Abstract 5168: The dual regulatory role of Neuropeptide Y in colon cancer

Introduction: Colon cancer is the third most common cancer and affects approximately one million people every year. Patients with inflammatory bowel diseases (IBDs) have a higher risk of developing colon cancer. The neuropeptides, particularly neuropeptide Y (NPY) which is a 36-amino acid neuropeptide found in the brain, the autonomic nervous system and different peripheral tissues including the colon is associated with the development and progression of IBD. Objective: The objective of this study was to determine the role of NPY in colon cancer and establish NPY and its receptors as new targets for colon cancer. Methods: Immunohistochemical analysis was performed to detect the expression of NPY in colon cancer. Colon cancer (CT26) bearing mice were treated with both NPY Y1 receptor (Y1R) (BIBO 3304) or Y2 receptor (Y2R) (BIIE0246) specific antagonists and the effect on tumor growth and progression was studied. In vitro tumor and endothelial cell proliferation assays and colonic endothelial cell (CEC) migration and tubule forming assays were also conducted. Results and Conclusion: Our results show that there is significant upregulation of NPY in colon cancer and NPY is profusely secreted by colonic epithelial cells. Treatment of CT26 tumor bearing mice with both Y1R and Y2R antagonists resulted in significant reduction of tumor growth. Treatment with Y1R antagonist was associated with reduced number of proliferative cells in tumor tissues, while Y2R antagonist treated tumor tissues showed significant reduction in angiogenesis (micro vessel density). However, tumor cell apoptosis was significantly increased in both the treated groups compared to vehicle treated control group. Our in vitro results showed that treatment with NPY (100nM) significantly increased CT26 tumor cell as well as CEC proliferation compared to respective untreated control cells. However, when CT26 tumor cells were previously treated with Y1R antagonist (1μM) the effect of NPY was abrogated. Y2R antagonist (1μM) prior treated tumor cells didn't show any significant reduction in NPY induced tumor cell proliferation. On the contrary, when CEC were prior treated with Y2R antagonist, NPY mediated CEC proliferation was abrogated. Prior treatment with Y1R antagonist had no effect on this function of NPY. NPY also promoted migration and tube formation capabilities of CEC. Prior treatment with Y2R antagonist also significantly decreased these NPY mediated functions of CEC. Y1 antagonist had no e