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Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance
The activation of the Notch pathway induces glioblastoma (GBM) development. Since KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) is involved in the Notch pathway, the detailed mechanism is still undetermined. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases revealed that...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555920/ https://www.ncbi.nlm.nih.gov/pubmed/32927743 http://dx.doi.org/10.3390/biomedicines8090339 |
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author | Tsai, Yu-Ling Chang, Hsin-Han Chen, Ying-Chuan Chang, Yu-Chan Chen, Ying Tsai, Wen-Chiuan |
author_facet | Tsai, Yu-Ling Chang, Hsin-Han Chen, Ying-Chuan Chang, Yu-Chan Chen, Ying Tsai, Wen-Chiuan |
author_sort | Tsai, Yu-Ling |
collection | PubMed |
description | The activation of the Notch pathway induces glioblastoma (GBM) development. Since KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) is involved in the Notch pathway, the detailed mechanism is still undetermined. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases revealed that KDELC2 mRNA was associated with oncologic factors of GBM. U87, LN229, LNZ308, U118MG, and GBM8401 cells showed higher KDELC2 expression than normal brain tissues. The results of MTT, wound healing, and invasion assays proved that KDELC2 knockdown suppressed GBM-aggressive behaviors. The inhibitory properties of GBM stemness and angiogenesis under KDELC2 knockdown were evaluated by tumor spheroid and tube formation assays. Suppression of KDELC2 downregulated Notch factors’ expressions, including KDELC1, pofut1, Notch receptors 1–3, and HES-1. Immunoblot assay showed that KDELC2 knockdown promoted tumor apoptosis by downregulating PI3k/mTOR/Akt, MAPK/ERK, and NF-kB pathways. The combination of KDELC2 knockdown and temozolomide (TMZ) treatment had an optimal therapeutic effect by suppressing MGMT expression. Results of an orthotopic xenograft animal model and human tissue confirmed that KDELC2 correlated with glioma proliferation, advanced grades, and poor prognosis. Therefore, KDELC2 might be a potential pharmacological target to inhibit tumorigenesis, epithelial–mesenchymal transition, angiogenesis, and chemo-resistance of GBM. |
format | Online Article Text |
id | pubmed-7555920 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75559202020-10-19 Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance Tsai, Yu-Ling Chang, Hsin-Han Chen, Ying-Chuan Chang, Yu-Chan Chen, Ying Tsai, Wen-Chiuan Biomedicines Article The activation of the Notch pathway induces glioblastoma (GBM) development. Since KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) is involved in the Notch pathway, the detailed mechanism is still undetermined. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases revealed that KDELC2 mRNA was associated with oncologic factors of GBM. U87, LN229, LNZ308, U118MG, and GBM8401 cells showed higher KDELC2 expression than normal brain tissues. The results of MTT, wound healing, and invasion assays proved that KDELC2 knockdown suppressed GBM-aggressive behaviors. The inhibitory properties of GBM stemness and angiogenesis under KDELC2 knockdown were evaluated by tumor spheroid and tube formation assays. Suppression of KDELC2 downregulated Notch factors’ expressions, including KDELC1, pofut1, Notch receptors 1–3, and HES-1. Immunoblot assay showed that KDELC2 knockdown promoted tumor apoptosis by downregulating PI3k/mTOR/Akt, MAPK/ERK, and NF-kB pathways. The combination of KDELC2 knockdown and temozolomide (TMZ) treatment had an optimal therapeutic effect by suppressing MGMT expression. Results of an orthotopic xenograft animal model and human tissue confirmed that KDELC2 correlated with glioma proliferation, advanced grades, and poor prognosis. Therefore, KDELC2 might be a potential pharmacological target to inhibit tumorigenesis, epithelial–mesenchymal transition, angiogenesis, and chemo-resistance of GBM. MDPI 2020-09-10 /pmc/articles/PMC7555920/ /pubmed/32927743 http://dx.doi.org/10.3390/biomedicines8090339 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tsai, Yu-Ling Chang, Hsin-Han Chen, Ying-Chuan Chang, Yu-Chan Chen, Ying Tsai, Wen-Chiuan Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance |
title | Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance |
title_full | Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance |
title_fullStr | Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance |
title_full_unstemmed | Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance |
title_short | Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance |
title_sort | molecular mechanisms of kdelc2 on glioblastoma tumorigenesis and temozolomide resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555920/ https://www.ncbi.nlm.nih.gov/pubmed/32927743 http://dx.doi.org/10.3390/biomedicines8090339 |
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