The aryl hydrocarbon receptor mediates integrin control of the TGF-β pathway
Manuela Silginer, Isabel Burghardt, Dorothee Gramatzki, Henning Leske, Elisabeth J. Rushing, Murray L. Whitelaw, Michael Weller, Patrick Roth
Glioblastoma is the most common and aggressive form of intrinsic brain tumor. Integrins are highly expressed on glioma cells and also interact with the transforming growth factor (TGF)-β pathway, an attractive therapeutic target in glioblastoma. Moreover, activity of the transcription factor aryl hydrocarbon receptor (AhR) has been linked to TGF-β expression.
Here we demonstrate that integrin inhibition, using neutralizing antibodies, RNA interference-mediated gene silencing or pharmacological inhibition, reduces AhR activity and AhR total and nuclear protein levels, whereas AhR mRNA expression was not affected. Moreover, silencing of AhR reduced sensitivity to integrin inhibition-mediated alterations in TGF-β signaling, indicating an interplay of integrins and AhR in the regulation of TGF-β signaling in glioblastoma. Accordingly, a significant correlation of αv integrin levels with nuclear AhR and pSmad2 levels was observed in human glioblastoma in vivo.
In summary, we have identified a novel mechanism in which integrin inhibitors interfere with AhR signaling at a posttranscriptional level, ultimately resulting in reduced TGF-β signaling.