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

Abstract

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 B 1 -and B 2 -selective antagonist, respectively. In addition, cell growth was stimulated by the nonselective adrenergic agonist, noradrenaline, and more effectively by the B-selective agonist, isoproterenol. The second message cyclic AMP level for B-adrenoceptor activation was elevated by isoproterenol and NNK treatment. These agents also up-regulated cyclooxygenase-2 expression, cytosolic phospholipase A 2 expression, and prostaglandin E 2 release. B 2 -adrenoceptor blockade with ICI 118,551, in contrast, significantly decreased cyclooxygenase-2 expression, cytosolic phospholipase A 2 expression and prostaglandin E 2 release induced by NNK and isoproterenol. To conclude, it is proposed that NNK stimulates HT-29 cell proliferation through B-adrenoceptors, preferentially B 2 receptors. Activation of the B-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 B-adrenoceptors in the development of colon cancer. (Cancer Res 2005; 65(12): 5272-7)

β-arrestin2 mediates β-2 adrenergic receptor signaling inducing prostate cancer cell progression

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Nongenomic β Estrogen Receptors Enhance β1 Adrenergic Signaling Induced by the Nicotine-Derived Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Human Small Airway Epithelial Cells

“…25,26). Other reports have shown that NNK-induced h-adrenergic signaling was associated with cell survival and growth regulation in several other nonsmall-cell and small-cell lung cancer cell lines and in colon cancer cells (27,28).…”

β2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NF-κB and AP-1

“…4,5 β-adrenoceptors, which are members of the G-proteincoupled receptor (GPCR) superfamily, can regulate tumor proliferation and are involved in cancer development. [6][7][8][9] Recent studies have shown that cell lines derived from human pancreatic tumors express high levels of β 1 -and β 2 -adrenoceptors. 4,10 The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) resembles a β-adrenergic β 2 -adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFκB and AP-1 β 2 -adrenoceptors in human pancreatic cancer cell lines.…”