Effects of adrenaline in human colon adenocarcinoma HT-29 cells Helen P.S. Wong a , Judy W.C. Ho b , Marcel W.L. Koo a , Le Yu c , William K.K. Wu c , Emily K.Y. Lam a , Emily K.K. Tai c , Joshua K.S. Ko d , Vivian Y. Shin b , Kent Man Chu b , Chi Hin Cho c, ⁎ a Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China b Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China c School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China d School of Chinese Medicine, The Hong Kong Baptist University, Hong Kong, China abstract article info Article history: Received 5 January 2011 Accepted 2 April 2011 Keywords: Adrenaline COX-2 Colon cancer Stress Aims: Stress has been implicated in the development of cancers. Adrenaline levels are increased in response to stress. The effects of adrenaline on colon cancer are largely unknown. The aims of the study are to determine the effects of adrenaline in human colon adenocarcinoma HT-29 cells and the possible underlying mechanisms involved. Main methods: The effect of adrenaline on HT-29 cell proliferation was determined by [ 3 H] thymidine incorporation assay. Expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) were detected by Western blot. Matrix metalloproteinase-9 (MMP-9) activity and prostaglandin E 2 (PGE 2 ) release were determined by zymography and enzyme immunoassay, respectively. Key findings: Adrenaline stimulated HT-29 cell proliferation. This was accompanied by the enhanced expression of COX-2 and VEGF in HT-29 cells. Adrenaline also upregulated MMP-9 activity and PGE 2 release. Adrenaline stimulated HT-29 cell proliferation which was reversed by COX-2 inhibitor sc-236. COX-2 inhibitor also reverted the action of adrenaline on VEGF expression and MMP-9 activity. Further study was performed to determine the involvement of β-adrenoceptors. The stimulatory action of adrenaline on colon cancer growth was blocked by atenolol and ICI 118,551, a β 1 - and β 2 -selective antagonist, respectively. This signified the role of β-adrenoceptors in this process. In addition, both antagonists also abrogated the stimulating actions of adrenaline on COX-2, VEGF expression, MMP-9 activity and PGE 2 release in HT-29 cells. Significance: These results suggest that adrenaline stimulates cell proliferation of HT-29 cells via both β 1 - and β 2 -adrenoceptors by a COX-2 dependent pathway. © 2011 Elsevier Inc. All rights reserved. Introduction Stress has been linked to the increased incidence and development of cancers (Antoni et al., 2006; Reiche et al., 2004). Adrenaline and noradrenaline are the most important catecholamines released during stress. Recent studies suggested that chronic stress promotes tumor growth and angiogenesis in vivo and catecholamines increase angiogenic cytokines in various cancer cells in vitro (Lutgendorf et al., 2003; Thaker et al., 2006; Wong et al., 2009; Yang et al., 2006). Colon cancer is the leading cause of cancers and cancer deaths worldwide (Jemal et al., 2010). Expression of β-adrenoceptors have been identified on colon cancer cells (Odore et al., 2003; Wu et al., 2005). Previous studies have shown that activation of β-adrenoceptors has been implicated in the arachidonic acid pathway especially cyclooxygenase-2 (COX-2) expression in relation to pulmonary and pancreatic cancer growth (Schuller et al., 1999; Weddle et al., 2001). The protective effects of nonsteroidal antiinflammatory drugs and COX-2 inhibitors in the treatment and prevention of colon cancers suggest the key role of COX-2 in the pathogenesis of colon cancer (Rice et al., 2003; Steinbach et al., 2000). Stimulation of β-adrenoceptors by catecholamines have also been shown to play a role in the progression of ovarian cancer and are associated with the production of vascular endothelial growth factor (VEGF) (Lutgendorf et al., 2003). In another study, activation of β-adrenoceptors by catecholamines increased the expression of matrix metalloproteinases (MMPs) in nasopharyngeal carcinoma tumor cells (Yang et al., 2006). VEGF is expressed by most human cancers including colon cancer (Brown et al., 1993; Folkman, 1990). The expression profiles of MMPs in different human cancers have been suggested to be associated with progression of the disease. Among them, MMP-9 has been implicated in colon cancer (Fingleton, 2006; Mook et al., 2004). All these findings indicate that there is a possible link between β-adrenoceptors and some of the carcinogenic mediators including COX-2, VEGF and MMP-9 in the development of colon cancer. Life Sciences 88 (2011) 1108–1112 ⁎ Corresponding author at: School of Biomedical Sciences Faculty of Medicine The Chinese University of Hong Kong Shatin, N.T. Hong Kong, China. Tel.: + 852 2609 6886; fax: +852 2603 5139. E-mail address: chcho@cuhk.edu.hk (C.H. Cho). 0024-3205/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2011.04.007 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie