11-Cl-BBQ, a select modulator of AhR-regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27Kip1

Bach D Nguyen; Brenna L Stevens; Daniel J Elson; Darren Finlay; John T Gamble; Prasad R Kopparapu; Robyn L Tanguay; Andrew B Buermeyer; Nancy I Kerkvliet; Siva K Kolluri

doi:10.1111/febs.16683

11-Cl-BBQ, a select modulator of AhR-regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27^Kip1

FEBS J. 2023 Apr;290(8):2064-2084. doi: 10.1111/febs.16683. Epub 2022 Dec 22.

Authors

Affiliations

¹ Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
² NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
³ Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR, USA.
⁴ Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
⁵ The Pacific Northwest Center for Translational Environmental Health Research, Oregon State University, Corvallis, OR, USA.

Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and functions as a tumour suppressor in different cancer models. In the present study, we report detailed characterization of 11-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ) as a select modulator of AhR-regulated transcription (SMAhRT) with anti-cancer actions. Treatment of lung cancer cells with 11-Cl-BBQ induced potent and sustained AhR-dependent anti-proliferative effects by promoting G1 phase cell cycle arrest. Investigation of 11-Cl-BBQ-induced transcription in H460 cells with or without the AhR expression by RNA-sequencing revealed activation of p53 signalling. In addition, 11-Cl-BBQ suppressed multiple pathways involved in DNA replication and increased expression of cyclin-dependent kinase inhibitors, including p27^Kip1 , in an AhR-dependent manner. CRISPR/Cas9 knockout of individual genes revealed the requirement for both p53 and p27^Kip1 for the AhR-mediated anti-proliferative effects. Our results identify 11-Cl-BBQ as a potential lung cancer therapeutic, highlight the feasibility of targeting AhR and provide important mechanistic insights into AhR-mediated-anticancer actions.

Keywords: 11-Cl-BBQ; AhR; G1 phase cell cycle arrest; SA-β-gal; p27Kip1; p53.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Cycle Proteins / genetics
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Humans
Lung / metabolism
Lung Neoplasms* / genetics
RNA
Receptors, Aryl Hydrocarbon* / genetics
Receptors, Aryl Hydrocarbon* / metabolism
Tumor Suppressor Protein p53 / genetics

Substances

Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p27
Receptors, Aryl Hydrocarbon
RNA
Tumor Suppressor Protein p53
11-Cl-BBQ

Abstract

Publication types

MeSH terms

Substances

Grants and funding