1. Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival
- Author
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Cristina Tringali, Stefania Brambilla, Paola Giussani, and Rosaria Bassi
- Subjects
0301 basic medicine ,sphingosine kinase 1 ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Sphingosine ,Epidermal growth factor receptor ,Biology (General) ,Spectroscopy ,Cells, Cultured ,biology ,Brain Neoplasms ,General Medicine ,Computer Science Applications ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Chemistry ,Sphingosine kinase 1 ,030220 oncology & carcinogenesis ,lipids (amino acids, peptides, and proteins) ,medicine.drug ,QH301-705.5 ,Cell Survival ,Antineoplastic Agents ,Models, Biological ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Sphingosine-1-phosphate ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Temozolomide ,Cell growth ,Organic Chemistry ,030104 developmental biology ,chemistry ,Cancer research ,biology.protein ,sphingosine-1-phosphate ,Lysophospholipids ,Glioblastoma ,epidermal growth factor receptor ,Proto-Oncogene Proteins c-akt - Abstract
Sphingosine-1-phosphate (S1P) is a crucial mediator involved in the progression of different cancers, including glioblastoma multiforme (GBM), the most frequent and deadly human brain tumor, characterized by extensive invasiveness and rapid cell growth. Most of GBMs overexpress the epidermal growth factor receptor (EGFR), and we investigated the possible link between S1P and EGFR signaling pathways, focusing on its role in GBM survival, using the U87MG human cell line overexpressing EGFR (EGFR+). We previously demonstrated that EGFR+ cells have higher levels of extracellular S1P and increased sphingosine kinase-1 (SK1) activity than empty vector expressing cells. Notably, we demonstrated that EGFR+ cells are resistant to temozolomide (TMZ), the standard chemotherapeutic drug in GBM treatment, and the inhibition of SK1 or S1P receptors made EGFR+ cells sensitive to TMZ, moreover, exogenous S1P reverted this effect, thus involving extracellular S1P as a survival signal in TMZ resistance in GBM cells. In addition, both PI3K/AKT and MAPK inhibitors markedly reduced cell survival, suggesting that the enhanced resistance to TMZ of EGFR+ cells is dependent on the increased S1P secretion, downstream of the EGFR-ERK-SK1-S1P pathway. Altogether, our study provides evidence of a functional link between S1P and EGFR signaling pathways enhancing the survival properties of GBM cells.
- Published
- 2021