ARL13B is regulated by the ERK/P90 pathway and mediates TMZ resistance in glioblastoma via microvesicles.

Temozolomide (TMZ) resistance presents a serious challenge in glioma treatment. It has been revealed that high expression of ADP-ribosylation factor-like GTPase 13B (ARL13B) is an important risk factor for glioma patients and is strongly related to RHO GTPase. Here, we presented a unique mechanism by which ARL13B induces TMZ resistance. The TCGA and CGGA datasets were used to conduct survival analysis. Metascape was utilized to perform pathway enrichment analysis. Western blot (WB), nanoparticle tracking analysis (NTA), and liquid chromatography-mass spectrometry (LC-MS) were used to explore the mechanisms of drug vesicular exocytosis that leads to ARL13B-mediated TMZ resistance. WB, qRT-PCR, and ChIP were used to validate the extracellular-regulated kinase (ERK)/P90 transcriptional regulatory signaling pathways. The expression of ARL13B increased ectosome efflux and decreased intracellular drug concentration. Besides, the ERK/P90 pathway could transcriptionally regulate ARL13B with C/EBPβ being one of the transcription factors of ARL13B. Inhibiting the ERK/P90 pathway could enhance the efficacy of TMZ. ARL13B was regulated by the ERK/P90 pathway and might impair the efficacy of TMZ by increasing drug efflux through ectosomes. Therefore, our study provided a novel mechanism of TMZ resistance and identifies a new target for glioma therapy.