Targeting NFE2L2, a transcription factor upstream of MMP-2: A potential therapeutic strategy for temozolomide resistant glioblastoma

Abstract

Glioblastoma (GBM) is the most malignant form of brain tumor posing a major threat to cancer amelioration. Temozolomide (TMZ) resistance is one of the major hurdles towards GBM prognosis. Oxidative stress and ECM remodeling are the two important processes involved in gaining chemo-resistance. Here, we established NFE2L2, an important member of oxidative stress regulation elevated in resistant cells, to be playing a transcriptional regulatory role on MMP-2, an ECM remodeling marker. This link led us to further explore targeted molecules to inhibit NFE2L2, thus affecting MMP-2, an important member promoting chemo-resistance. Thus, diosgenin was proposed as a novel NFE2L2 inhibitor acting as an alternative strategy to prevent the high dose administration of TMZ. Combinatorial therapy of diosgenin and TMZ significantly reduced the dosage regimen of TMZ and also showed affectivity in hitherto TMZ resistant GBM cells. GBM cells underwent apoptosis and early cell cycle arrest with significant reduction in MMP-2 levels. Thus preclinical validation of molecular interaction between diosgenin and NFE2L2 down-regulating MMP-2, EMT markers and promoting apoptosis, offers rationale for new therapeutic horizons in the field of glioblastoma management.