IL-37 drives temozolomide resistance in glioblastoma via MAPK pathway activation.

Abstract

The features of high heterogeneity and aggressiveness of glioblastoma (GBM) predispose it to temozolomide (TMZ) resistance, which notably impairs therapeutic efficacy. Cytokine family members have been shown to activate pro-survival pathways in GBM cells and facilitate the formation of immunosuppressive microenvironments, contributing to TMZ resistance in GBM. The present study aimed to investigate the role of cytokine IL-37 in the malignant progression and TMZ resistance of GBM. Recombinant human IL-37b (rIL-37) enhanced the survival of TMZ-treated GBM U251 cells. IL-37 silencing or overexpression notably reduced or increased the survival rate of U251 cells exposed to TMZ, respectively. In TMZ-resistant U251 (U251-TR) cells, IL-37 knockdown also improved cellular sensitivity to TMZ. Consistent with these findings, rIL-37 treatment promoted proliferation and suppressed apoptosis of U251 cells under TMZ exposure, whereas IL-37 silencing significantly suppressed growth and enhanced the apoptotic responses of U251-TR cells receiving TMZ. To explore the underlying mechanisms, RNA sequencing was performed and revealed that the U251 cells undergoing TMZ exposure and rIL-37 treatment exhibited an altered transcriptomic profile, characterized by the activation of both mitogen-activated protein kinase (MAPK) pathways and senescence-related pathways. After confirming the activation of cellular MAPK cascades and senescence, Adezmapimod, a p38 MAPK-specific inhibitor, effectively counteracted rIL-37-induced improvements in cellular survival and proliferative capacity, suppression of apoptosis and activation of senescence in U251 cells under TMZ exposure, indicating the necessity of the MAPK pathway in TMZ resistance. The present study expands the current knowledge of the roles of IL-37 during the malignant progression of GBM and demonstrates that IL-37 enhances TMZ resistance in GBM cells by activating the MAPK pathway and inhibiting apoptosis, suggesting that targeted inhibition of MAPK cascades in GBM is promising in future clinical practice.