Title11-Cl-BBQ, a select modulator of AhR-regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27.
Publication TypeJournal Article
Year of Publication2023
AuthorsNguyen BD, Stevens BL, Elson DJ, Finlay D, Gamble JT, Kopparapu PR, Tanguay RL, Buermeyer AB, Kerkvliet NI, Kolluri SK
JournalFEBS J
Date Published2023 Apr
KeywordsCell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p27, Humans, Lung, Lung Neoplasms, Receptors, Aryl Hydrocarbon, RNA, Tumor Suppressor Protein p53

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 , in an AhR-dependent manner. CRISPR/Cas9 knockout of individual genes revealed the requirement for both p53 and p27 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.

Alternate JournalFEBS J
PubMed ID36401795
PubMed Central IDPMC10807707
Grant ListR01 ES016651 / ES / NIEHS NIH HHS / United States
P30 ES030287 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
T32ES007060,5R01ES016651,P30ES030287 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States