Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA.
Increased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells rema...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3906156?pdf=render |
| _version_ | 1818361391874048000 |
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| author | Dongfeng Chen Duo Zuo Cheng Luan Min Liu Manli Na Liang Ran Yingyu Sun Annette Persson Elisabet Englund Leif G Salford Erik Renström Xiaolong Fan Enming Zhang |
| author_facet | Dongfeng Chen Duo Zuo Cheng Luan Min Liu Manli Na Liang Ran Yingyu Sun Annette Persson Elisabet Englund Leif G Salford Erik Renström Xiaolong Fan Enming Zhang |
| author_sort | Dongfeng Chen |
| collection | DOAJ |
| description | Increased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells remains poorly characterized. Here, we report that cell surface PDGFRA expression in gliomas is negatively regulated by an ERK-dependent mechanism, resulting in reduced proliferation of glioma cells. Glioma tumor tissues and their corresponding cell lines were isolated from 14 patients and analyzed by single-cell imaging and flow cytometry. In both cell lines and their corresponding tumor samples, glioma cell proliferation correlated with the extent of surface expression of PDGFRA. High levels of surface PDGFRA also correlated to high tubulin expression in glioma tumor tissue in vivo. In glioma cell lines, surface PDGFRA declined following treatment with inhibitors of tubulin, actin and dynamin. Screening of a panel of small molecule compounds identified the MEK inhibitor U0126 as a potent inhibitor of surface PDGFRA expression. Importantly, U0126 inhibited surface expression in a reversible, dose- and time-dependent manner, without affecting general PDGFRA expression. Treatment with U0126 resulted in reduced co-localization between PDGFRA and intracellular trafficking molecules e.g. clathrin, RAB11 and early endosomal antigen-1, in parallel with enhanced co-localization between PDGFRA and the Golgi cisternae maker, Giantin, suggesting a deviation of PDGFRA from the endosomal trafficking and recycling compartment, to the Golgi network. Furthermore, U0126 treatment in glioma cells induced an initial inhibition of ERK1/2 phosphorylation, followed by up-regulated ERK1/2 phosphorylation concomitant with diminished surface expression of PDGFRA. Finally, down-regulation of surface PDGFRA expression by U0126 is concordant with reduced glioma cell proliferation. These findings suggest that manipulation of spatial expression of PDGFRA can potentially be used to combat gliomas. |
| first_indexed | 2024-12-13T21:15:57Z |
| format | Article |
| id | doaj.art-dde889ec1b024d5c9bce010e23448f2b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T21:15:57Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-dde889ec1b024d5c9bce010e23448f2b2022-12-21T23:31:15ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0191e8728110.1371/journal.pone.0087281Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA.Dongfeng ChenDuo ZuoCheng LuanMin LiuManli NaLiang RanYingyu SunAnnette PerssonElisabet EnglundLeif G SalfordErik RenströmXiaolong FanEnming ZhangIncreased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells remains poorly characterized. Here, we report that cell surface PDGFRA expression in gliomas is negatively regulated by an ERK-dependent mechanism, resulting in reduced proliferation of glioma cells. Glioma tumor tissues and their corresponding cell lines were isolated from 14 patients and analyzed by single-cell imaging and flow cytometry. In both cell lines and their corresponding tumor samples, glioma cell proliferation correlated with the extent of surface expression of PDGFRA. High levels of surface PDGFRA also correlated to high tubulin expression in glioma tumor tissue in vivo. In glioma cell lines, surface PDGFRA declined following treatment with inhibitors of tubulin, actin and dynamin. Screening of a panel of small molecule compounds identified the MEK inhibitor U0126 as a potent inhibitor of surface PDGFRA expression. Importantly, U0126 inhibited surface expression in a reversible, dose- and time-dependent manner, without affecting general PDGFRA expression. Treatment with U0126 resulted in reduced co-localization between PDGFRA and intracellular trafficking molecules e.g. clathrin, RAB11 and early endosomal antigen-1, in parallel with enhanced co-localization between PDGFRA and the Golgi cisternae maker, Giantin, suggesting a deviation of PDGFRA from the endosomal trafficking and recycling compartment, to the Golgi network. Furthermore, U0126 treatment in glioma cells induced an initial inhibition of ERK1/2 phosphorylation, followed by up-regulated ERK1/2 phosphorylation concomitant with diminished surface expression of PDGFRA. Finally, down-regulation of surface PDGFRA expression by U0126 is concordant with reduced glioma cell proliferation. These findings suggest that manipulation of spatial expression of PDGFRA can potentially be used to combat gliomas.http://europepmc.org/articles/PMC3906156?pdf=render |
| spellingShingle | Dongfeng Chen Duo Zuo Cheng Luan Min Liu Manli Na Liang Ran Yingyu Sun Annette Persson Elisabet Englund Leif G Salford Erik Renström Xiaolong Fan Enming Zhang Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. PLoS ONE |
| title | Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. |
| title_full | Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. |
| title_fullStr | Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. |
| title_full_unstemmed | Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. |
| title_short | Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. |
| title_sort | glioma cell proliferation controlled by erk activity dependent surface expression of pdgfra |
| url | http://europepmc.org/articles/PMC3906156?pdf=render |
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