Knockdown a Water Channel Protein, Aquaporin-4, Induced Glioblastoma Cell Apoptosis

Ding, Ting; Zhou, Ying; Sun, Kai; Jiang, Weizhong; Li, Wenliang; Liu, Xiaoli; Tian, Chunying; Li, Zhihui; Ying, Guoguang; Fu, Li; Gu, Feng; Li, Weidong; Ma, Yihui

doi:10.1371/journal.pone.0066751

Cited by 43 publications

(40 citation statements)

References 23 publications

(24 reference statements)

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“…Fascinatingly, knocking-down AQP4 expression concurrently led to the suppression of migration and invasion of glioblastoma cells. Ding et al reported an association of AQP4 downregulation with death of glioblastoma cells [22]. Speedy migration and invasion of glioblastoma cells into surrounding healthy brain tissues are two typical characteristics leading to poor outcomes for GBM patients [7].…”

Section: Discussionmentioning

confidence: 99%

The Bradykinin-BDKRB1 Axis Regulates Aquaporin 4 Gene Expression and Consequential Migration and Invasion of Malignant Glioblastoma Cells via a Ca2+-MEK1-ERK1/2-NF-κB Mechanism

Sun

Chen

Lin

et al. 2020

Cancers

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Glioblastoma multiforme (GBM) is the most common form of brain tumor and is very aggressive. Rapid migration and invasion of glioblastoma cells are two typical features driving malignance of GBM. Bradykinin functionally prompts calcium influx via activation of bradykinin receptor B1/B2 (BDKRB1/2). In this study, we evaluated the roles of bradykinin in migration and invasion of glioblastoma cells and the possible mechanisms. Expressions of aquaporin 4 (AQP4) mRNA and protein were upregulated in human glioblastomas. Furthermore, exposure of human U87 MG glioblastoma cells to bradykinin specifically increased levels of BDKRB1. Successively, bradykinin stimulated influx of calcium, phosphorylation of MEK1 and extracellular signal-regulated kinase (ERK)1/2, translocation and transactivation of nuclear factor-kappaB (NF-κB), and expressions of AQP4 mRNA and protein. Concomitantly, migration and invasion of human glioblastoma cells were elevated by bradykinin. Knocking-down BDKRB1 concurrently decreased AQP4 mRNA expression and cell migration and invasion. The bradykinin-induced effects were further confirmed in murine GL261 glioblastoma cells. Therefore, bradykinin can induce AQP4 expression and subsequent migration and invasion through BDKRB1-mediated calcium influx and subsequent activation of a MEK1-ERK1/2-NF-κB pathway. The bradykinin-BDKRB1 axis and AQP4 could be precise targets for treating GBM patients.

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Section: Discussionmentioning

confidence: 99%

The Bradykinin-BDKRB1 Axis Regulates Aquaporin 4 Gene Expression and Consequential Migration and Invasion of Malignant Glioblastoma Cells via a Ca2+-MEK1-ERK1/2-NF-κB Mechanism

Sun

Chen

Lin

et al. 2020

Cancers

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“…For instance aberrant expression of the brain aquaporin 1 (AQ1) and 4 (AQ4), which regulate water flow in and out of the cells, have been found in glioblastoma sphere cultures and their role in this tumor has just started to be elucidated [39, 40]. Of note, AQ4 was the second most downregulated gene in the UCHL1 KDs (~37-fold reduction compared to controls), thus consistent with a possible function of UCHL1 in glioma CSCs.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma

