title: 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.
abstract: 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.
authors.affiliation: College of Life Science, Jilin Univercity, Chang Chun 130023, PR China; College of Life Science and Engineering, Qiqihar Univercity, Qiqihar 161000, PR China.
authors.forename: Zhi-Bo
authors.initials: ZB
authors.lastname: Chen
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Feng-Qing
authors.initials: FQ
authors.lastname: Chen
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Li
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liang
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Liu