Modulation of the sphingolipid metabolism with the sphingosine kinase inhibitor SKI-II to overcome hypoxia-induced chemotherapy resistance in glioblastoma cells
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Abstract
Glioblastoma patients commonly develop resistance to temozolomide (TMZ) chemotherapy. Tumor hypoxia, which supports chemotherapy resistance, favors the expansion of glioblastoma stem cells (GSCs), contributing to tumor relapse. Because of a deregulated sphingolipid metabolism, glioblastoma tissues contain high levels of the pro-survival sphingosine-1-phosphate (S1P) and low levels of the pro-apoptotic ceramide. Ceramide can be metabolized to S1P by sphingosine kinase (SK) 1 that is overexpressed in glioblastoma. Thus, blocking SK might prevent this conversion and support the efficacy of TMZ. The small molecule SKI-II inhibits SK and dihydroceramide desaturase 1, which converts dihydroceramide to ceramide. Previous studies from the laboratory of Anne Régnier-Vigouroux reported that SKI-II combined with TMZ induces caspase-dependent cell death, preceded by dihydrosphingolipids accumulation and autophagy in normoxia. In the present study, I investigated the effects of a lower dose combination of TMZ and SKI-II under normoxia and hypoxia in human glioblastoma cells and patient-derived GSCs.
I observed that TMZ resistance of glioblastoma cells was increased under hypoxia. However, combination of TMZ (48 μM) and SKI-II (2.66 μM) synergistically inhibited glioblastoma cell growth and potentiated glioblastoma cell death relative to single treatments under hypoxia. This lower dose combination did not induce dihydrosphingolipids accumulation, but a decrease in ceramide and its metabolites. It induced oxidative and endoplasmic reticulum stress and triggered caspase-independent cell death. It impaired the self-renewal capacity of TMZ-resistant GSCs, particularly under hypoxia. Furthermore, it decreased invasion of glioblastoma cell spheroids.
This study provides novel insights on the interplay between the sphingolipid metabolism and invasion, a hallmark of cancer, and cancer stem cells, key drivers of cancer. It demonstrates the therapeutic potential of approaches that combine modulation of sphingolipid metabolism with first-line agent TMZ in overcoming tumor growth and relapse by reducing hypoxia-induced resistance to chemotherapy and by targeting both differentiated and stem-like glioblastoma cells.