Sphingosine-1-phosphate activates the AKT pathway to protect small intestines from radiation-induced endothelial apoptosis Journal Article
| Authors: | Bonnaud, S.; Niaudet, C.; Legoux, F.; Corre, I.; Delpon, G.; Saulquin, X.; Fuks, Z.; Gaugler, M. H.; Kolesnick, R.; Paris, F. |
| Article Title: | Sphingosine-1-phosphate activates the AKT pathway to protect small intestines from radiation-induced endothelial apoptosis |
| Abstract: | 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. ©2010 AACR. |
| Keywords: | immunohistochemistry; signal transduction; protein kinase b; controlled study; overall survival; nonhuman; radiation dose; t lymphocyte; animal cell; mouse; animals; mice; cells, cultured; apoptosis; bone marrow; cell line; animal experiment; animal model; in vivo study; in vitro study; phosphorylation; mice, inbred c57bl; b lymphocyte; cell type; endothelium cell; endothelial cells; blotting, western; syndrome; proto-oncogene proteins c-akt; irradiation; intestine epithelium cell; sphingosine; gastrointestinal tract; lymphoid tissue; small intestine; intestine, small; intestine cell; cell protection; gastrointestinal disease; radiation enteropathy; radiation protection; radiation injuries, experimental; inhibitory guanine nucleotide binding protein; pertussis toxin; sphingosine 1 phosphate; endothelium injury; lysophospholipids |
| Journal Title: | Cancer Research |
| Volume: | 70 |
| Issue: | 23 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-12-01 |
| Start Page: | 9905 |
| End Page: | 9915 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-10-2043 |
| PUBMED: | 21118968 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus" |
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