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J. Biol. Chem., Vol. 279, Issue 44, 45875-45886, October 29, 2004

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Orexins Acting at Native OX₁ Receptor in Colon Cancer and Neuroblastoma Cells or at Recombinant OX₁ Receptor Suppress Cell Growth by Inducing Apoptosis^*

Patricia Rouet-Benzineb, Christiane Rouyer-Fessard, Anne Jarry¶, Virgile Avondo, Cécile Pouzet||, Masashi Yanagisawa**, Christian Laboisse¶, Marc Laburthe, and Thierry Voisin

From the INSERM U410, Neuroendocrinologie et Biologie Cellulaire Digestives and ^||IFR 02 Claude Bernard, Faculté de Médecine Xavier Bichat, 16 Rue Henri Huchard, BP 416, 75870 Paris Cedex 18, ^¶INSERM U539, Faculté de Médecine, 44035 Nantes, France, and ^**Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050

Screening of 26 gut peptides for their ability to inhibit growth of human colon cancer HT29-D4 cells grown in 10% fetal calf serum identified orexin-A and orexin-B as anti-growth factors. Upon addition of either orexin (1 µM), suppression of cell growth was total after 24 h and >70% after 48 or 72 h, with an EC₅₀ of 5 nM peptide. Orexins did not alter proliferation but promoted apoptosis as demonstrated by morphological changes in cell shape, DNA fragmentation, chromatin condensation, cytochrome c release into cytosol, and activation of caspase-3 and caspase-7. The serpentine G protein-coupled orexin receptor OX₁R but not OX₂R was expressed in HT29-D4 cells and mediated orexin-induced Ca²⁺ transients in HT29-D4 cells. The expression of OX₁R and the pro-apoptotic effects of orexins were also indicated in other colon cancer cell lines including Caco-2, SW480, and LoVo but, most interestingly, not in normal colonic epithelial cells. The role of OX₁R in mediating apoptosis was further demonstrated by transfecting Chinese hamster ovary cells with OX₁R cDNA, which conferred the ability of orexins to promote apoptosis. A neuroblastoma cell line SK-N-MC, which expresses OX₁R, also underwent growth suppression and apoptosis upon treatment with orexins. Promotion of apoptosis appears to be an intrinsic property of OX₁R regardless of the cell type where it is expressed. In conclusion, orexins, acting at native or recombinant OX₁R, are pro-apoptotic peptides. These findings add a new dimension to the biological activities of these neuropeptides, which may have important implications in health and disease, in particular colon cancer.

Received for publication, April 14, 2004 , and in revised form, August 6, 2004.

^* This work was supported by INSERM. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: INSERM U460, Bat 13, 46 Rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France.

To whom correspondence should be addressed: INSERM U410, Faculté de Médecine Xavier Bichat, 16 Rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France. Fax: 33-0-42288765; E-mail: tvoisin{at}bichat.inserm.fr.

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