Regulation of Nrf2 signaling during the antitumoral activity of Sorafenib in hepatoma cells

Introduction Sorafenib is the accepted treatment for patients in advanced stage of hepatocarcinoma. Goal: The study evaluated the regulation of the endoplasmic reticulum stress (ERS), Nrf2, oxidative/nitrosative stress, autophagy, cell proliferation and apoptosis by Sorafenib. Methods: The study includes in vitro and in vivo experimental designs. Results: Sorafenib induced ERS, Thr183JNK/JNK and transient autophagy that was followed by apoptosis, and reduction of cell proliferation. Sorafenib reduced dose-dependent nitric oxide, O2.- and H2O2 generation, and S-nitrosylated, carbonylated and tyrosine nitrated proteins. Sorafenib reduced S-nitrosylation of cell death receptors that shifted caspase-8- to caspase-3-related apoptosis. Sorafenib decreased luciferase activity in control, VEGF- and PDGF-stimulated ARE-Luc-transfected HepG2, and went down the expression of Nrf2-related redox genes. The reduction of Nrf2 signaling was related to increased Ser9GSK3β/Tyr216GSK3β. The in vivo study confirmed the antitumoral properties and molecular signaling of Sorafenib in xenograft mice model. Conclusions: 1) Sorafenib induced ERS, autophagy and apoptosis in Sorafenib-treated HepG2. 2) Sorafenib reduced Nrf2-dependent signaling through regulation of GSK3β activity. 3) Nrf2 signaling and thioredoxin were involved in the reduction of S-nitrosylation of cell death receptor by Sorafenib.