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01.12.2016 | Primary research | Ausgabe 1/2016 Open Access

Cancer Cell International 1/2016

Topoisomerase IIβ mediates the resistance of glioblastoma stem cells to replication stress-inducing drugs

Zeitschrift:
Cancer Cell International > Ausgabe 1/2016
Autoren:
Saša Kenig, Valentina Faoro, Evgenia Bourkoula, Neža Podergajs, Tamara Ius, Marco Vindigni, Miran Skrap, Tamara Lah, Daniela Cesselli, Paola Storici, Alessandro Vindigni
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Electronic supplementary material

The online version of this article (doi:10.​1186/​s12935-016-0339-9) contains supplementary material, which is available to authorized users.

Abstract

Background

Glioblastoma stem cells (GSC) have been extensively recognized as a plausible cause of glioblastoma resistance to therapy and recurrence resulting in high glioblastoma mortality. Abnormalities in the DNA repair pathways might be responsible for the inability of the currently used chemotherapeutics to eliminate the (GSC) subpopulation.

Methods

In this work, we compared the expression of sixty DNA repair related genes between primary glioblastoma cell cultures and the glioblastoma enriched stem cell primary cultures. MTT test was used to analyze the effect of selected drugs and immunofluorescence to evaluate the load of DNA damage.

Results

We found several differentially expressed genes and we identified topoisomerase IIβ (Top2β) as the gene with highest up-regulation in GSC. Also among the tested cell lines the expression of Top2β was the highest in NCH421k cells, a well-characterized glioblastoma cell line with all the stemness characteristics. On the other hand, Top2β expression markedly decreased upon the induction of differentiation by all trans-retinoic acid. Depletion of Top2β increased the sensitivity of NCH421k cells to replication stress inducing drugs, such as cisplatin, methyl-methanesulfonate, hydrogen peroxide, and temozolomide. Consistently, we found an increased load of DNA damage and increased Chk1 activation upon Top2β depletion in NCH421k cells.

Conclusion

We suggest that Top2β may represent a new target for gene therapy in glioblastoma. In addition, the other genes that we found to be up-regulated in GSC versus glioblastoma primary cells should be further investigated as glioblastoma theranostics.
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