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,Karl Köhrer,Jörg Felsberg,Dayana Herrera Rios,Hans-Jakob Steiger,Constanze Uhlmann,Isabella Ogorek,Katharina Koch,René Deenen,Philippe Aretz,Jaroslaw Maciaczyk,Ulf D Kahlert,Guido Reifenberger

doi:10.18632/oncotarget.25210

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 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.

Highlights

Glioblastoma is the most common primary malignant brain tumor in adults and is characterized by a dismal prognosis
We found aldehyde dehydrogenase 3A1 (ALDH3A1), an enzyme involved in cellular metabolic clearance and detoxification of alcohol-derived acetaldehyde [15], to be down-regulated in cells treated with LGK974 and TMZ as compared to monotherapy with either TMZ or LGK974
We found that the combination of TMZ with LGK974 reduced cell growth significantly more effectively as compared to treatments with either drug alone irrespective on the methylguanine-DNA methyltransferase (MGMT) promoter-methylation status (Figure 1A)

Summary

Introduction

Glioblastoma is the most common primary malignant brain tumor in adults and is characterized by a dismal prognosis. TMZ is less effective in glioblastomas lacking MGMT promoter methylation, resulting in worse outcome of this group of patients [4] New therapeutic options, such as anti-angiogenic strategies www.oncotarget.com employing blocking antibodies against vascular endothelial growth factor, did not result in significant overall survival benefit [5]. Similar to somatic stem cells, GSCs are governed by deregulated phylogenetically conserved stem cell signaling pathways modulating differentiation, proliferation, invasion and stress regeneration capability [8]. One of these cascades is the Wingless (Wnt) pathway. Targeting ALDH3A1 can be an innovative strategy to increase TMZ sensitivity in brain cancer cells independently of the MGMT promoter methylation status

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Conclusion