Discovery and mechanistic characterization of a novel AhR receptor ligand that induces apoptosis in cancer cells

Background: 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 AhR’s role in the suppression of cancer cell growth. We hypothesized that that the AhR is a molecular target for therapeutic interventions, and that activation of the AhR by select AhR modulators in cancer cells could have anti-cancer properties including cell death. This study describes the discovery and characterization of a new class of anti-cancer agents targeting the AhR. Methods: We employed two independent small molecule screening approaches to identify novel modulators of the AhR with unique anti-cancer properties. We established the AhR selective effects of a highly selective modulator in cancer cells with or without the AhR expression and identified the mechanism of action of this anti-cancer compound. Results: We report the identification of CGS-15943, uniquely selective AhR modulator, that activates AhR signaling and induces apoptosis in an AhR-dependent manner in liver and breast cancer cell models. Investigation of the downstream signaling pathway of this newly identified modulator revealed novel upregulation of Fas-ligand, which is required for AhR-mediated apoptosis. Conclusions: We identified CGS-15943 as a novel AhR-selective modulator with anti-cancer properties using two parallel and distinct screening strategies. This compound induced AhR-dependent apoptosis in multiple mouse and human liver cancer cells. Our results provide a basis for the development of a new class of anti-cancer therapeutics targeting an underappreciated molecular target, the AhR.