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.
Highlights
IntroductionThe 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 aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the bHLH/PAS family of proteins
Our results provide a basis for the development of a new class of anti-cancer therapeutics targeting an underappreciated molecular target, the AhR
Summary
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. This study describes the discovery and characterization of a new class of anti-cancer agents targeting the AhR. The aryl hydrocarbon receptor is a ligand-activated transcription factor belonging to the bHLH-PAS (basichelix-loop helix-Per/ARNT/Sim) protein family [1]. The AhR translocates to the nucleus where it complexes with its obligate heterodimer partner, Aryl Hydrocarbon Receptor Nuclear Translocation (ARNT) [6], to regulate the transcription of gene targets. The AhR has been extensively studied for its role in mediating the toxic effects of 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) [7]. The most wellknown gene targets of AhR-activation are those involved in xenobiotic metabolism. TCDD inhibits proliferation of hepatocytes by increasing expression of the CDK inhibitor p27kip1 [10], and loss of AhR expression in hepatocytes results in decreased proliferation [11]
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