Sánchez-Díaz

Chang²,

Moses

et al. 2017

PLoS ONE

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Pediatric high-grade gliomas represent 8–12% of all primary tumors of the nervous system in children. Five-year survival for these pediatric aggressive tumors is poor (15–35%) indicating the need to develop better treatments for pediatric high-grade gliomas. In this work we used SF188 and SJ-GBM2 cell lines to study the function of the ubiquitin carboxyl-terminal esterase L1 (UCHL1), a deubiquitinase de-regulated in several cancers, in pediatric high-grade gliomas. UCHL1 depletion in SF188 and SJ-GBM2 glioma cells was associated with decreased cell proliferation and invasion, along with a reduced ability to grow in soft agar and to form spheres (i.e. self-renewal measure). A 70% reduction in Wnt signaling was also observed in the SF188 and SJ-GBM2 UCHL1 knockdowns (KDs) using a TCF-dependent TOPflash reporter assay. Transcriptome comparisons of UCHL1 KDs versus vector control identified a list of 306 differentially expressed genes (at least 2-fold change; p <0.05) which included genes known to be involved in cancer like ACTA2, POSTN, LIF, FBXL7, FBXW11, GDF15, HEY2, but also potential novel genes such us IGLL5, ABCA4, AQP3, AQP4, CALB1, and ALK. Bioinformatics gene ontology (GO) analysis of these 306 genes revealed significant enrichment in “signal peptides”, “extracellular matrix”and “secreted proteins” GO Terms. “Angiogenesis and blood vessel development”, “neuron differentiation/development”, cell adhesion”, and “cell migration” also showed significant enrichment in our GO analysis. Top canonical pathways identified by Ingenuity Pathway Analysis (IPA) included “Clathrin-mediated Endocytosis Signaling” (p = 5.14x10-4), “Virus Entry via Endocytic Pathways” (p = 6.15x 10−4), and “High Mobility Group-Box 1 (HMGB1) Signaling” (p = 6.15x10-4). While FGF2, IL1B, TNF and PDGFB were predicted as top upstream regulators (p < 2x10-16) of the UCHL1 KD-associated transcriptome. Aberrant expression of UCHL1 in pediatric high-grade gliomas may promote cell invasion, transformation, and self-renewal properties, at least in part, by modulating Wnt/Beta catenin activity. UCHL1 might act as an oncogene in glioma within the gene network that imparts stem-like characteristics to these cancer cells.

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“…Hua et al 36) also found that AQP4 played an important role in modulating brain water transport in an astrocytic oxygen-glucose deprivation and reintroduction model. By siRNA knockdown approach, Ding et al 37) showed that downregulation of AQP4 induced glioblastoma cell apoptosis in vitro and in vivo. Moreover, Chu et al 38) found that Granulocyte-colony stimulating factor (G-CSF) led to neurological functional improvement in mice by associating with reduction of brain edema and neuronal death and apoptosis and statistical analysis suggested AQP4 was required for these effects.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Ginsenoside Rg1 on Astrocytes and Cerebral Ischemic-Reperfusion Mice

Sun¹,

Lai²,

Huang³

et al. 2014

Biological & Pharmaceutical Bulletin

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Ginsenoside Rg1 (Rg1), one of the active ingredients in Panax ginseng, has been known to regulate many cellular processes. The purpose of this study was to investigate the protective effects of Rg1 on apoptosis in mouse cultured astrocytes in vitro and a mouse model of cerebral ischemia and reperfusion in vivo. The cell apoptosis was measured by fluorescence microplate reader and xCELLigence system and the Ca 2 overload was recorded by confocal microscopy. The mitochondrial membrane potential and reactive oxygen species (ROS) were determined by flow cytometry. BALB/c mice were subjected to transient middle cerebral artery occlusion (MCAO) and randomly divided into four groups: Sham (sham-operated 0.9% saline), MCAO (MCAO 0.9% saline), Rg1-L (MCAO Rg1 20 mg/kg) and Rg1-H (MCAO Rg1 40 mg/kg). Neurological deficit scores, brain water content and infarct volume were evaluated at 24 h after reperfusion. The results showed that Rg1 significantly attenuated H 2 O 2 -induced apoptosis in astrocytes. Rg1 efficiently inhibited intracellular Ca 2 overload, loss of mitochondrial membrane potential, and ROS production in astrocytes. In vivo study, it was also observed that Rg1 markedly reduced the neurological deficit scores, brain edema, and infarct volume in the model mice. These results suggest that Rg1 possesses significant neuroprotective effects, which might be related to the prevention of astrocytes from apoptosis.

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Knockdown a Water Channel Protein, Aquaporin-4, Induced Glioblastoma Cell Apoptosis

Cited by 43 publications

References 23 publications

The Bradykinin-BDKRB1 Axis Regulates Aquaporin 4 Gene Expression and Consequential Migration and Invasion of Malignant Glioblastoma Cells via a Ca2+-MEK1-ERK1/2-NF-κB Mechanism

The Bradykinin-BDKRB1 Axis Regulates Aquaporin 4 Gene Expression and Consequential Migration and Invasion of Malignant Glioblastoma Cells via a Ca2+-MEK1-ERK1/2-NF-κB Mechanism

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma

Protective Effects of Ginsenoside Rg1 on Astrocytes and Cerebral Ischemic-Reperfusion Mice

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