Abstract
Blocking glioma cell invasion has been challenging due to cancer cells that can swiftly switch their migration mode, and agents that can block more than one migration mode are sought after. We found that small molecule 2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous aryl hydrocarbon receptor (AHR) agonist, can block more than one mode of glioma cell migration, based on cultured cell behavior captured by videos. Data from wound-healing assays and mouse xenograft glioma models corroborated ITE's migration-inhibiting effects while knocking down AHR by siRNA abolished these effects. To identify genes that mediated ITE-AHR's effect, we first collected gene expression changes upon ITE treatment by RNA-seq, then compared them against literature reported migration-related genes in glioma and that were potentially regulated by AHR. MYH9, a component of nonmuscle myosin IIA (NMIIA), was confirmed to be reduced by ITE treatment. When MYH9 was overexpressed in the glioma cells, a good correlation was observed between the expression level and the cell migration ability, determined by wound-healing assay. Correspondingly, overexpression of MYH9 abrogated ITE's migration-inhibiting effects, indicating that ITE-AHR inhibited cell migration via inhibiting MYH9 expression. MYH9 is essential for cell migration in 3D confined space and not a discovered target of AHR; the fact that ITE affects MYH9 via AHR opens a new research and development avenue.
Highlights
Glioblastoma (GBM), the most common and advanced form of glioma, is one of the most lethal human cancers
We knocked down aryl hydrocarbon receptor (AHR) expression in U87MG cells by siRNA (Figures 1(e)–1(f)) and found that 100, 1000, and 10000 nM ITE significantly inhibited cell migration in the nontargeting control (NC) siRNA group, showing similar efficacy as in untransfected cells
In the AHR siRNA knockdown group, migration was significantly reduced in the DMSO, 0.1, 1, and 10 nM ITE groups, highlighting AHR’s role in regulating glioma cell migration
Summary
Glioblastoma (GBM), the most common and advanced form of glioma, is one of the most lethal human cancers. GBM patients survive, on average, 12–15 months despite aggressive surgical resection, radiation, and chemotherapy [1]. The diffuse invasion of the GBM tumor cells and the blood-brain barrier pose major challenges for successful therapy since invaded tumor cells are sheltered from complete surgical removal and radiation. We targeted AHR, a ligand-activated transcription factor, and E3 ubiquitin ligase. AHR regulates cytotoxic immune cells in cancer by controlling the function and differentiation of multiple types of immune cells. AHR’s effects on cancer are complex, highly depends on the ligands in the microenvironment and the cell types. Its reported that AHR regulated tumor cell migration and may serve as a tumor suppressor [5]
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