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Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects

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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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Abbreviations

AhR:

Aryl hydrocarbon Receptor

Arnt:

Aryl Hydrocarbon Receptor Nuclear Translocator

bHLH-PAS:

Basichelix-loop-helix-Per/Arnt/Sim

DBD:

DNA-binding domain

DEN:

Diethylnitrosamine

DMBA:

7,12-Dimethylbenz[a]anthracene

FICZ:

6-Formylindolo[3,2-b]carbazole

HSCs:

Hematopoietic stem cells

ITE:

2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester

NQO1:

NADPH: quinone oxidoreductase

SMAhRTs:

Select modulators of AhR-regulated transcription

TRAMP:

Transgenic adenocarcinoma of the mouse prostate

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Acknowledgments

The authors wish to thank Samuel Bradford for excellent technical assistance with flow cytometry and Kyla Guertin for excellent laboratory assistance.

Funding

This work was supported by the American Cancer Society (RSG-13-132-01-CDD) and in part by National Institute of Environmental Health Sciences (NIEHS) grant numbers ES016651, ES019000, P30 ES030287 and The US Army Medical Research and Material Command. EFO was supported by pre-doctoral fellowships from NIEHS training grant (T32 ES007060) and the Department of Defense Breast Cancer Research Program (W81XWH-10-1-0160). DFL was supported by NIEHS training grant (T32 ES007060), Diversity advancement pipeline fellowship (Oregon State University), P.F. Yerex and Nellie Buck graduate fellowship (Oregon State University), and the National Research Service Award (1F31CA144571) from the National Cancer Institute.

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Author notes

  1. Edmond Francis O’Donnell III

    Present address: Department of Orthopaedic Surgery, University of California Davis Medical Center, Davis, CA, USA

  2. Daniel F Liefwalker

    Present address: Department of Molecular and Medical Genetics, School of Medicine, Oregon Health and Science University, Portland, OR, USA

Authors and Affiliations

  1. Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA

    Edmond Francis O’Donnell III, Hyo Sang Jang, Daniel F Liefwalker & Siva Kumar Kolluri

  2. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA

    Nancy I Kerkvliet

  3. Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331, USA

    Siva Kumar Kolluri

  4. Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR, 97331, USA

    Siva Kumar Kolluri

  5. The Pacific Northwest Center for Translational Environmental Health Research, Oregon State University, Corvallis, OR, 97331, USA

    Nancy I Kerkvliet & Siva Kumar Kolluri

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  1. Edmond Francis O’Donnell III
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Contributions

EFO contributed to study design, execution of experiments, data analysis, and wrote the manuscript. HSJ performed experiments and contributed to data analysis. DCK performed experiments, contributed to data analysis, and provided input on study design. NIK provided input on study design and provided material support. SKK designed and supervised the study, and helped prepare and revise the manuscript.

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Correspondence to Siva Kumar Kolluri.

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O’Donnell, E.F., Jang, H.S., Liefwalker, D.F. et al. Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects. Apoptosis 26, 307–322 (2021). https://doi.org/10.1007/s10495-021-01666-0

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