4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors.
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 beta1- and beta2-selective antagonist, respectively. In addition, cell growth was stimulated by the nonselective adrenergic agonist, noradrenaline, and more effectively by the beta-selective agonist, isoproterenol. The second message cyclic AMP level for beta-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. Beta2-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 beta-adrenoceptors, preferentially beta2 receptors. Activation of the beta-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 beta-adrenoceptors in the development of colon cancer.
Wu
William K K
WK
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Wong
Helen P S
HP
Luo
Shi W
SW
Chan
Kevin
K
Huang
Fung Y
FY
Hui
Marco K C
MK
Lam
Emily K Y
EK
Shin
Vivian Y
VY
Ye
Yi N
YN
Yang
Ying H
YH
Cho
Chi H
CH
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D001262:Atenolol / Q000494:pharmacology; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004347:Drug Interactions; D019073:HT29 Cells; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008565:Membrane Proteins; D009602:Nitrosamines / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009638:Norepinephrine / Q000494:pharmacology; D010741:Phospholipases A / Q000096:biosynthesis / Q000235:genetics; D054467:Phospholipases A2; D011412:Propanolamines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects; D015854:Up-Regulation; D014026:Nicotiana
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002273:Carcinogens; D008565:Membrane Proteins; D009602:Nitrosamines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D012906:Smoke; C026777:ICI 118551; D001262:Atenolol; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone; D007545:Isoproterenol; D009638:Norepinephrine