Pharmacological Blockade of NMUR2 Suppresses Glioma Growth by Inhibiting STAT5-Mediated Transcription of Cell Cycle-associated Genes

Abstract

Glioma is a highly aggressive brain tumor with poor prognosis and limited therapeutic options. Although temozolomide (TMZ) remains the standard chemotherapeutic agent for glioma, frequent recurrence and the development of therapeutic resistance continue to limit clinical benefit, highlighting the need for new molecular targets and treatment strategies. Here, we identify neuromedin U receptor 2 (NMUR2) as a driver of glioma progression and a potential therapeutic target. NMUR2 expression was markedly elevated in glioma tissues and positively associated with tumor grade. Functional analyses showed that NMUR2 promoted glioma cell proliferation and migration, whereas NMUR2 silencing attenuated these malignant phenotypes. Mechanistically, NMUR2 activated Gαq-dependent Ca²⁺ signaling, leading to STAT5 phosphorylation and subsequent transcriptional upregulation of the cell cycle-associated genes PIM1 and FOXM1. Drug-repurposing screening of 6,331 compounds identified NNC 05-2090 as a candidate NMUR2 antagonist. NNC 05-2090 blocked NMUR2-mediated Gαq/Ca²⁺/STAT5 signaling, which was associated with reduced PIM1 and FOXM1 expression, cell cycle arrest, and suppression of glioma growth in vitro and in vivo. In addition, combination treatment with TMZ produced synergistic anti-tumor effects in glioma models. Collectively, our findings define a previously unrecognized NMUR2/Gαq/STAT5/PIM1-FOXM1 signaling axis in glioma and support pharmacological inhibition of NMUR2 as a potential therapeutic strategy.