Colon cancer is a leading cause of cancer deaths worldwide. Cigarette smoking is one of the environmental risk factors for colon cancer. Cigarette smoking is related to adenomatous colon polyps, which are the precursor to colon cancer. Nicotine is a major component in tobacco smoke which mediates the biochemical and pharmacological effects of cigarette smoking. It has also been implicated as playing a significant role in carcinogenesis. The constitutive expressions of β-adrenoceptors on different colon cancer cells, which are the prerequisite for adrenergic modulation of cellular activities, support the notion for the involvement of β-adrenoceptors in tumorigenesis. Catecholamines have also been shown to play a direct role in tumor progression but their biological effects on colon cancer are undefined. We investigated the involvement of catecholamine-synthesizing enzymes and adrenaline in colon cancer growth and also its interaction with nicotine both in vitro and in vivo. Results showed that catecholamine-synthesizing enzymes, namely tyrosine hydroxylase (TH), aromatic-L-amino acid decarboxylase, dopamine-β-hydroxylase and phenylethanolamine-N-methyltransferase were expressed in cultured colon cancer cells (HT-29 and SW1116). Inhibition of TH reduced adrenaline release concomitant with inhibition of cell proliferation of HT-29 cells. β2-selective antagonist ICI 118, 551 not only inhibited the basal cell proliferation but also abolished the stimulatory action of adrenaline on cell growth. In the colon cancer xenograft model, HT-29 cells were implanted subcutaneously into the right flank of athymic nude mice. Mice were randomized to different treatment groups that received either tap water or nicotine in their drinking water. Tumor volume was measured. The concentrations of adrenaline and cotinine in plasma were determined by enzyme immunoassays. The expression of β-adrenoceptors was detected by reverse transcription-polymerase chain reaction. Results showed that nicotine treatment in drinking water did not affect the body weight and drinking solution consumption. However it promoted tumor growth when compared to the control group drinking tap water. Oral nicotine administration resulted in dose-dependent elevations of adrenaline and cotinine levels in plasma. Nicotine also increased β1- and β2-adrenoceptors expression in the tumors. β2-selective antagonist blocked the stimulatory action of nicotine dose-dependently on tumor growth. In connection with this animal study, β-adrenoceptors and catecholamine-synthesizing enzymes were highly expressed in more than 80% of the surgical specimens in colon cancer patients. Taken together, our findings show that adrenaline contribute to colon cancer cell proliferation through the β2-adrenoceptors-mediated pathway. Nicotine from cigarette smoke could modulate this biological process and promote cancer growth. These data suggest that tobacco-related carcinogenesis is probably mediated through β-adrenoceptors signaling pathway and this opens up a new avenue for colon cancer prevention and treatment especially in smokers.
This study was supported by the Hong Kong Research Grants Council, Hong Kong, China.