Inhibition of ABCG2 enhances chemo-sensitivity of murine glioma stem cell-like cells to temozolomide and reduces spheroid-forming capability

Abstract

[Abstract] Current evidence indicates that glioma stem cell-like cells (GSC_S) in humans play critical roles in the pathogenesis of carcinogenesis ofglioblastoma (GBM ). The GSC_S are known to overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters to exhibit multidrug resistance. Eradication of the GSC compartment is therefore essential to achieve a stable and long-lasting remission of GBM. To elucidate the characteristics of GSC_S in detail, we generated murine GSC lines from Sleeping Beauty transposon-mediated spontaneous GBM . Using these several cell lines, we evaluated the significance of ABC transporters in the GSC kinetics by cell morphology assays, flow cytometry, and quantitativeRT-PCR for mRNA expressions. As a consequence, we show that siRNA-mediated ABCG2 inhibition enhances the sensitivity of GSC_S to temozolomide (TMZ) and in turn reduces their spheroid-forming capability. Furthermore, we show that GSC_S treated with Abcg2-specific siRNA become sensitive to TMZ and reduce their spheroid-forming capability. In conclusion, our data suggest that targeting of drug transporters in GSC_S is a promising strategy to enhance their chemo-sensitivity for achieving a longlasting remission of GBM