FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells

Abstract

In this study, we aimed to reveal the resistance mechanism of hepatocellular carcinoma (HCC) cells to sorafenib by exploring the effect of FNDC5 on sorafenib-induced ferroptosis in HCC cells. We compared the expression level of FNDC5 between sorafenib-resistant and sorafenib-sensitive HCC cell lines and the level of ferroptosis between the groups after treatment with sorafenib. We knocked down FNDC5 in drug-resistant cell lines and overexpressed it in sorafenib-sensitive HCC cell lines to further demonstrate the role of FNDC5 in sorafenib-induced ferroptosis. Using PI3K inhibitors, we revealed the specific mechanism by which FNDC5 functions. In addition, we verified our findings obtained in in vitro experiments using a subcutaneous tumorigenic nude mouse model. The findings revealed that FNDC5 inhibits sorafenib-induced ferroptosis in HCC cells. In addition, FNDC5 activated the PI3K/Akt pathway, which in turn promoted the nuclear translocation of Nrf2 and increased the intracellular antioxidant response, thereby conferring resistance to ferroptosis. Our study provides novel insights for improving the efficacy of sorafenib.

Orlistat Resensitizes Sorafenib-Resistance in Hepatocellular Carcinoma Cells through Modulating Metabolism

“…Although the KEAP1 was suppressed in both cell lines after combination treatment, the opposite effect was observed on NRF2 expression. Activation of the p62-Keap1-NRF2 pathway has been shown to protect HCC cells against ferroptosis [ 65 ], leading to the development of sorafenib resistance [ 66 ]. Orlistat alone caused reductions in xCT and GPX4, indicating that orlistat might be a potential ferroptosis inducer.…”

Clinical applications of circulating tumor cells in hepatocellular carcinoma

“…Sorafenib is a small molecule multi-kinase inhibitor with multiple antitumor effects and is the first-line targeted drug for the treatment of HCC in the advanced stage (113). Numerous studies have shown that the inactivation of Ras/Raf/ERK pathway and the activation of PI3K/Akt/mTOR pathway plays a crucial role in sorafenib resistance (114)(115)(116)(117). CTCs are released from tumor tissue to the bloodstream and carry drug resistance information of the primary tumor or metastases, therefore pERK/pAkt phenotype of CTCs can be used to monitor the therapeutic effect and drug resistance of sorafenib (48).…”

Fibronectin Type III Domain Containing 5 Contributes to Nab-paclitaxel Chemoresistance by Promoting Autophagy via the AMPK/mTOR Signaling Pathway in Hepatocellular Carcinoma Cells

“…Immunohistochemistry methods were used as our team did in previous experiments (31,32). Tumor samples from 60 individuals with liver cancer were obtained and xed in 4.0% paraformaldehyde before being embedded in para n. Next, the tissue wax blocks were sliced into 4-mm slices and treated with 3.0% hydrogen peroxide before being sealed with 5.0% FBS.…”

“…A western blotting analysis was performed by our team as in the previous experiments (31,32). The total proteins were recovered from HCC cells by lysis with radioimmunoprecipitation assay buffer in a 4°C environment.…”