Anti-tumorigenic effects of small cholinergic peptides of the ly6 protein family
Sergei A. Grando Cancer Center and Research Institute, University of California, Irvine, USA
Abstract:
Tobacco users have an increased risk for developing lung and oral cancer. The complex process of tobacco-induced tumorigenesis includes both carcinogenic and tumor promoting effects of smoke constituents. Recent studies have established an important role for the nicotinic class of acetylcholine receptors (nAChRs), expressed by respiratory and oral epithelial cells in the malignant transformation caused by pharmacologic doses of tobacco-derived carcinogenic nitrosamines 4-(methylnitrosamino)-1-(3–pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). Radioligand binding experiments and cell function assays showed that a7 nAChR predominantly mediates the effect of NNK and non-a7 nAChR—that of NNN. Nicotine and its carcinogenic derivatives can also contribute to the development of cancer by acting as tumor promoters that facilitate the outgrowth of cells with genetic damage. Therefore, pulmonary and oral nAChRs, a7 in particular, provide a novel molecular target to prevent, reverse, or retard progression tobacco-related cancer. The goal of our research is to develop novel anti-cancer therapies using canonical and non-canonical ligands of epithelial nAChRs. A novel paradigm of cell regulation via nAChRs has been discovered in studies of the cholinergic proteins termed secreted mammalian Ly-6/urokinase plasminogen activator receptor-related proteins (SLURP)-1 and -2 that bind to predominantly a7 and non-a7 nAChRs, respectively. In preliminary studies, the anti-tumorigenic activities of SLURP-1 and -2 were demonstrated both in vitro and in vivo. SLURPs could abolish, in part, the abilities of NNK and NNN to cause tumorigenic transformation of immortalized bronchial and oral epithelial cells, and reduce by 3-fold the number of NNK-induced lung tumors in A/J mice. Furthermore, the NNK-transformed cells were highly sensitive to the SLURP-1 induced apoptosis. Transfection with either SLURP-1 or -2 cDNA in both cases diminished the number of colonies produced by NNK exposed cells. These results suggested that SLURP-like proteins may become useful for developing novel anti-cancer therapies. To elucidate the nAChR-mediated mechanism of anti-tumorigenic action of SLURP-1, we measured the effects of functional inactivation of a3 and a7 nAChRs by RNA interference on the ability of SLURP-1 to inhibit NNK-induced malignant transformation of Het-1A and BEP2D cells. Both NNK and SLURP-1 exhibited most of their pro- and anti-tumorigenic effects, respectively, by acting on the a7 nAChR subtype. Thus, the existence of a non-neuronal cholinergic auto/paracrine regulatory system in the aerodigestive epithelium provides a basis for understanding the mechanism of tobacco-related lung and oral cancers and identification of new targets for potential therapeutic intervention.
