Cargando…
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...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437287/ https://www.ncbi.nlm.nih.gov/pubmed/34516577 http://dx.doi.org/10.1371/journal.pone.0257375 |
_version_ | 1783752141999964160 |
---|---|
author | Lee, Shin Heon Kwon, Hyung Joon Park, Saewhan Kim, Chan Il Ryu, Haseo Kim, Sung Soo Park, Jong Bae Kwon, Jeong Taik |
author_facet | Lee, Shin Heon Kwon, Hyung Joon Park, Saewhan Kim, Chan Il Ryu, Haseo Kim, Sung Soo Park, Jong Bae Kwon, Jeong Taik |
author_sort | Lee, Shin Heon |
collection | PubMed |
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 | Online Article Text |
id | pubmed-8437287 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-84372872021-09-14 Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme Lee, Shin Heon Kwon, Hyung Joon Park, Saewhan Kim, Chan Il Ryu, Haseo Kim, Sung Soo Park, Jong Bae Kwon, Jeong Taik PLoS One Research Article 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. Public Library of Science 2021-09-13 /pmc/articles/PMC8437287/ /pubmed/34516577 http://dx.doi.org/10.1371/journal.pone.0257375 Text en © 2021 Lee et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Lee, Shin Heon Kwon, Hyung Joon Park, Saewhan Kim, Chan Il Ryu, Haseo Kim, Sung Soo Park, Jong Bae Kwon, Jeong Taik Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437287/ https://www.ncbi.nlm.nih.gov/pubmed/34516577 http://dx.doi.org/10.1371/journal.pone.0257375 |
work_keys_str_mv | AT leeshinheon macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme AT kwonhyungjoon macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme AT parksaewhan macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme AT kimchanil macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme AT ryuhaseo macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme AT kimsungsoo macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme AT parkjongbae macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme AT kwonjeongtaik macrophagemigrationinhibitoryfactormifinhibitor4ippdownregulatesstemnessphenotypeandmesenchymaltransdifferentiationafterirradiationinglioblastomamultiforme |