IKKβ downregulation is critical for triggering JNKs-dependent cell apoptotic response in the human hepatoma cells under arsenite exposure

Arsenite has a long history in treating leukemia, which might be also effective in the therapy of other cancers. Our previous published data have demonstrated that arsenite exposure induces apoptosis in the HepG2 human hepatoma cells via activating JNKs/AP-1 pathway, but the upstream signaling events responsible for JNKs (c-Jun N-terminal kinase) cascade activation have not been fully discovered. Since cross-talk between IKK/NF-kappa B and JNKs pathways under stress conditions is a hot topic, in this article, we investigate the potential roles of IKK alpha and IKK beta, the catalytic subunits of IKK complexes, in the arsenite-induced JNKs pathway activation in the HepG2 cells. We found that arsenite exposure induced JNKs and AP-1 activation accompanying with a significant reduction of both IKK alpha and IKK beta expressions. Overexpression of IKK beta, but not of IKK alpha, inhibited arsenite-induced MKK7/JNKs/AP-1 pathway activation as well as the apoptotic response. Therefore, we conclude that the downregulation of IKK beta expression is the prerequisite signaling event for mediating JNKs pathway activation and the cellular apoptotic response in the HepG2 cells under arsenite exposure. Targeting IKK beta might be helpful to enhance the tumor therapeutic effect of arsenite.