|ZFIN ID: ZDB-PUB-180509-23|
Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor
Narasimhan, S., Stanford Zulick, E., Novikov, O., Parks, A.J., Schlezinger, J.J., Wang, Z., Laroche, F., Feng, H., Mulas, F., Monti, S., Sherr, D.H.
|Source:||International Journal of Molecular Sciences 19(5): (Journal)|
|Registered Authors:||Feng, Hui|
|Keywords:||AHR agonist, AHR antagonist, aryl hydrocarbon receptor, cancer, cancer therapeutics|
|PubMed:||29735912 Full text @ Int. J. Mol. Sci.|
Narasimhan, S., Stanford Zulick, E., Novikov, O., Parks, A.J., Schlezinger, J.J., Wang, Z., Laroche, F., Feng, H., Mulas, F., Monti, S., Sherr, D.H. (2018) Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor. International Journal of Molecular Sciences. 19(5).
ABSTRACTWe have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER−/PR−/Her2− and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin, VCAM1, Thrombospondin, MMP1) and an increase in CDH1/E-cadherin, previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.
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