Inhibition of Wnt/beta-catenin signaling downregulates expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) to reduce resistance against temozolomide in glioblastoma in vitro
| Autor: | Karl Köhrer, Jaroslaw Maciaczyk, Philippe Aretz, Ulf Dietrich Kahlert, Guido Reifenberger, Hans-Jakob Steiger, Constanze Uhlmann, Abigail K. Suwala, Isabella Ogorek, Dayana Herrera Rios, Katharina Koch, Jörg Felsberg, René Deenen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
temozolomide Stem cell marker Wnt 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine SOX2 glioma Glioma medicine ALDH3A1 neoplasms Temozolomide Wnt signaling pathway chemoresistance medicine.disease 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Cancer research Growth inhibition Stem cell Signal transduction Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.25210 |
| Popis: | Glioblastoma is the most aggressive type of glioma. The Wingless (Wnt) signaling pathway has been shown to promote stem cell properties and resistance to radio- and chemotherapy in glioblastoma. Here, we demonstrate that pharmacological Wnt pathway inhibition using the porcupine inhibitor LGK974 acts synergistically with temozolomide (TMZ), the chemotherapeutic drug currently used as standard treatment for glioblastoma, to suppress in vitro growth of glioma cells. Synergistic growth inhibition was independent of the O6-alkylguanine DNA alkyltransferase (MGMT) promoter methylation status. Transcriptomic analysis revealed that expression of aldehyde dehydrogenase 3A1 (ALDH3A1) was significantly down-regulated when cells were treated with LGK974 and TMZ. Suppressing ALDH3A1 expression increased the efficacy of TMZ and reduced clonogenic potential accompanied by decreased expression of stem cell markers CD133, Nestin and Sox2. Taken together, our study suggests that previous observations concerning Wnt signaling blockade to reduce chemoresistance in glioblastoma is at least in part mediated by inhibition of ALDH3A1. |
| Databáze: | OpenAIRE |
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