Abstract 1215: Orexin and their 7-membrane spanning receptors OX1R: a new colon cancer therapeutic target

Abstract

Abstract Orexins are hypothalamic peptides involved in sleep/wake control. Unexpectedly, we have shown that orexins promote robust apoptosis in various colorectal cancer cells1. The cell death is mediated by the orexin 1 receptor (OX1R) through an original mechanism. OX1R, a G protein-coupled receptor class I (GPCR), is aberrantly expressed in primary colorectal tumors and liver metastases2. We next investigated the molecular mechanism of OX1Rmediated cell death. OX1R makes use of “tyrosine-based motifs” ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif)3 and ITSM (Immunoreceptor Tyrosine-based Switch Motif)4 to drive apoptosis. These “tyrosine-based motifs” are mandatory for recruitment and activation of the tyrosine phosphatase SHP-2, leading to apoptosis. Orexins promote cell death through Mitogen-/Stress-activated Protein Kinase (MAPK/SAPK) p38 activation in a SHP-2 dependent manner. The present work is original for two reasons: 1) OX1R is the first example of the involvement of both ITSM and ITIM in GPCR signal transduction. ITIM and ITSM sequences are more frequent than initially thought in GPCRs. This emphasizes the need to explore this mechanism of signal transduction in various GPCRs for regulating cellular processes including at least cell apoptosis and proliferation; 2) we provide evidence that OX1R is aberrantly expressed in all primary colorectal tumors and liver metastases and that its activation by exogenous orexins result in robust apoptosis of colon cancer cells in culture and strong decrease of tumor development in mice xenografted with colon cancer cells in vivo. OX1R represent a new promising target in colorectal cancer therapy and/or for metastases imaging. 1 J.Biol.Chem, 279: 45875 (2004) 2 Can. Res. 71: 3341 (2011) 3 FASEB J. 22: 1993 (2008) 4 FASEB J. 23: 4069 (2009) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1215. doi:1538-7445.AM2012-1215