Swelling‐induced chloride current in glioblastoma proliferation, migration, and invasion

Abstract

Glioblastoma (GBM) remains as the most common and aggressive brain tumor. The survival of GBM has been linked to the aberrant activation of swelling-induced chloride current I Cl,swell . In this study, we investigated the effects of I Cl,swell on cell viability, proliferation, and migration in the human GBM cell lines, U251 and U87, using a combination of patch clamp electrophysiology, MTT, colony formation, wound healing assays and Western immunoblotting. First, we showed that the specific inhibitor of I Cl,swell , DCPIB, potently reduced the I Cl,swell in U87 cells.Next, in both U87 and U251 cells, we found that DCPIB reduced GBM viability, proliferation, colony formation, migration, and invasion. In addition, our Western immunoblot assay showed that DCPIB-treated U251 cells had a reduction in JAK2, STAT3, and Akt phosphorylation, thus, suggesting that DCPIB potentially suppresses GBM functions through inhibition of the JAK2/ STAT3 and PI3K/Akt signaling pathways. Therefore, the I Cl,swell may be a potential drug target for GBM. K E Y W O R D S

Blockade of the swelling-induced chloride current attenuates the mouse neonatal hypoxic-ischemic brain injury in vivo

“…Since the molecular identities of the swelling-induced Clchannels remain elusive, we first measured the electrophysiological properties of the swelling-induced Clcurrent I Cl,swell in primary neurons and pharmacologically verified with DCPIB ( Figure 1). When exposed to 30% hypotonic solution, there was activation of swelling-induced Clcurrent I Cl,swell , with a reversal potential that is consistent with what we previously reported [18] . In the continued presence of the hypotonic solution, application of DCPIB (10 μmol/L) inhibited the activated current ( Figure 1A and 1B).…”

“…Recordings were carried out in the whole-cell configuration using the Axopatch 700B (Axon Instruments, Inc), similar to our previous studies [18,[29][30][31] . The ramp protocol was from -100 to +100 mV (400 ms; -70 mV holding; 5 s interval at 2 kHz; digitized at 5 kHz).…”

“…The authors found that pharmacologically inhibiting the swelling-induced Clcurrent I Cl,swell with DCPIB endowed neuroprotection by reducing infarction and improving neurobehavioural scores in a rat transient middle cerebral artery occlusion (MCAO) model when the drug was delivered intracisternally [16] . In our laboratory, we previously described the pharmacological role of DCPIB in reducing HI brain injury in vivo [17] , and suppressing glioblastoma cellular functions in vitro by inhibiting the swelling-induced Clcurrent I Cl,swell [18] . Additionally, we also reported that pharmacologically inhibiting the swelling-induced Clcurrent I Cl,swell in vitro with DCPIB decreased the hypotonic-inducing intracellular Clconcentration, and reduced the oxygen and glucose deprivation (OGD)-induced cell death in PC12 cell line [17] .…”

TRPM2‐AS inhibits the growth, migration, and invasion of gliomas through JNK, c‐Jun, and RGS4

“…Uncover the underlying molecular mechanisms of gliomas is an important way to control tumor progress. Previous studies have demonstrated signal pathways such as lipid metabolism disorder, stress-induced cell death, and ion channel in gliomas (Leaver, Rizzo, & Whittle, 2010;Wong et al, 2018;Wong, Turlova, Feng, Rutka, & Sun, 2017). In recent years, the roles of lncRNAs in the pathophysiological process of gliomas have been F I G U R E 4 The overlapped differentially expressed genes in datasets GSE40687 and GSE4290.…”

Transcriptional repression of human epidermal growth factor receptor 2 by ClC‐3 Cl−/H+ transporter inhibition in human breast cancer cells

“…20 Liu et al 22 showed that ClC-3 activators with potent antitumor activities inhibited the PI3K/AKT/mTOR signaling pathway. In contrast, Wong et al 23 showed that the Cl − channel inhibitor exerted suppressive effects on the PI3K/AKT and JAK/STAT3 signaling pathways. HER2 is an attractive therapeutic target for gastric, colorectal, and ovarian cancers, and the STAT3 signaling pathway is associated with the high expression of HER2 in ovarian cancer.…”