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 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.
The Rausing Laboratory, Department of Neurosurgery, Lund University, Lund, Sweden.
Dongfeng
D
Chen
Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing, China.
Duo
D
Zuo
Department of Clinical Science, Lund University, Malmö, Sweden.
Cheng
C
Luan
The Rausing Laboratory, Department of Neurosurgery, Lund University, Lund, Sweden.
Min
M
Liu
The Rausing Laboratory, Department of Neurosurgery, Lund University, Lund, Sweden.
Manli
M
Na
Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing, China.
Liang
L
Ran
Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing, China.
Yingyu
Y
Sun
Department of Pathology, Lund University, Lund, Sweden.
Annette
A
Persson
Department of Pathology, Lund University, Lund, Sweden.
Elisabet
E
Englund
The Rausing Laboratory, Department of Neurosurgery, Lund University, Lund, Sweden.
Leif G
LG
Salford
Department of Clinical Science, Lund University, Malmö, Sweden.
Erik
E
Renström
Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing, China.
Xiaolong
X
Fan
Department of Clinical Science, Lund University, Malmö, Sweden.
Enming
E
Zhang
D002070:Butadienes / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
D002070:Butadienes; D048049:Extracellular Signal-Regulated MAP Kinases; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C113580:U 0126; C093846:early endosome antigen 1