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

D Gramatzki1, G Pantazis, J Schittenhelm

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

Oncogene
|May 26, 2009
PubMed

Insights

The aryl hydrocarbon receptor (AhR) promotes malignant glioma growth by upregulating transforming growth factor-beta (TGF-beta) signaling. Inhibiting AhR reduces glioma cell survival and invasiveness, suggesting AhR as a potential therapeutic target.

Area of Science:

  • Molecular biology
  • Oncology
  • Cell signaling

Background:

  • The aryl hydrocarbon receptor (AhR) is a transcription factor implicated in cancerogenesis and transforming growth factor-beta (TGF-beta) signaling.
  • TGF-beta is a key mediator of the malignant phenotype in human gliomas.

Purpose of the Study:

  • To investigate the expression and function of AhR in glioma cells.
  • To determine the role of AhR in TGF-beta signaling within gliomas.
  • To evaluate AhR as a potential therapeutic target for malignant gliomas.

Main Methods:

  • Immunohistochemistry to detect AhR expression in human gliomas.
  • Treatment with an AhR agonist (3-methylcholanthrene) and antagonist (CH-223191).
  • AhR gene silencing using small interfering RNA.
  • Analysis of TGF-beta1, TGF-beta2, latent TGF-beta-binding protein-1, and CYP1A1 mRNA and protein levels.
  • Assessment of glioma cell clonogenic survival and invasiveness.

Main Results:

  • AhR was expressed in glioma cells in vitro and detected in vivo, with nuclear localization in glioblastomas.
  • AhR activation upregulated its target gene CYP1A1.
  • AhR inhibition or silencing reduced TGF-beta1, TGF-beta2, and latent TGF-beta-binding protein-1 levels in malignant glioma cells.
  • AhR antagonism decreased glioma cell clonogenic survival and invasiveness.
  • AhR negatively regulated TGF-beta signaling in non-neoplastic astrocytes.

Conclusions:

  • Altered AhR regulation of the TGF-beta/Smad pathway is involved in glioma pathogenesis.
  • AhR antagonism shows potential for treating malignant gliomas.
  • AhR may be a therapeutic target for diseases involving pathological TGF-beta activity.

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