Neuropeptides and Colon Cancer; Another Notch in the Complexity of Tumorigenesis

Abstract

In 2009 an estimated 50,000 deaths in the United States will be attributed to colon cancer. Dysregulation of tumor suppressors and oncogenes are a major cause of uncontrolled cellular proliferation, leading to tumerogenesis. The proto‐oncogene, Notch, is associated with colon cancer. It has been previously shown that cleavage of membrane tethered Notch releases the intracellular domain fragment (NICD) which can enter the nucleus. Manifestation of tumerogenesis is caused by elevated NICD entering the nucleus and activating gene transcription. A proliferative G‐protein coupled receptor, vasoactive intestinal peptide receptor 1 (VPAC1), is highly expressed in colon cancer cells and contains numerous Notch putative consensus sequences within its promoter. We hypothesize that the reason why colon cancer cells, HT‐29, have elevated VPAC1 expression levels is due to enhanced Notch signaling. To this end, Dibenzazepine, a γ_secretase inhibitor which prevents the cleavage of Notch was utilized to determine whether VPAC1 expression was altered. By SYBR green qPCR, VPAC1 mRNA was found downregulated by Dibenzazepine in a concentration dependent manner over 48 hours. This observation is the first to link VPAC1 regulation to Notch signaling and therefore further elucidation of this mechanism will allow for greater insight into the etiology of colon cancer.Funding: NIH‐K01 1K01DK064828 and COBRE 2P20RR05566.