A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation

Kirsten Strømme Kierulf-Vieira; Cecilie Jonsgar Sandberg; Jo Waaler; Kaja Lund; Erlend Skaga; Birthe Mikkelsen Saberniak; Ioannis Panagopoulos; Petter Brandal; Stefan Krauss; Iver Arne Langmoen; Einar Osland Vik-Mo

doi:10.3390/cancers12061630

A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation

Cancers (Basel). 2020 Jun 19;12(6):1630. doi: 10.3390/cancers12061630.

Authors

Kirsten Strømme Kierulf-Vieira^{1

2

3}, Cecilie Jonsgar Sandberg^{1

2}, Jo Waaler^{4

5}, Kaja Lund^{4

5}, Erlend Skaga^{1

2

3}, Birthe Mikkelsen Saberniak^{1

2}, Ioannis Panagopoulos⁶, Petter Brandal^{6

7

8}, Stefan Krauss^{4

5}, Iver Arne Langmoen^{1

2

3

8

9}, Einar Osland Vik-Mo^{1

2

3

8

9}

Affiliations

¹ Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway.
² Norwegian Stem Cell Center, Oslo University Hospital, University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway.
³ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway.
⁴ Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway.
⁵ Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 OSLO, Norway.
⁶ Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, P.O. Box 49534 Nydalen, 0424 Oslo, Norway.
⁷ Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, P.O. Box 49534 Nydalen, 0424 Oslo, Norway.
⁸ Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway.
⁹ 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.

Keywords: Hippo; WNT; glioblastoma; glioma stem cells; tankyrase; temozolomide; β-catenin.

Abstract

Grants and funding