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

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.

Integrated analysis identified core signal pathways and hypoxic characteristics of human glioblastoma

“…Most of them were involved in tumour development and progression. ALDH3A1 could mediate GBM resistance . As a downstream gene of HIF‐1, TGFB1 promoted the malignant phenotype of GBM by regulating proliferation and metastasis .…”

OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth

“…Other TMZ combined therapies that have been recently investigated include silencing GLI1, which is associated with Hedgehog signaling and specifically affected glioma-like stem cells (U87-MG, T98G) [12] ; inhibiting Wnt/β-catenin signaling, which downregulates the expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) [37] ; using a miR-519a mimic, where miR-519a functions as a tumor suppressor by targeting the signal transducer and activator of transcription 3 (STAT3)–mediated autophagy, and promoting TMZ-induced autophagy (U87-MG/TMZ) [38] ; inhibiting PI3K to sensitize GBM cells to TMZ [14] ; inhibiting the SOX9/CA9 (carbonic anhydrase 9)-mediated oncogenic pathway to enhance TMZ sensitivity [15] ; and co-delivery of TMZ and siRNA targeting the BCL-2 gene using a folate-conjugated triblock copolymer (Fa-PEG-PEI-PCL, Fa-PEC) of poly(ε-caprolactone) (PCL), poly(ethylenimine) (PEI), and poly(ethylene glycol) (PEG) nanocarrier construct [39] . All of the therapies combined with TMZ either are used to augment the effect of TMZ and/or effect TMZ-resistant GBM cells.…”

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

“…LGK97 was recently shown to have a synergistic effect with TMZ in vitro, reducing the clonogenic potential, with decreased expression of CD133, Nestin and SOX2. Importantly, these effects were shown to be independent of O 6alkylguanine DNA alkyltransferase (MGMT) promoter methylation status (207). Some WNT signaling inhibitors are currently being tested in clinical trials, such as Enzastaurin and alisertib.…”