Investigation of the Role of Nrf2 in Hepatocellular Carcinoma Cell Lines with Sorafenib Resistance-Developed
Project no. 22011 · Status: Kapanmış (Yayın bekleniyor) · 2020
Summary
<p>Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Sorafenib, a multikinase inhibitor, is currently the most effective treatment agent. The most important factor that affects the success of treatment is the development of resistance in cancer cells.Once sorafenib resistance is develops in cells, patients cannot benefit from sorafenib, and the mortality rate of HCC increases. Antioxidant pathways are activated during sorafenib resistance. One of the most important cellular antioxidant pathways is the Nrf2 pathway. However, the effects of the Nrf2 pathway on the development of sorafenib resistance remain unknown. In this study, we aimed to determine the effects of the Nrf2 pathway in sorafenib resistent HCC cells with sorafenib resistance is developed. Sorafenib resistance was developed in a well-differentiated HCC cell line (HuH-7) and a poorly differentiated HCC cell line by increasing doses and prolonged sorafenib treatment. The effects of blocking/inducing of the Nrf2 pathway and its combination with regorafenib on cell proliferation, apoptosis, autophagy, migration, and reactive oxygen species levels were determined. In addition, the effects of Nrf2 on the AKT, ERK1/2, MMP 9, Caspase 3 pathways were determined by western blot analysis. Inhibition of the Nrf2 pathway in sorafenib resistant cells decreased proliferation and motility, increased apoptosis and autophagy, and these effects were further strengthened when combined with regorafenib. Similarly, AKT, ERK1/2 pathways and Caspase3 protein levels were also decreased in combination with Nrf2 and Regorafenib, on the other hands, in the cells that Nrf2 pathway is induced cells, it was determined that the opposite responses of these effects. In addition, it was determined that these cellular biological responses occur in parallel with the suppression/inhibition of Nrf2 and the increase/decrease in ROS levels. In conclusion, our results show that blocking the Nrf2 pathway in sorafenib resistant cells may be a treatment target and may overcome sorafenib resistance in combination with regorafenib.</p>