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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo

Authors: Mrinal Joel, Awais A. Mughal, Zanina Grieg, Wayne Murrell, Sheryl Palmero, Birthe Mikkelsen, Hege B. Fjerdingstad, Cecilie J. Sandberg, Jinan Behnan, Joel C. Glover, Iver A. Langmoen, Biljana Stangeland

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

Glioblastomas are invasive therapy resistant brain tumors with extremely poor prognosis. The Glioma initiating cell (GIC) population contributes to therapeutic resistance and tumor recurrence. Targeting GIC-associated gene candidates could significantly impact GBM tumorigenicity. Here, we investigate a protein kinase, PBK/TOPK as a candidate for regulating growth, survival and in vivo tumorigenicity of GICs.

Methods

PBK is highly upregulated in GICs and GBM tissues as shown by RNA and protein analyses. We knocked down PBK using shRNA vectors and inhibited the function of PBK protein with a pharmacological PBK inhibitor, HITOPK-032. We assessed viability, tumorsphere formation and apoptosis in three patient derived GIC cultures.

Results

Gene knockdown of PBK led to decreased viability and sphere formation and in one culture an increase in apoptosis. Treatment of cells with inhibitor HITOPK-032 (5 μM and 10 μM) almost completely abolished growth and elicited a large increase in apoptosis in all three cultures. HI-TOPK-032 treatment (5 mg/kg and 10 mg/kg bodyweight) in vivo resulted in diminished growth of experimentally induced subcutaneous GBM tumors in mice. We also carried out multi-culture assays of cell survival to investigate the relative effects on GICs compared with the normal neural stem cells (NSCs) and their differentiated counterparts. Normal NSCs seemed to withstand treatment slightly better than the GICs.

Conclusion

Our study of identification and functional validation of PBK suggests that this candidate can be a promising molecular target for GBM treatment.
Appendix
Available only for authorised users
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Metadata
Title
Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo
Authors
Mrinal Joel
Awais A. Mughal
Zanina Grieg
Wayne Murrell
Sheryl Palmero
Birthe Mikkelsen
Hege B. Fjerdingstad
Cecilie J. Sandberg
Jinan Behnan
Joel C. Glover
Iver A. Langmoen
Biljana Stangeland
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0398-x

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