Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex

Abstract

AbstractDespite 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 identifiedmiR-19b. Our study reveals a novel axis betweenmiR-19band PPP2R5E subunit of serine/threonine protein phosphatase PP2A and establishes a so far unappreciated contribution ofmiR-19bin TMZ resistance of GBM. Specifically, our results demonstrate that attenuation ofmiR-19bin 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-19battenuation or PPP2R5E activation could potentially be exploited in adjuvant therapy of GBM patients.