Inhibiting HOX-PBX binding in paediatric glioblastoma as a novel therapeutic treatment


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William Rogers1,Richard Morgan2,Hardev Pandha1
1University of Surrey,2University of Bradford

Abstract

Background

The HOX genes encode a family of transcription factors that play an essential role in embryonic patterning, but are dysregulated in numerous cancers, including glioblastoma. Previous research indicates that all HOX genes are expressed at varying levels in glioblastoma cells, but are highly expressed in glioma stem cells. Previously we reported that disrupting HOX-PBX binding using the HXR9 peptide induced adult glioblastoma cell lines to undergo apoptosis, and that glioma stem cells were the most sensitive to HXR9-mediated death. In this study we assessed whether HXR9 could also kill paediatric glioblastoma cells.

Method

HOX and PBX expression was determined using quantitative RT-PCR. Glioma and glioma stem cells were then treated with HXR9, and cell viability was determined by MTS assay. Mode of death was determined via RT-PCR and western blots.

Results

Glioma cell lines showed elevated HOX and PBX expression compared to normal healthy normal paediatric brain tissue. HXR9 showed dose dependent cytotoxicity in all cell lines, with IC50 results below 80uM for all cell lines. Mode of death was determined to be apoptosis mediated by C-Fos up regulation and Bcl-2 down regulation.

Conclusion

Initial results show that HOX and PBX genes are aberrantly expressed in paediatric glioma cells, and up regulated compared to healthy normal brain. HXR9 is cytotoxic against glioma cells This is mediated by an up regulation of C-Fos, and subsequent down regulation of Bcl-2 leading to apoptosis.