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7-Nicotinic Acetylcholine Receptors Affect Growth Regulation of Human Mesothelioma Cells

Role of Mitogen-Activated Protein Kinase Pathway

¹Department of Biology, University of Genoa, Genoa; ²Department of Oncogenesis, Unit of Experimental Oncology, National Institute for Research on Cancer Genoa, Genoa; ³Department of Surgical Science, Division of Thoracic Surgery, Catholic University, Rome; and ⁴Department of Integrated Methodologies, Unit of Thoracic Surgery, University of Genoa, Genoa, Italy

This study presents data suggesting that both human mesothelioma (cell lines and human mesothelioma biopsies) and human normal mesothelial cells express receptors for acetylcholine and that stimulation of these receptors by nicotine prompted cell growth via activation of nicotinic cholinergic receptors. Thus, these data demonstrate that: (a) human mesothelioma cells and human biopsies of mesothelioma as well as of normal pleural mesothelial cells express functionally -7 nicotinic acethlycholine receptors, evaluated by -bungarotoxin-FITC binding, receptor binding assay, Western blot, and reverse transcription-PCR; (b) choline acetyltransferase immunostaining is present in mesothelioma cells; (c) mesothelioma cell growth is modulated by the cholinergic system in which agonists (i.e., nicotine) has a proliferative effect, and antagonists (i.e., curare) has an inhibitory effect, evaluated by cell cloning, DNA synthesis and cell cycle; (d) nicotine induces Ca⁺² influx, evaluated by [⁴⁵Ca²⁺] uptake, and consequently activation of mitogen-activated protein kinase pathway (extracellular signal-regulated kinase and p90^RSK phosphorylation), evaluated by Western blot; and (e) apoptosis mechanisms in mesothelioma cells are under the control of the cholinergic system (nicotine antiapoptotic via induction of nuclear factor-B complexes and phosphorylation of Bad at Ser¹¹²; curare proapoptotic via G₀-G₁ arrest p21^waf-1 dependent but p53 independent). The involvement of the nonneuronal cholinergic system in mesothelioma appears reasonable and open up new therapeutic strategies.

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