Inhibition of Wnt/beta-catenin signaling downregulates expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) to reduce resistance against temozolomide in glioblastoma in vitro
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Abigail Kora Suwala1, Katharina Koch1, Dayana Herrera Rios1, Philippe Aretz1, Constanze Uhlmann1, Isabella Ogorek2, Jörg Felsberg2, Guido Reifenberger2,3, Karl Köhrer4, René Deenen4, Hans-Jakob Steiger1, Ulf D. Kahlert1,3 and Jaroslaw Maciaczyk1,5
1Department of Neurosurgery, University Hospital Düsseldorf, Düsseldorf, Germany
2Department of Neuropathology, University Hospital Düsseldorf, Düsseldorf, Germany
3German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany
4Genomics and Transcriptomics Laboratory, Biological and Medical Research Center (BMFZ), Heinrich Heine University, Düsseldorf, Germany
5Department of Surgical Sciences-Neurosurgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
Jaroslaw Maciaczyk, email: [email protected]
Keywords: ALDH3A1; glioma; Wnt; chemoresistance; temozolomide
Received: April 28, 2017 Accepted: April 04, 2018 Published: April 27, 2018
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.
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