A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation
Kirsten Strømme Kierulf-Vieira1,2,3, Cecilie Jonsgar Sandberg1,2, Jo Waaler4,5
1Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway.
Abstract:
Evidence suggests that the growth and therapeutic resistance of glioblastoma (GBM) may be enabled by a population of glioma stem cells (GSCs) that are regulated by typical stem cell pathways, including the WNT/β-catenin signaling pathway. We wanted to explore the effect of treating GSCs with a small-molecule inhibitor of tankyrase, G007-LK, which has been shown to be a potent modulator of the WNT/β-catenin and Hippo pathways in colon cancer. Four primary GSC cultures and two primary adult neural stem cell cultures were treated with G007-LK and subsequently evaluated through the measurement of growth characteristics, as well as the expression of WNT/β-catenin and Hippo signaling pathway-related proteins and genes. Treatment with G007-LK decreased in vitro proliferation and sphere formation in all four primary GSC cultures in a dose-dependent manner. G007-LK treatment altered the expression of key downstream WNT/β-catenin and Hippo signaling pathway-related proteins and genes. Finally, cotreatment with the established GBM chemotherapeutic compound temozolomide (TMZ) led to an additive reduction in sphere formation, suggesting that WNT/β-catenin signaling may contribute to TMZ resistance. These observations suggest that tankyrase inhibition may serve as a supplement to current GBM therapy, although more work is needed to determine the exact downstream mechanisms involved.
Insights
Tankyrase inhibition with G007-LK reduces glioblastoma stem cell growth and sphere formation. This approach may enhance chemotherapy effectiveness, offering a potential new strategy for glioblastoma (GBM) treatment.
Area of Science:
- Cancer Biology
- Stem Cell Research
- Pharmacology
Background:
- Glioblastoma (GBM) growth and therapeutic resistance are linked to glioma stem cells (GSCs).
- GSCs are regulated by stem cell pathways, notably the WNT/β-catenin signaling pathway.
- Tankyrase inhibitors modulate WNT/β-catenin and Hippo pathways, showing promise in other cancers.
Purpose of the Study:
- To investigate the effect of the tankyrase inhibitor G007-LK on GSCs.
- To explore G007-LK's impact on WNT/β-catenin and Hippo signaling in GSCs.
- To assess G007-LK's potential as an adjunct therapy for glioblastoma.
Main Methods:
- Treatment of four primary GSC cultures and two neural stem cell cultures with G007-LK.
- Evaluation of in vitro proliferation and sphere formation.
- Analysis of WNT/β-catenin and Hippo pathway-related gene and protein expression.
Main Results:
- G007-LK significantly decreased GSC proliferation and sphere formation in a dose-dependent manner.
- G007-LK altered the expression of key proteins and genes in the WNT/β-catenin and Hippo pathways.
- Combined treatment with temozolomide (TMZ) and G007-LK showed an additive reduction in sphere formation.
Conclusions:
- Tankyrase inhibition via G007-LK demonstrates anti-proliferative effects on glioblastoma stem cells.
- The WNT/β-catenin pathway may contribute to temozolomide resistance in glioblastoma.
- Tankyrase inhibition presents a potential supplementary therapeutic strategy for glioblastoma, warranting further mechanistic investigation.
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