Glioma stem cells deliver ABCB4 transcribed by ATF3 via exosomes conferring glioma resistance to temozolomide

Abstract

Glioma stem cells (GSCs) play a key role in glioma resistance to temozolomide (TMZ) chemotherapy. With the gradual increase in research on the tumor microenvironment, exosomes secreted by GSCs have become a new focus in glioma research. However, the molecular mechanism by which GSCs affect drug resistance in glioma cells via exosomes remains unclear. Using bioinformatics analysis, we identified the specific expression of ABCB4 in GSCs. Subsequently, we established GSC cell lines and used ultracentrifugation to extract secreted exosomes. We conducted in vitro and in vivo investigations to validate the promoting effect of ABCB4- and ABCB4-containing exosomes on TMZ resistance. Finally, to identify the transcription factors regulating the transcription of ABCB4, we performed luciferase assays and chromatin immunoprecipitation-quantitative PCR. Our results indicated that ABCB4 is highly expressed in GSCs. Moreover, high expression of ABCB4 promoted the resistance of GSCs to TMZ. Our study found that GSCs can also transmit their highly expressed ABCB4 to differentiated glioma cells through exosomes, leading to high expression of ABCB4 in these cells and promoting their resistance to TMZ. Mechanistic studies have shown that the overexpression of ABCB4 in GSCs is mediated by the transcription factor ATF3. In conclusion, our results indicate that GSCs can confer resistance to TMZ in gliomas by transmitting ABCB4, which is transcribed by ATF3, through exosomes. This mechanism may lead to drug resistance and recurrence of glioma. These findings contribute to a deeper understanding of the mechanisms underlying drug resistance in glioma and provide novel insights into its treatment.