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4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone from Cigarette Smoke Stimulates Colon Cancer Growth via ß-Adrenoceptors

¹ Department of Pharmacology, Faculty of Medicine, The University of Hong Kong and ² School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China

Requests for reprints: Chi H. Cho, Department of Pharmacology, The University of Hong Kong, 21 Sassoon Road, Hong Kong, China. Phone: 852-2819-9250; Fax: 852-2817-0859; E-mail: chcho{at}hkusua.hku.hk.

Cigarette smoking is a risk factor for colorectal cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, the proliferative response of a cultured colon cancer cell line HT-29 to NNK was determined. It was found that NNK dose-dependently stimulated HT-29 cell proliferation. In this regard, the stimulatory action of NNK was abolished by atenolol and ICI 118,551, a ß₁- and ß₂-selective antagonist, respectively. In addition, cell growth was stimulated by the nonselective adrenergic agonist, noradrenaline, and more effectively by the ß-selective agonist, isoproterenol. The second message cyclic AMP level for ß-adrenoceptor activation was elevated by isoproterenol and NNK treatment. These agents also up-regulated cyclooxygenase-2 expression, cytosolic phospholipase A₂ expression, and prostaglandin E₂ release. ß₂-adrenoceptor blockade with ICI 118,551, in contrast, significantly decreased cyclooxygenase-2 expression, cytosolic phospholipase A₂ expression and prostaglandin E₂ release induced by NNK and isoproterenol. To conclude, it is proposed that NNK stimulates HT-29 cell proliferation through ß-adrenoceptors, preferentially ß₂ receptors. Activation of the ß-adrenoceptors, and the consequent cyclic AMP elevation coupled with the downstream arachidonic acid pathway, is perhaps an important mechanistic cascade in the promotion of colon cancer growth. These findings partly elucidate the carcinogenic actions of cigarette smoke and shed new light on the novel modulatory role of ß-adrenoceptors in the development of colon cancer.

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