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http://doi.org/10.25358/openscience-9701Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.author | Sousa, Nadia | - |
| dc.contributor.author | Geiß, Carsten | - |
| dc.contributor.author | Bindila, Laura | - |
| dc.contributor.author | Lieberwirth, Ingo | - |
| dc.contributor.author | Kim, Ella | - |
| dc.contributor.author | Régnier-Vigouroux, Anne | - |
| dc.date.accessioned | 2023-11-24T08:05:06Z | - |
| dc.date.available | 2023-11-24T08:05:06Z | - |
| dc.date.issued | 2023 | - |
| dc.identifier.uri | https://openscience.ub.uni-mainz.de/handle/20.500.12030/9719 | - |
| dc.description.abstract | Background: Glioblastoma patients commonly develop resistance to temozolomide chemotherapy. Hypoxia, which supports chemotherapy resistance, favors the expansion of glioblastoma stem cells (GSC), contributing to tumor relapse. Because of a deregulated sphingolipid metabolism, glioblastoma tissues contain high levels of the pro-survival sphingosine-1-phosphate and low levels of the pro-apoptotic ceramide. The latter can be metabolized to sphingosine-1-phosphate by sphingosine kinase (SK) 1 that is overexpressed in glioblastoma. The small molecule SKI-II inhibits SK and dihydroceramide desaturase 1, which converts dihydroceramide to ceramide. We previously reported that SKI-II combined with temozolomide induces caspase-dependent cell death, preceded by dihydrosphingolipids accumulation and autophagy in normoxia. In the present study, we investigated the effects of a low-dose combination of temozolomide and SKI-II under normoxia and hypoxia in glioblastoma cells and patient-derived GCSs. Methods: Drug synergism was analyzed with the Chou-Talalay Combination Index method. Dose–effect curves of each drug were determined with the Sulforhodamine B colorimetric assay. Cell death mechanisms and autophagy were analyzed by immunofluorescence, flow cytometry and western blot; sphingolipid metabolism alterations by mass spectrometry and gene expression analysis. GSCs self-renewal capacity was determined using extreme limiting dilution assays and invasion of glioblastoma cells using a 3D spheroid model. Results: Temozolomide resistance of glioblastoma cells was increased under hypoxia. However, combination of temozolomide (48 µM) with SKI-II (2.66 µM) synergistically inhibited glioblastoma cell growth and potentiated glioblastoma cell death relative to single treatments under hypoxia. This low-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 temozolomide-resistant GSCs, especially under hypoxia. Furthermore, it decreased invasion of glioblastoma cell spheroids. Conclusions: This in vitro study provides novel insights on the links between 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 temozolomide in overcoming tumor growth and relapse by reducing hypoxia-induced resistance to chemotherapy and by targeting both differentiated and stem glioblastoma cells. | en_GB |
| dc.language.iso | eng | de |
| dc.rights | CC BY | * |
| dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | * |
| dc.subject.ddc | 570 Biowissenschaften | de_DE |
| dc.subject.ddc | 570 Life sciences | en_GB |
| dc.subject.ddc | 610 Medizin | de_DE |
| dc.subject.ddc | 610 Medical sciences | en_GB |
| dc.title | Targeting sphingolipid metabolism with the sphingosine kinase inhibitor SKI-II overcomes hypoxia-induced chemotherapy resistance in glioblastoma cells: effects on cell death, self-renewal, and invasion | en_GB |
| dc.type | Zeitschriftenaufsatz | de |
| dc.identifier.doi | http://doi.org/10.25358/openscience-9701 | - |
| jgu.type.contenttype | Scientific article | de |
| jgu.type.dinitype | article | en_GB |
| jgu.type.version | Published version | de |
| jgu.type.resource | Text | de |
| jgu.organisation.department | FB 10 Biologie | de |
| jgu.organisation.number | 7970 | - |
| jgu.organisation.name | Johannes Gutenberg-Universität Mainz | - |
| jgu.rights.accessrights | openAccess | - |
| jgu.journal.title | BMC Cancer | de |
| jgu.journal.volume | 23 | de |
| jgu.pages.alternative | 762 | de |
| jgu.publisher.year | 2023 | - |
| jgu.publisher.name | Springer | de |
| jgu.publisher.place | Berlin ; Heidelberg | de |
| jgu.publisher.issn | 1471-2407 | de |
| jgu.organisation.place | Mainz | - |
| jgu.subject.ddccode | 570 | de |
| jgu.subject.ddccode | 610 | de |
| jgu.publisher.doi | 10.1186/s12885-023-11271-w | de |
| jgu.organisation.ror | https://ror.org/023b0x485 | - |
| jgu.subject.dfg | Lebenswissenschaften | de |
| Appears in collections: | DFG-491381577-G | |
Files in This Item:
| File | Description | Size | Format | ||
|---|---|---|---|---|---|
 | targeting_sphingolipid_metabo-20231124084243801.pdf | 3.01 MB | Adobe PDF | View/Open |