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

Oncogene volume 28, pages 2593–2605 (2009)Cite this article

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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Abbreviations

AhR:

aryl hydrocarbon receptor

ARNT:

AhR nuclear translocator

BrdU:

5-bromo-2-deoxyuridine

CA-AhR:

constitutive active AhR

CI:

confidence interval

CYP1A1:

cytochrome P450 1A1

DRE:

dioxin responsive element

LTBP-1:

latent TGF-β-binding protein

PAS:

Per-Arnt-Sim

pSmad2:

phosphorylated Smad2

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TGF-β:

transforming growth factor-β

3-MC:

3-methylcholanthrene

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Acknowledgements

We are indebted to Dr Gabrielle Haas for support with confocal microscopy. This study was supported by grants from the Jacqueline Seroussi Memorial Foundation for Cancer Research and the Swiss National Fund (NCCR Neuro) to MW.

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Authors and Affiliations

  1. Department of General Neurology and Hertie Institute for Clinical Brain Research, Laboratory of Molecular Neuro-Oncology, University of Tuebingen, Tuebingen, Germany

    D Gramatzki, G Tabatabai, W Wick, M Weller & I Tritschler

  2. Department of Neuropathology, Institute of Brain Research, University of Tuebingen, Tuebingen, Germany

    G Pantazis & J Schittenhelm

  3. Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tuebingen, Tuebingen, Germany

    C Köhle & M Schwarz

  4. Department of Neurooncology, University of Heidelberg, Heidelberg, Germany

    W Wick

  5. Department of Neurology, University Hospital Zurich, Zurich, Switzerland

    M Weller

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Correspondence to M Weller.

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Gramatzki, D., Pantazis, G., Schittenhelm, J. et al. Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells. Oncogene 28, 2593–2605 (2009). https://doi.org/10.1038/onc.2009.104

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