Abstract
Radiation therapy is among the most essential treatment methods for glioblastoma multiforme (GBM). Radio-resistance and cancer stem cell properties can cause therapeutic resistance, cancer heterogeneity, and poor prognoses in association with GBM. Furthermore, the GBM subtype transition from proneural to the most malignant mesenchymal subtype after radiation therapy also accounts for high resistance to conventional treatments. Here, we demonstrate that the inhibition of macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT) by 4-iodo-6-phenylpyrimidine (4-IPP), a dual inhibitor targeting MIF and DDT, downregulates stemness phenotype, intracellular signaling cascades, mesenchymal trans-differentiation, and induces apoptosis in proneural glioma stem cells (GSCs). In an analysis of The Cancer Genome Atlas, high MIF and DDT expression were associated with poor prognosis. GSC growth was effectively inhibited by 4-IPP in a time- and dose-dependent manner, and 4-IPP combined with radiation therapy led to significantly reduced proliferation compared with radiation therapy alone. The expression of stemness factors, such as Olig2 and SOX2, and the expression of pAKT, indicating PI3K signaling pathway activation, were decreased in association with both 4-IPP monotherapy and combination treatment. The expression of mesenchymal markers, TGM2 and NF-κB, and expression of pERK (indicating MAPK signaling pathway activation) increased in association with radiation therapy alone but not with 4-IPP monotherapy and combination therapy. In addition, the combination of 4-IPP and radiation therapy significantly induced apoptosis compared to the monotherapy of 4-IPP or radiation. In vivo results demonstrated a significant tumor-suppressing effect of 4-IPP when combined with radiation therapy. Collectively, our results showed that the targeted inhibition of MIF and DDT has the potential to strengthen current clinical strategies by enhancing the anticancer effects of radiation therapy.
Highlights
Glioblastoma multiforme (GBM) is the most malignant type of brain tumor, with rapid recurrence and an extremely low survival rate [1]
To analyze the clinical importance of migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT) expression in gliomas, we first investigated the relationship of MIF and DDT expression with the survival of glioma patients using The Cancer Genome Atlas (TCGA)-GBMLGG cohort dataset (n = 694) from the University of California Santa Cruz (UCSC) Xena platform
The quartiles Kaplan-Meier survival plots showed that the MIF and DDT RNA levels were negatively associated with patient survival (Fig 1A–1C)
Summary
Glioblastoma multiforme (GBM) is the most malignant type of brain tumor, with rapid recurrence and an extremely low survival rate [1]. For GBM, radiation therapy is among the most essential treatment methods, along with chemotherapy [2]. Recurrence occurs frequently after radiation therapy due to the survival of radio-resistant tumor cells, inflammatory responses, immune suppression, and neo-vascularization of the irradiated areas [3,4]. Macrophage migration inhibitory factor (MIF) exerts multimodal functions in glioma, including proliferation, migration, angiogenesis promotion, inhibition of apoptosis, and immune evasion properties [5]. MIF is triggered by autocrine and paracrine signals by the tumor, and its expression level increases with the higher-grade tumors [6]. Evaluation of bioinformatics databases has shown significantly higher levels of MIF in GBM compared with nontumor tissues, and MIF expression has been associated with poor prognoses and early recurrence in association with gliomas [7,8]
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