Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.

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 proneur...

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Autores principales:	Shin Heon Lee, Hyung Joon Kwon, Saewhan Park, Chan Il Kim, Haseo Ryu, Sung Soo Kim, Jong Bae Park, Jeong Taik Kwon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a71165f687d94d9c9f2fcf1b5b961627
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spelling	oai:doaj.org-article:a71165f687d94d9c9f2fcf1b5b9616272021-12-02T20:14:39ZMacrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.1932-620310.1371/journal.pone.0257375https://doaj.org/article/a71165f687d94d9c9f2fcf1b5b9616272021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0257375https://doaj.org/toc/1932-6203Radiation 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.Shin Heon LeeHyung Joon KwonSaewhan ParkChan Il KimHaseo RyuSung Soo KimJong Bae ParkJeong Taik KwonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0257375 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shin Heon Lee Hyung Joon Kwon Saewhan Park Chan Il Kim Haseo Ryu Sung Soo Kim Jong Bae Park Jeong Taik Kwon Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
description	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.
format	article
author	Shin Heon Lee Hyung Joon Kwon Saewhan Park Chan Il Kim Haseo Ryu Sung Soo Kim Jong Bae Park Jeong Taik Kwon
author_facet	Shin Heon Lee Hyung Joon Kwon Saewhan Park Chan Il Kim Haseo Ryu Sung Soo Kim Jong Bae Park Jeong Taik Kwon
author_sort	Shin Heon Lee
title	Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
title_short	Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
title_full	Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
title_fullStr	Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
title_full_unstemmed	Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
title_sort	macrophage migration inhibitory factor (mif) inhibitor 4-ipp downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a71165f687d94d9c9f2fcf1b5b961627
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Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.

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