Oral cancer cells secrete stress neurotransmitter and proliferate in response to tobacco carcinogen NNK through a cellular adrenergic pathway.

Abstract

Abstract Although there is a growing body of evidence showing the effects of stress-related catecholamines on oral cancer progression, to date there are no studies that have investigated whether oral squamous cells carcinoma (OSCC)-cells are capable of producing these hormones and whether this phenomenon is modulated by tobacco-related nitrosamines. In this study we investigated whether keratinocytes (HaCaT) and OSCC-derived cell lines (SSC9 and SCC25) are able to secrete the neurotransmitter norepinephrine (NE) as also the effects of the tobacco carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on the NE secretion and OSCC proliferation. Supernatant from the HaCaT, SCC9, and SCC25 cells showed higher NE levels (6-, 14.9- and 15.1-fold more, respectively) compared to culture media without cells. When the cells were stimulated with NNK, a tobacco-specific carcinogen, there were increases in the levels of NE secretion by HaCaT and SCC25 cells, but not by SCC9 cells. NNK (10 µM) induced cell proliferation in the HaCaT, SCC9, and SCC25 cell lines and these effects were totally inhibited by blocking β-adrenergic receptors with propranolol. The NNK-induced OSCC cell proliferation was further dependent on nicotinic acetylcholine receptors α4 (nAChR-α4) activation (totally in SCC9 cells and partially in SCC25 cells), but not dependent on nAChR-α7 activation. Inhibition of the β-adrenergic receptors, nAChR-α4 and nAChR-α7 did not block NNK-induced HaCaT proliferation. Our findings suggest that oral cancer cells secrete the neurotransmitter norepinephrine and the tobacco nitrosamine NNK promotes increased cell proliferation through a stress-related cellular adrenergic pathway.