Down‐Regulation of AQP4 Expression via p38 MAPK Signaling in Temozolomide‐Induced Glioma Cells Growth Inhibition and Invasion Impairment

Abstract

Glioma is the most common and lethal central nervous system tumors. Temozolomide (TMZ) is an effective drug for malignant glioma, however, the intracellular and molecular mechanisms behind this anti-cancer effect have yet to be fully understood. The aim of the present study was to determine whether TMZ inhibits proliferation, invasion of glioma cells in vitro and whether these effects can be mediated through modulation of aquaporin 4 (AQP4) and phosphorylation of the MAPK pathway. The viability of U87 and U251 human glioma cells was evaluated using MTT assay. The cell cycle distribution was detected with flow cytometry. Migration ability and invasion ability were tested by scratch assays and transwell assays, respectively. The levels of AQP4 and MAPK were measured using immunoblot analyses. Our results showed that TMZ inhibited proliferation, migration and invasion, and induced G2/M arrest in U87 and U251 glioma cell lines. These changes were associated with a decrease in the levels of AQP4 expression as well as activation phosphorylated level of p38. Treatment with a p38 chemical activator (anisomycin) resulted in similar effects as TMZ treatment on glioma cells. And p38 chemical inhibitor (SB203580) could block these effects in glioma treated with TMZ, suggesting a direct up-regulation of the p38 signaling pathway. Therefore, we identified that TMZ might have therapeutic potential for controlling proliferation, invasion of malignant glioma by inhibiting AQP4 expression through activation of p38 signal transduction pathway. J. Cell. Biochem. 118: 4905-4913, 2017. © 2017 Wiley Periodicals, Inc.

Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers

“…Genetic deletion of AQP4 impairs cell migration, actin polymerization and apoptosis [ 89 , 90 ]. Downregulation of AQP4 expression in glioma by pentamidine and temozolomide promoted apoptosis and inhibited cell migration, which could be a potential treatment for glioma [ 87 , 88 ]. The incidence of epileptiform seizures in glioma patients correlated with increased membrane levels of AQP4 protein, though transcript levels were not altered [ 114 ], raising the important point that not just translational synthesis but also subcellular localization of proteins is essential for deciphering functional outcomes.…”

Dysfunction of 67-kDa Laminin Receptor Disrupts BBB Integrity via Impaired Dystrophin/AQP4 Complex and p38 MAPK/VEGF Activation Following Status Epilepticus

“…For example, p38 MAPK and JNK inhibitors decrease AQP4 protein levels in cultured human primary cortical astrocytes (Salman et al, 2017). In contrast, temozolomide (an effective drug for malignant glioma) decreases AQP4 expression level with increasing p38 MAPK phosphorylation, which is blocked by p38 MAPK inhibitor (Chen et al, 2017). Similarly, ERK1/2 pathway down-regulates AQP4 expression in scratch-injured astrocytes (Shi et al, 2015), while ERK1/2 activation up-regulates AQP4 expression in oxygen-glucose deprivation-recovery-induced injury (Qi et al, 2011).…”

Synergistic anticancer effect of acteoside and temozolomide-based glioblastoma chemotherapy

“…Previous studies have demonstrated that TMZ regulates the MAPK pathway, including p38, JNK and ERK (30). Therefore, the present study investigated whether acteoside affects TMZ-related MAPK gene expression.…”