WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells

Abstract

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass followed by combined chemoradiotherapy. The highly malignant nature of IDH-wildtype glioblastoma is thought to be driven by glioblastoma stem-like cells (GSCs) that harbor the ability of self-renewal, survival, and adaptability to challenging environmental conditions. The wingless (WNT) signaling pathway is a phylogenetically highly conserved stemness pathway, which promotes metabolic plasticity and adaptation to a nutrient-limited tumor microenvironment. To unravel the reciprocal regulation of the WNT pathway and the nutrient-limited microenvironment, glioblastoma cancer stem-like cells were cultured in a medium with either standard or reduced glucose concentrations for various time points (24, 48, and 72 h). Glucose depletion reduced cell viability and facilitated the survival of a small population of starvation-resistant tumor cells. The surviving cells demonstrated increased clonogenic and invasive properties as well as enhanced chemosensitivity to pharmacological inhibitors of the WNT pathway (LGK974, berberine). Glucose depletion partially led to the upregulation of WNT target genes such as CTNNB1, ZEB1, and AXIN2 at the mRNA and corresponding protein levels. LGK974 treatment alone or in combination with glucose depletion also altered the metabolite concentration in intracellular compartments, suggesting WNT-mediated metabolic regulation. Taken together, our findings suggest that WNT-mediated metabolic plasticity modulates the survival of GSCs under nutrient-restricted environmental conditions.

Systematic integration of m6A regulators and autophagy-related genes in combination with long non-coding RNAs predicts survival in glioblastoma multiforme

“…Given the growing evidences that m6A is associated with Wnt signaling 5 , 6 , while recognizing that Wnt/β-catenin plays an inevitable role in GBM 7 – 9 , there may be possible mechanisms for their yet to be elucidated interplay in the pathogenesis of GBM. Concerning the functional regulation of m6A, the fine-tuning and interactions between the m6A and long non-coding RNAs (lncRNA) axis have been considered.…”

Pancreatic stellate cell‐derived exosomal tRF‐19‐PNR8YPJZ promotes proliferation and mobility of pancreatic cancer through AXIN2

“…33 AXIN2, a negative inhibitor of the Wnt signalling pathway, regulates the phosphorylation and degradation of β-catenin, thus promoting the overexpression of target genes, affecting cell proliferation and differentiation, and promoting the occurrence of tumours. [34][35][36] In this study, we showed that tRF…”

“… 33 AXIN2, a negative inhibitor of the Wnt signalling pathway, regulates the phosphorylation and degradation of β‐catenin, thus promoting the overexpression of target genes, affecting cell proliferation and differentiation, and promoting the occurrence of tumours. 34 , 35 , 36 In this study, we showed that tRF‐19‐PNR8YPJZ bound to AXIN2 and that overexpression of this receptor activated the Wnt/β‐catenin pathway by decreasing AXIN2 expression. Knockdown of tRF‐19‐PNR8YPJZ prior to PSC‐derived exosome treatment reversed its effects on Wnt/β‐catenin pathway activation.…”

“…AXIN2 is a homologous protein of the Axin family and has a high degree of structural and functional similarity with AXIN 33 . AXIN2, a negative inhibitor of the Wnt signalling pathway, regulates the phosphorylation and degradation of β‐catenin, thus promoting the overexpression of target genes, affecting cell proliferation and differentiation, and promoting the occurrence of tumours 34–36 . In this study, we showed that tRF‐19‐PNR8YPJZ bound to AXIN2 and that overexpression of this receptor activated the Wnt/β‐catenin pathway by decreasing AXIN2 expression.…”

SENP1-Mediated deSUMOylation Regulates the Tumor Remodeling of Glioma Stem Cells Under Hypoxic Stress

“… 30 The elevated expression of HIF1α can activate multiple intracellular signaling pathways, such as the Wnt/β-catenin axis, to maintain the stemness of GSCs, promote the expression and clonal proliferation of GSCs, and finally induce GSCs to differentiation into surrounding progeny tumor cells, further promoting tumor angiogenesis and enhancing invasion ability of tumor. 31 , 32 SENP1 can maintain HIF1 α stability, and activation of multiple signaling pathways under hypoxic conditions, promoting tumor growth and invasiveness. 33 Based on the phenomenon that the malignant behaviors of GSCs under hypoxia depended on deSUMOylation revealed by our experimental results, it is reasonable to deduce that SENP1-mediated deSUMOylation can serve as an important target for regulating the malignant behaviors of GSCs, which implied that downregulation of SENP1 not only inhibited the proliferation, migration, and differentiation abilities of GSC but also prevented tumor tissue remodeling.…”