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...
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MDPI AG
2020-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/9/339 |
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| author | Yu-Ling Tsai Hsin-Han Chang Ying-Chuan Chen Yu-Chan Chang Ying Chen Wen-Chiuan Tsai |
| author_facet | Yu-Ling Tsai Hsin-Han Chang Ying-Chuan Chen Yu-Chan Chang Ying Chen Wen-Chiuan Tsai |
| author_sort | Yu-Ling Tsai |
| collection | DOAJ |
| 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. |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T16:25:08Z |
| publishDate | 2020-09-01 |
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| series | Biomedicines |
| spelling | doaj.art-11f9053a86d84871b288648408d8825a2023-11-20T13:14:01ZengMDPI AGBiomedicines2227-90592020-09-018933910.3390/biomedicines8090339Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide ResistanceYu-Ling Tsai0Hsin-Han Chang1Ying-Chuan Chen2Yu-Chan Chang3Ying Chen4Wen-Chiuan Tsai5Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanGraduate Institute of Life Science, National Defense Medical Center, Taipei 114, TaiwanDepartment of Physiology and Biophysics, National Defense Medical Center, Taipei 114, TaiwanDepartment of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 115, TaiwanDepartment of Biology and Anatomy, National Defense Medical Center, Taipei 114, TaiwanDepartment of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanThe 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.https://www.mdpi.com/2227-9059/8/9/339KDELC2glioblastomaNotchtemozolomide |
| spellingShingle | Yu-Ling Tsai Hsin-Han Chang Ying-Chuan Chen Yu-Chan Chang Ying Chen Wen-Chiuan Tsai Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance Biomedicines KDELC2 glioblastoma Notch temozolomide |
| 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 | KDELC2 glioblastoma Notch temozolomide |
| url | https://www.mdpi.com/2227-9059/8/9/339 |
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