Background: Glioblastomas are the most frequent and deadly human brain tumors, their intrinsic/acquired resistance limiting therapy effectiveness. Increasing evidence supports that sphingosine-1-phosphate (S1P) is implicated in sustaining cell survival, and in the development of drug-resistance in cancer cells. We investigated the possible involvement of S1P in the resistance of glioblastoma cells to temozolomide (TMZ), a pro-autophagic drug currently used as the mainstay of chemotherapy for this cancer. Results: We selected a TMZ-resistant cell line from the T98G glioblastoma cell one, and found that its S1P levels were significantly higher than in the parental sensitive line. This feature was also associated with a higher expression of the sphingosine kinase-1. In addition, the exposure of resistant cells to sphingosine kinase inhibitors restored cell sensitivity to TZ, thus reverting their TMZ resistance. Immunofluorescence studies revealed that sphingosine kinase-1 was mainly localized in the cytosol of T98G cells, but preferentially in the plasma membrane of TMZ-resistant cells. Interestingly, this surface localization was associated with an efficient extracellular release S1P by the TMZ-resistant cells. Moreover, extracellular S1P, but not intracellular one, was able to protect T98G cells from temozolomide toxicity, and this was reverted by the inhibition of Gi-coupled receptors. Conclusions: Altogether our data suggest that S1P secretion and signalling play an important role in glioblastoma drug-resistance, by providing a survival advantage over TMZ-induced autophagic death.

Extracellular sphingosine-1-phosphate provides a survival advantage over autophagic death in human glioblastoma cells / P. Giussani, L. Brioschi, F. De Zen, E. Riccitelli, P. Viani, L. Riboni. ((Intervento presentato al 9. convegno Sphingolipid Club Meeting tenutosi a Favignana nel 2011.

Extracellular sphingosine-1-phosphate provides a survival advantage over autophagic death in human glioblastoma cells

P. Giussani;L. Brioschi;F. De Zen;E. Riccitelli;P. Viani;L. Riboni
2011

Abstract

Background: Glioblastomas are the most frequent and deadly human brain tumors, their intrinsic/acquired resistance limiting therapy effectiveness. Increasing evidence supports that sphingosine-1-phosphate (S1P) is implicated in sustaining cell survival, and in the development of drug-resistance in cancer cells. We investigated the possible involvement of S1P in the resistance of glioblastoma cells to temozolomide (TMZ), a pro-autophagic drug currently used as the mainstay of chemotherapy for this cancer. Results: We selected a TMZ-resistant cell line from the T98G glioblastoma cell one, and found that its S1P levels were significantly higher than in the parental sensitive line. This feature was also associated with a higher expression of the sphingosine kinase-1. In addition, the exposure of resistant cells to sphingosine kinase inhibitors restored cell sensitivity to TZ, thus reverting their TMZ resistance. Immunofluorescence studies revealed that sphingosine kinase-1 was mainly localized in the cytosol of T98G cells, but preferentially in the plasma membrane of TMZ-resistant cells. Interestingly, this surface localization was associated with an efficient extracellular release S1P by the TMZ-resistant cells. Moreover, extracellular S1P, but not intracellular one, was able to protect T98G cells from temozolomide toxicity, and this was reverted by the inhibition of Gi-coupled receptors. Conclusions: Altogether our data suggest that S1P secretion and signalling play an important role in glioblastoma drug-resistance, by providing a survival advantage over TMZ-induced autophagic death.
Settore BIO/10 - Biochimica
Extracellular sphingosine-1-phosphate provides a survival advantage over autophagic death in human glioblastoma cells / P. Giussani, L. Brioschi, F. De Zen, E. Riccitelli, P. Viani, L. Riboni. ((Intervento presentato al 9. convegno Sphingolipid Club Meeting tenutosi a Favignana nel 2011.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/166360
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