Konjac glucomannan enhances 5-FU-induced cytotoxicity of hepatocellular carcinoma cells via TLR4/PERK/CHOP signaling to induce endoplasmic reticulum stress

5-Fluorouracil(5-FU)is a commonly used chemotherapeutic agent for various cancers.However,the drug resistance developed by tumor cells hinders the therapeutic effect.Konjac glucomannan(KGM)is indicated to sensitize 5-FU-resistant hepatocellular carcinoma(HCC)cells to 5-FU.In our study,we found that KGM or 5-FU treatment alone did not affect the malignant cell behaviors and endoplasmic reticulum(ER)stress of 5-FU-resistant HCC cells or HepG2/5-FU and Bel-7402/5-FU cells,while cotreatment with KGM and 5-FU significantly facilitated HCC cell apoptosis and ER stress and suppressed cell proliferation potential and migration abilities.Moreover,we explored the underlying mechanism by which KGM induces 5-FU cytotoxicity in HCC cells.We found that Toll-like receptor 4(TLR4)was downregulated in KGM-and 5-FU-treated HCC cells.TLR4 overexpression reversed the KGM and 5-FU cotreatment-induced inhibition of the malignant behaviors of 5-FU-resistant HCC cells.Furthermore,KGM enhanced 5-FU-induced ER stress by inhibiting TLR4 to activate PERK/ATF4/CHOP signaling.Xenograft mouse models were established using HepG2/5-FU cells,and KGM was demonstrated to reverse 5-FU resistance in HCC tumors in vivo by suppressing TLR4 to enhance ER stress and activate PERK/ATF4/CHOP signaling.In conclusion,KGM combined with 5-FU treatment significantly promoted apoptosis and reduced cell proliferation,migration and ER stress in 5-FU-resistant HCC cells compared with KGM or 5-FU treatment alone by downregulating TLR4 to activate PERK/ATF4/CHOP signaling.