Inhibition of Wnt/beta-catenin signaling downregulates expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) to reduce resistance against temozolomide in glioblastoma in vitro

// Abigail Kora Suwala 1 , Katharina Koch 1 , Dayana Herrera Rios 1 , Philippe Aretz 1 , Constanze Uhlmann 1 , Isabella Ogorek 2 , Jorg Felsberg 2 , Guido Reifenberger 2, 3 , Karl Kohrer 4 , Rene Deenen 4 , Hans-Jakob Steiger 1 , Ulf D. Kahlert 1, 3 and Jaroslaw Maciaczyk 1, 5 1 Department of Neurosurgery, University Hospital Dusseldorf, Dusseldorf, Germany 2 Department of Neuropathology, University Hospital Dusseldorf, Dusseldorf, Germany 3 German Cancer Consortium (DKTK), Partner Site Essen/Dusseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Genomics and Transcriptomics Laboratory, Biological and Medical Research Center (BMFZ), Heinrich Heine University, Dusseldorf, Germany 5 Department of Surgical Sciences-Neurosurgery, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand Correspondence to: Jaroslaw Maciaczyk, email: Jaroslaw.Maciaczyk@med.uni-duesseldorf.de Keywords: ALDH3A1; glioma; Wnt; chemoresistance; temozolomide Received: April 28, 2017      Accepted: April 04, 2018      Published: April 27, 2018 ABSTRACT 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 O 6 -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.