Effects of tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on the activation of ERK1/2 MAP kinases and the proliferation of human mammary epithelial cells

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Cigarette smoking is a risk factor in the developing of various cancers including breast tumors. There are more than 60 chemical carcinogens in the cigarette smoke; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being one of the strongest tobacco-specific carcinogens. In this study, we demonstrated that NNK rapidly activated ERK1 and ERK2 MAP kinases and stimulated proliferation in human normal mammary epithelial cells. MEK1/2 specific inhibitor UO126 completely blocked NNK-induced ERK1/2 activation and cell proliferation, whereas nicotinic receptor nAchR antagonist mecamylamine partially and the selective α 7-nAchR antagonist α-bungarotoxin essentially inhibited the NNK-induced ERK1/2 activation and cell proliferation. Surprisingly, receptor tyrosine kinase inhibitor genistein, the selective β 1-adrenergic antagonist atenolol, and the selective β 2-adrenergic antagonist ICI118.551 had a strong inhibitory effect on ERK1/2 activation and cell proliferation induced by NNK. These results suggest that there are at least two different routes in activating ERK1/2 by NNK. One is through nicotinic receptor α 7-nAchR to MEK1/2; the other is from β 1/β 2-adrenergic transactivation of tyrosine kinase containing receptor(s) to MEK1/2. In human cancer mammary epithelial cell lines, we found that ERK MAPK signaling pathway was deregulated: (1) ERK1/2 was constitutively activated at various levels; (2) ERK1/2 was further significantly activated in response to NNK induction; (3) UO126 partially or totally failed to inhibit ERK1/2 activation induced by NNK; (4) The expression levels of ERK1/2 in the cancer cell lines were much higher than those in the normal mammary epithelial cells. The tobacco-specific carcinogen NNK showed a strong proliferative effect on human normal and cancer mammary epithelial cells; the proliferation multitudes of these cells are well correlated with the activation levels of ERK1/2 MAP kinases.