Exosome Secretion Drives Chemo‐Resistance of Temozolomide in Glioblastoma

Temozolomide (TMZ) is a first-line chemotherapeutic agent for the treatment of glioblastoma (GBM), while a majority of patients do not effectively respond to TMZ owing to the multiple resistance mechanisms. In this study, we found that TMZ treatment substantially increased the exosome secretion from GBM cell line. The secreted exosomes from TMZ-treated C6 cells maintained typical physicochemical properties, with only slight fluctuation in expression profile of surface markers compared to untreated cell-derived exosomes. Further investigation revealed that increased expression of p53 might be the predominant reason to promote exosome secretion, potentially through the upregulation of six-transmembrane epithelial antigen of prostate 3 (STEAP3) expression under stress condition. Moreover, we identified that pre-treatment with TMZ-induced exosomes could reduce the sensitivity of C6 cells to TMZ and considered that exosome secretion may serve as a potent TMZ resistance mechanism via enhancing anti-apoptotic ability of GBM cells towards TMZ exposure. Proteomics analysis revealed a strategic mechanism to resist TMZ-induced apoptosis by upregulating exosomal proteins associated with biogenesis, chemoresistance, and therapeutic adaption. This finding revealed a considerable TMZ resistance mechanism and provided a new inspiration for preventing exosome biogenesis to resensitise TMZ cytotoxicity towards GBM.