ROLES OF SPHINGOSINE 1-PHOSPHATE RECEPTOR 2 (S1P2) IN NEURAL AND CANCER CELLS: IMPLICATION FOR PREVENTION OF CISPLATIN-INDUCED PERIPHERAL NEUROPATHY

Abstract

Platinum drugs are important chemotherapeutics currently used for cancer treatment. However, several major side effects have been reported, with peripheral neuropathy being the most critical dose-limiting factor. Here, we demonstrate that pharmacological activation of S1P2, a G protein-coupled receptor that mediates the effects of sphingosine 1-phosphate, confers neuroprotection against cisplatin. Cell-based assays show that CYM-5478, a potent agonist of S1P2, attenuates cisplatin-induced cytotoxicity in neural-derived cells via inhibition of ROS production. In vivo studies show that CYM-5478 attenuates cisplatin-induced neuropathy. Despite the well-established anti-proliferative role of S1P2 in cancer cells, we provide evidence that S1P2 is associated with epithelial-mesenchymal transition (EMT), a key process in cancer metastasis, through the regulation of SNAI2. Taken together, S1P2 represents a bona fide target for treatment of cisplatin-induced neuropathy, but its influence on cancer metastasis needs further investigation.