Suppression of global protein synthesis and hepatocellular carcinoma cell growth by Benzimidazoisoquinoline, 4,11-Dichloro-BBQ.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor best known for mediating biological responses to a wide range of xenobiotics, such as dioxins and polycyclic aromatic hydrocarbons. Recently, AhR has emerged as an important player in cancer biology, with the potential for therapeutic applications through targeted modulation of its activity in specific cancer types. In this study, we report that 4,11-dichloro-BBQ (DiCl-BBQ), a benzimidazoisoquinoline, exhibits AhR-mediated antiproliferative activity in HepG2 hepatocellular carcinoma cells. DiCl-BBQ was found to decrease cell growth at nanomolar concentrations, and this antiproliferative effect persisted even after the compound's removal. Using inducible shRNA expression system, we demonstrated that the inhibitory effect of DiCl-BBQ was significantly reduced following AhR knockdown. Flow cytometric analysis revealed that DiCl-BBQ halted cell division and induced G1 cell cycle arrest in an AhR-dependent manner. Proteomic profiling identified the top four enriched pathways following DiCl-BBQ exposure: metabolism of RNA, translation, ribonucleoprotein complex biogenesis, and carboxylic acid metabolic processes. Notably, DiCl-BBQ caused a dramatic downregulation of translation-associated proteins, with this response diminished in AhR-depleted cells. Consistently, global protein synthesis was significantly repressed in DiCl-BBQ-treated cells. Together, these results indicate that DiCl-BBQ effectively inhibits HepG2 cells growth by inducing G1 cell cycle arrest and downregulating the protein translation machinery in an AhR-dependent manner.