Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

D Gramatzki, G Pantazis, J Schittenhelm, G Tabatabai… - Oncogene, 2009 - nature.com
D Gramatzki, G Pantazis, J Schittenhelm, G Tabatabai, C Köhle, W Wick, M Schwarz
Oncogene, 2009nature.com
The dioxin/aryl hydrocarbon receptor (AhR) is a transcription factor, which has been
attributed a role in human cancerogenesis, cell cycle progression and transforming growth
factor-β (TGF-β) signaling. As TGF-β is an important mediator of the malignant phenotype of
human gliomas, we studied AhR expression and function in glioma cells. AhR was not only
expressed in glioma cells in vitro, but was also detected in human gliomas in vivo by
immunohistochemistry, with a predominantly nuclear staining in glioblastomas. The AhR …
Abstract
The dioxin/aryl hydrocarbon receptor (AhR) is a transcription factor, which has been attributed a role in human cancerogenesis, cell cycle progression and transforming growth factor-β (TGF-β) signaling. As TGF-β is an important mediator of the malignant phenotype of human gliomas, we studied AhR expression and function in glioma cells. AhR was not only expressed in glioma cells in vitro, but was also detected in human gliomas in vivo by immunohistochemistry, with a predominantly nuclear staining in glioblastomas. The AhR agonist, 3-methylcholanthrene, induced AhR nuclear translocation and upregulated mRNA levels of the AhR target gene, cytochrome P450 1A1 (CYP1A1). Conversely, pharmacological inhibition of AhR using the novel AhR antagonist, CH-223191, or AhR gene silencing using small interfering RNA showed that constitutive AhR activity positively controls TGF-β1, TGF-β2 and latent TGF-β-binding protein-1 protein levels in malignant glioma cells. Moreover, antagonism of AhR reduced clonogenic survival and invasiveness of glioma cells. In contrast, AhR regulates TGF-β signaling negatively in non-neoplastic astrocytes. Thus, the pathogenesis of glioma formation may involve altered AhR regulation of the TGF-β/Smad pathway, and AhR may represent a promising target for the treatment of human malignant gliomas and other diseases associated with pathological TGF-β activity.
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