Abstract
Hepatocellular carcinoma(HCC)is one of the most prevalent and deadly cancers in the world,which is frequently diagnosed at a late stage.HCC patients have a poor prognosis due to the lack of an efficacious therapeutic strategy.Approved drug repurposing is a way for accelerating drug discovery and can significantly reduce the cost of drug development.Carfilzomib(CFZ)is a second-generation proteasome inhibitor,which is highly efficacious against multiple myeloma and has been reported to possess potential antitumor activities against multiple cancers.However,the underlying mechanism of CFZ on HCC is still unclear.Here,we show that CFZ inhibits the proliferation of HCC cells through cell cycle arrest at the G2/M phase and suppresses the migration and invasion of HCC cells by inhibiting epithelial-mesenchymal transition.We also find that CFZ promotes reactive oxygen species production to induce endoplasmic reticulum(ER)stress and activate JNK/p38 MAPK signaling in HCC cells,thus inducing cell death in HCC cells.Moreover,CFZ significantly inhibits HCC cell growth in a xenograft mouse model.Collectively,our study elucidates that CFZ impairs mitochondrial function and activates ER stress and JNK/p38 MAPK signaling,thus inhibiting HCC cell and tumor growth.This indicates that CFZ has the potential as a therapeutic drug for HCC.
基金项目
国家自然科学基金(31771534)
国家自然科学基金(31570772)
Special Funding for the Construction of Innovative Provinces in Hunan Province(2021SK4031)
Project of Wenzhou Science and Technology(Y20190206)
Project of Wenzhou Science and Technology(Y2020178)
Project of Wenzhou Science and Technology(Y20210184)
Zhejiang Medical and Health Platform Project(Key Talents)(2014RCA014)
Zhejiang Provincial Health Department Medical Support Discipline-Nutrition(11-ZC24)
国家科技期刊平台
NSTL
万方数据