Abstract 4887: FTY720 prevent tumorigenesis and suppress the progression of colitis-associated cancer.

Abstract

Abstract Inflammatory bowel disease is an important risk factor for colorectal cancer. Sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite formed by two sphingosine kinases, SphK1 and SphK2, is involved in inflammation and cancer. Enhanced tumor number and size, with a concomitant increase in tumor load was observed in mice overexpressing SphK1 treated with the colonotropic mutagen azoxymethane (AOM) followed by three rounds of oral administration of the luminal toxin dextran sodium sulfate (DSS) to induce colitis-associated cancer (CAC). There was also a large increase in adenomas with a high grade of dysplasia associated with increased SphK1 expression and formation of S1P. We demonstrated that the SphK1/S1P axis is important for production of IL-6 and is involved in persistent activation of STAT3 and consequent upregulation of one of its target genes, the S1P receptor S1PR1. Because the pro-drug FTY720 modulates the immune system by acting as a functional antagonist of S1PR1, inducing its internalization and degradation, we examined its effect on CAC progression. FTY720 drastically reduced colitis-associated tumorigenesis, when it was administered during CAC induction. Remarkably, FTY720 blocked CAC progression even when it was administered later after the last DSS treatment when tumors were already established. Moreover, it reduced SphK1 expression, production of IL-6, and persistent activation of STAT3. These findings suggest that FTY720 may be beneficial for preventing tumor formation in individuals with inflammatory bowel disease. This work was supported by grants from the National Institute of Health (R37GM043880, R01CA61774, U19AI077435 to S.S. and R01CA160688 to K.T.). M.N. is a Japan Society for the Promotion of Science Postdoctoral Fellow. Citation Format: Akimitsu Yamada, Jie Liang, Masayuki Nagahashi, Eugene Y. Kim, Kuzhuvelil B. Harikumar, Wei-Ching Huang, Nitai C. Hait, Jeremy C. Allegood, Megan M. Price, Dorit Avni, Tomasz Kordula, Milstien Sheldon, Kazuaki Takabe, Sarah Spiegel. FTY720 prevent tumorigenesis and suppress the progression of colitis-associated cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4887. doi:10.1158/1538-7445.AM2013-4887