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-beta (
TGF-beta) signaling. As
TGF-beta 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-beta1,
TGF-beta2 and latent
TGF-beta-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-beta signaling negatively in non-neoplastic astrocytes. Thus, the pathogenesis of
glioma formation may involve altered AhR regulation of the
TGF-beta/Smad pathway, and AhR may represent a promising target for the treatment of human
malignant gliomas and other diseases associated with pathological
TGF-beta activity.