Article ; Online: Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects.
Apoptosis : an international journal on programmed cell death
2021 Volume 26, Issue 5-6, Page(s) 307–322
Abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of proteins. The AhR was cloned and characterized for its role in mediating the toxicity of dioxins. ... ...
| Abstract | The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of proteins. The AhR was cloned and characterized for its role in mediating the toxicity of dioxins. Subsequent research has identified the role of AhR in suppression of cancer cell growth. We hypothesized that the AhR is a molecular target for therapeutic intervention in cancer, and that activation of the AhR by unique AhR ligands in cancer cells could have anti-cancer effects including induction of cell death. This study describes the discovery and characterization of a new class of anti-cancer agents targeting the AhR, that we designate as Select Modulators of AhR-regulated Transcription (SMAhRTs). We employed two independent small molecule screening approaches to identify potential SMAhRTs. We report the identification of CGS-15943 that activates AhR signaling and induces apoptosis in an AhR-dependent manner in liver and breast cancer cells. Investigation of the downstream signaling pathway of this newly identified SMAhRT revealed upregulation of Fas-ligand (FasL), which is required for AhR-mediated apoptosis. Our results provide a basis for further development of a new class of anti-cancer therapeutics targeting an underappreciated molecular target, the AhR. |
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| MeSH term(s) | Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Aryl Hydrocarbon Receptor Nuclear Translocator/genetics ; Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism ; Cell Line, Tumor ; Fas Ligand Protein/genetics ; Fas Ligand Protein/metabolism ; Humans ; Ligands ; Mice ; Quinazolines/pharmacology ; Receptors, Aryl Hydrocarbon/genetics ; Receptors, Aryl Hydrocarbon/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/pharmacology ; Transcriptional Activation/drug effects ; Triazoles/pharmacology | |||||
| Chemical Substances | 9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline ; Antineoplastic Agents ; Fas Ligand Protein ; Ligands ; Quinazolines ; Receptors, Aryl Hydrocarbon ; Small Molecule Libraries ; Triazoles ; Aryl Hydrocarbon Receptor Nuclear Translocator (138391-32-9) ; 9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine (Y5A5D5E2AQ) | |||||
| Language | English | |||||
| Publishing date | 2021-04-24 | |||||
| Publishing country | Netherlands | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1452360-7 | |||||
| ISSN | 1573-675X ; 1360-8185 | |||||
| ISSN (online) | 1573-675X | |||||
| ISSN | 1360-8185 | |||||
| DOI | 10.1007/s10495-021-01666-0 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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