The orexin receptor OX1R in colon cancer: a promising therapeutic target and a new paradigm in G protein-coupled receptor signalling through ITIMs


Marc Laburthe, INSERM U773, CRB3, Faculté de Médecine X. Bichat, 75018 Paris, France. E-mail:


An exciting aspect of the heptahelical orexin receptor 1 (OX1R) has emerged recently, when it was shown that it drives apoptosis in human colon cancer cell lines. Here we review recent findings related to the role of OX1R in colorectal cancers and the unexpected mechanism whereby this G protein-coupled receptor works. The OX1R is aberrantly expressed at all steps of primary colorectal tumour progression and after local (lymph node) or distant (liver, lung) metastasis. No OX1R is detected in normal colonic epithelial cells. Treatment of human colon cancer cells in culture with orexins promotes robust apoptosis and subsequent reduction of growth including in cells that are resistant to 5-fluorouracil, the most commonly used drug in chemotherapy. When human colon cancer cells are xenografted in nude mice, treatment with orexins dramatically slows tumour growth and even reverses the development of established tumours. Thus, OX1R agonists might be novel candidates for colon cancer therapy. Activation of OX1R drives apoptosis through Gq protein but independently of classical Gαq activation of phospholipase C. In fact, it is the freed βγ dimer of Gq that plays a pivotal role by stimulating Src-tyrosine kinase. This results in phosphorylation of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in OX1R and subsequent recruitment by OX1R of the phosphotyrosine phosphatase SHP-2, which is activated thereby. Downstream events include release of cytochrome c from mitochondria and activation of caspase-3 and caspase-7. The role of ITIMs in OX1R-driven apoptosis represents a new paradigm of G protein-coupled receptor signalling.

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