IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced.
Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5215606?pdf=render |
| _version_ | 1819044045237780480 |
|---|---|
| author | Huixia Zhu Ye Zhang Jianfeng Chen Jiangdong Qiu Keting Huang Mindan Wu Chunlin Xia |
| author_facet | Huixia Zhu Ye Zhang Jianfeng Chen Jiangdong Qiu Keting Huang Mindan Wu Chunlin Xia |
| author_sort | Huixia Zhu |
| collection | DOAJ |
| description | Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation.Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively. NADP+/NADPH and GSH quantification assays were performed to evaluate effects of IDH1 R132H mutation on the production of antioxidant NADPH and GSH.We found that over expression of IDH1 R132H mutation decreased cell proliferation consistent with previous reports; however, it increased cell migration and enhanced AKT-mTOR signaling pathway activation. Mutations in isocitrate dehydrogenase (IDH) 1 also change the function of the enzymes and cause them to produce 2-hydroxyglutarate and not produce NADPH. We tested the level of NADPH and GSH and demonstrated that IDH1 R132H mutant stable cells had significantly low NADPH and GSH level compared to control or IDH1 wild type stable cells. The reduced antioxidants (NADPH and GSH) sensitized U87MG cells with IDH R132H mutant to 5-FU treatment.Our study highlights the important role of IHD1 R132H mutant in up- regulating AKT-mTOR signaling pathway and enhancing cell migration. Furthermore, we demonstrate that IDH1 R132H mutation affects cellular redox status and sensitizes gliomas cells with IDH1 R132H mutation to 5FU treatment. |
| first_indexed | 2024-12-21T10:06:26Z |
| format | Article |
| id | doaj.art-dadaab27491b49998e0f4ff41b70b18a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T10:06:26Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-dadaab27491b49998e0f4ff41b70b18a2022-12-21T19:07:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01121e016903810.1371/journal.pone.0169038IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced.Huixia ZhuYe ZhangJianfeng ChenJiangdong QiuKeting HuangMindan WuChunlin XiaMutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation.Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively. NADP+/NADPH and GSH quantification assays were performed to evaluate effects of IDH1 R132H mutation on the production of antioxidant NADPH and GSH.We found that over expression of IDH1 R132H mutation decreased cell proliferation consistent with previous reports; however, it increased cell migration and enhanced AKT-mTOR signaling pathway activation. Mutations in isocitrate dehydrogenase (IDH) 1 also change the function of the enzymes and cause them to produce 2-hydroxyglutarate and not produce NADPH. We tested the level of NADPH and GSH and demonstrated that IDH1 R132H mutant stable cells had significantly low NADPH and GSH level compared to control or IDH1 wild type stable cells. The reduced antioxidants (NADPH and GSH) sensitized U87MG cells with IDH R132H mutant to 5-FU treatment.Our study highlights the important role of IHD1 R132H mutant in up- regulating AKT-mTOR signaling pathway and enhancing cell migration. Furthermore, we demonstrate that IDH1 R132H mutation affects cellular redox status and sensitizes gliomas cells with IDH1 R132H mutation to 5FU treatment.http://europepmc.org/articles/PMC5215606?pdf=render |
| spellingShingle | Huixia Zhu Ye Zhang Jianfeng Chen Jiangdong Qiu Keting Huang Mindan Wu Chunlin Xia IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced. PLoS ONE |
| title | IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced. |
| title_full | IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced. |
| title_fullStr | IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced. |
| title_full_unstemmed | IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced. |
| title_short | IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced. |
| title_sort | idh1 r132h mutation enhances cell migration by activating akt mtor signaling pathway but sensitizes cells to 5 fu treatment as nadph and gsh are reduced |
| url | http://europepmc.org/articles/PMC5215606?pdf=render |
| work_keys_str_mv | AT huixiazhu idh1r132hmutationenhancescellmigrationbyactivatingaktmtorsignalingpathwaybutsensitizescellsto5futreatmentasnadphandgsharereduced AT yezhang idh1r132hmutationenhancescellmigrationbyactivatingaktmtorsignalingpathwaybutsensitizescellsto5futreatmentasnadphandgsharereduced AT jianfengchen idh1r132hmutationenhancescellmigrationbyactivatingaktmtorsignalingpathwaybutsensitizescellsto5futreatmentasnadphandgsharereduced AT jiangdongqiu idh1r132hmutationenhancescellmigrationbyactivatingaktmtorsignalingpathwaybutsensitizescellsto5futreatmentasnadphandgsharereduced AT ketinghuang idh1r132hmutationenhancescellmigrationbyactivatingaktmtorsignalingpathwaybutsensitizescellsto5futreatmentasnadphandgsharereduced AT mindanwu idh1r132hmutationenhancescellmigrationbyactivatingaktmtorsignalingpathwaybutsensitizescellsto5futreatmentasnadphandgsharereduced AT chunlinxia idh1r132hmutationenhancescellmigrationbyactivatingaktmtorsignalingpathwaybutsensitizescellsto5futreatmentasnadphandgsharereduced |