Cyclooxygenase-2 as a potential therapeutic target in the treatment of chemoresistant glioblastomas.

Abstract

Glioblastoma multiforme (GBM) remains one of the most lethal malignancies due to its marked resistance to standard therapies and a profoundly immunosuppressive tumor microenvironment. Cyclooxygenase-2 (COX-2), via its enzymatic product prostaglandin E2 (PGE2), has emerged as a central driver of multiple oncogenic processes in GBM, including immune evasion, therapy resistance, glioma stemness, and vascular mimicry. This review consolidates recent molecular findings on the COX-2/PGE2 axis, with particular focus on EP2/EP4-mediated signaling pathways such as PI3K/AKT, MAPK, β-catenin/TCF4, and JAK/STAT3, which collectively contribute to tumor proliferation, radioresistance, and PD-L1 expression. Notably, COX-2 promotes extracellular matrix degradation and glioma invasiveness by upregulating matrix metalloproteinase-9 (MMP-9) through TGF-β1 derived from tumor-associated macrophages (TAMs). In parallel, COX-2 facilitates TAM polarization toward an M2-like phenotype and supports the self-renewal of glioblastoma stem cells (GSCs), reinforcing both immune suppression and therapeutic escape. Furthermore, recent data reveal that COX-2 inhibition by celecoxib contributes to mitochondrial dysfunction by downregulating respiratory complexes and mitochondrial biogenesis regulators such as TFAM and NRF2, ultimately leading to bioenergetic collapse and sensitization to chemotherapy-induced apoptosis. By integrating diverse yet interconnected mechanisms under the umbrella of COX-2 signaling, this review outlines potential therapeutic opportunities aimed at disrupting its multifaceted role in GBM pathogenesis and treatment resistance.