Sphingosine-1-Phosphate Activates the AKT Pathway to Protect Small Intestines from Radiation-Induced Endothelial Apoptosis

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 23; pp. 9905 - 9915
• Main Authors: Bonnaud, Stéphanie, Niaudet, Colin, Legoux, François, Corre, Isabelle, Delpon, Gregory, Saulquin, Xavier, Fuks, Zvi, Gaugler, Marie-Hélène, Kolesnick, Richard, Paris, François
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2010
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - radiation effects; Biological and medical sciences; Blotting, Western; Bone Marrow - drug effects; Bone Marrow - pathology; Bone Marrow - radiation effects; Cell Line; Cells, Cultured; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - radiation effects; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - pathology; Gastrointestinal Tract - radiation effects; Humans; Immunohistochemistry; Intestine, Small - cytology; Intestine, Small - drug effects; Intestine, Small - radiation effects; Life Sciences; Lymphoid Tissue - drug effects; Lymphoid Tissue - pathology; Lymphoid Tissue - radiation effects; Lysophospholipids - pharmacology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; Phosphorylation - drug effects; Phosphorylation - radiation effects; Proto-Oncogene Proteins c-akt - metabolism; Radiation Injuries, Experimental - drug therapy; Signal Transduction - drug effects; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Syndrome; Tumors; Prevention; Endothelial cell; Digestive system; Cell death; Radiation; Sphingosine-1-phosphate; Akt protein kinase; Small intestine; Apoptosis; Endothelium; radiation enteropathy; intestine cell; apoptosis; in vitro study; cell type; gastrointestinal disease; irradiation; mouse; sphingosine 1 phosphate; radiation protection; pertussis toxin; overall survival; radiation dose; priority journal; animal model; protein kinase B; signal transduction; animal cell; B lymphocyte; in vivo study; endothelium injury; cell protection; inhibitory guanine nucleotide binding protein; animal experiment; article; intestine epithelium cell; controlled study; small intestine; nonhuman; T lymphocyte; endothelium cell; male
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-2043

A previous in vitro study showed that sphingosine-1-phosphate (S1P), a ceramide antagonist, preserved endothelial cells in culture from radiation-induced apoptosis. We proposed to validate the role of S1P in tissue radioprotection by inhibiting acute gastrointestinal (GI) syndrome induced by endothelial cell apoptosis after high dose of radiation. Retro-orbital S1P was injected in mice exposed to 15 Gy, a dose-inducing GI syndrome within 10 days. Overall survival and apoptosis on intestines sections were studied. Intestinal cell type targeted by S1P and early molecular survival pathways were researched using irradiated in vitro cell models and in vivo mouse models. We showed that retro-orbital S1P injection before irradiation prevented GI syndrome by inhibiting endothelium collapse. We defined endothelium as a specific therapeutic target because only these cells and not intestinal epithelial cells, or B and T lymphocytes, were protected. Pharmacologic approaches using AKT inhibitor and pertussis toxin established that S1P affords endothelial cell protection in vitro and in vivo through a mechanism involving AKT and 7-pass transmembrane receptors coupled to Gi proteins. Our results provide strong pharmacologic and mechanistic proofs that S1P protects endothelial cells against acute radiation enteropathy. Cancer Res; 70(23); 9905–15. ©2010 AACR.