF receptor