Abstract

Despite the standard of care, glioblastoma IDH wildtype (GBM) inevitably recurs, underscoring the need to develop new treatment strategies. To address the role of microRNAs in temozolomide (TMZ) response, we performed functional microRNA screens and consistently identified miR-19b. Our study reveals a novel axis between miR-19b and PPP2R5E subunit of serine/threonine protein phosphatase PP2A and establishes a so far unappreciated contribution of miR-19b in TMZ resistance of GBM. Specifically, our results demonstrate that attenuation of miR-19b in GBM cell lines and glioblastoma stem cells (GSCs) induces DNA damage, which further enhances the cytotoxic effects of TMZ treatment. We confirmed TMZ resistance induced by knocking down PPP2R5E in orthotopic mouse xenografts of GSCs. Furthermore, our results indicate that treating cells with the PP2A-activating drug FTY720 or knocking down endogenous PP2A-inhibiting proteins potentiates the cytotoxic effects of TMZ. MiR-19b attenuation or PPP2R5E activation could potentially be exploited in adjuvant therapy of GBM patients.