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. Cancer Res; 70(23); 9905-15. Ó2010 AACR.

miRNA-95 Mediates Radioresistance in Tumors by Targeting the Sphingolipid Phosphatase SGPP1

“…Although we do not address the S1P levels in miR-95-overexpressing cancer cells directly, our observations about radiation resistance in miR-95-overexpressing cancer cells are likely explained through an increase in S1P mediated by the suppression of SGPP1 expression, which has been shown to protect against radiation-induced cell death (31). Indeed, the regulation of SGPP1 and hence S1P/sphingosine balance by miR-95 highlights the potential importance of this miR, because S1P can act as an intracellular second messenger, or bind to S1P receptors (G-protein-linked receptors), and thus regulate diverse cancer processes including migration, invasion, cell death, and angiogenesis (reviewed in ref.…”

“…Engagement of the PI3K-Akt pathway is a major determinant of survival after radiation (23). S1P is a highly bioactive sphingolipid known to activate Akt and protect against ionizing radiation-induced cell death (31). S1P can be generated by phosphorylation of sphingosine by sphingosine kinase 1 (SK1), whereas S1P dephosphorylation by SGPP1 produces sphingosine, which is known to promote cell death (27).…”

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

“…It antagonizes ceramide and sphingosine and favors cell survival. When endothelial cells are beamed with ionizing radiation, S1P was shown to activate AKT pathway to protect the cells from apoptosis [109]. Loss of sphingosine kinase activity was shown to increase the sensitivity to the DNA damaging chemotherapy with the concomitant increase in reactive oxygen species [110].…”

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

“…Stress-activated protein kinase (28) and Bcl-2 family-induced mitochondrial depolarization pathways (25) are proximal downstream targets of ceramide accumulation after IR. However, radioresistance may be elicited by either defects in ceramide generation (29)(30)(31)(32) or rapid turnover of ceramide into S1P (33)(34)(35). Rescue of the apoptotic phenotype by restoring ceramide accumulation or limiting S1P signaling is currently being studied both at the basic science and clinical levels (36)(37)(38).…”