Quercetin Modulates NF-κ B and AP-1/JNK Pathways to Induce Cell Death in Human Hepatoma Cells

Abstract

Quercetin, a dietary flavonoid, has been shown to possess anticarcinogenic properties, but the precise molecular mechanisms of action are not thoroughly elucidated. The aim of this study was to investigate the regulatory effect of quercetin (50 μ M) on two main transcription factors (NF-κ B and AP-1) related to survival/proliferation pathways in a human hepatoma cell line (HepG2) over time. Quercetin induced a significant time-dependent inactivation of the NF-κ B pathway consistent with a downregulation of the NF-κ B binding activity (from 15 min onward). These features were in concert with a time-dependent activation (starting at 15 min and maintained up to 18 h) of the AP-1/JNK pathway, which played an important role in the control of the cell death induced by the flavonoid and contributed to the regulation of survival/proliferation (AKT, ERK) and death (caspase-3, p38, unbalance of Bcl-2 proapoptotic and antiapoptotic proteins) signals. These data suggest that NF-κ B and AP-1 play a main role in the tight regulation of survival/proliferation pathways exerted by quercetin and that the sustained JNK/AP-1 activation and inhibition of NF-κ B provoked by the flavonoid induced HepG2 death.

ACKNOWLEDGMENTS

This work was supported by the grants AGL2004-302 and CSD2007-00063 from the Spanish Ministry of Science and Technology (CICYT). A. B. Granado-Serrano is a predoctoral fellow of the Spanish Ministry of Science and Education. This article has not been published elsewhere and has not been submitted simultaneously for publication elsewhere.