title: Aberrant expression of OX1 receptors for orexins in colon cancers and liver metastases: an openable gate to apoptosis.
abstract: Resistance to apoptosis is a recurrent theme in colon cancer. We have shown previously that the 7-transmembrane spanning receptor OX1R for orexins promotes robust apoptosis in the human colon cancer cell line HT29 through an entirely novel mechanism involving phosphorylation of tyrosine-based motifs in OX1R. Here, we investigated the status of OX1R in a large series of human colorectal tumors and hepatic metastases. All primary colorectal tumors regardless of their localization and Duke's stages and all hepatic metastases tested expressed OX1R mRNA and/or protein. In sharp contrast, adjacent normal colonocytes or hepatocytes as well as control normal tissues were negative. Next, we showed that nine human colon cancer cell lines established from primary tumors or metastases expressed OX1R mRNA and underwent important apoptosis on orexin-A challenge. Most interestingly, orexin-A also promoted robust apoptosis in cells that are resistant to the most commonly used drug in colon cancer chemotherapy, 5-fluorouracil. When human colon cancer cells were xenografted in nude mice, orexin-A administered at day 0 strongly slowed the tumor growth and even reversed the development of established tumors when administered 7 days after cell inoculation. Orexin-A also acts by promoting tumor apoptosis in vivo because caspase-3 is activated in tumors on orexin treatment of nude mice. These findings support that OX1R is an Achilles heel of colon cancers, even after metastasis or chemoresistance. They suggest that OX1R agonists might be novel candidates for colon cancer therapy.
authors.affiliation: Université Paris Diderot, Paris, France. thierry.voisin@inserm.fr
authors.forename: Thierry
authors.initials: T
authors.lastname: Voisin
authors.forename: Aadil
authors.initials: A
authors.lastname: El Firar
authors.forename: Magali
authors.initials: M
authors.lastname: Fasseu
authors.forename: Christiane
authors.initials: C
authors.lastname: Rouyer-Fessard
authors.forename: Véronique
authors.initials: V
authors.lastname: Descatoire
authors.forename: Francine
authors.initials: F
authors.lastname: Walker
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.forename: Dominique
authors.initials: D
authors.lastname: Henin
authors.forename: Thérèse
authors.initials: T
authors.lastname: Lehy
authors.forename: Marc
authors.initials: M
authors.lastname: Laburthe
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics; D018013:Receptors, Neuropeptide / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C000596229:HCRT protein, human; C578627:Hcrtr1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D005472:Fluorouracil