Open Access
ARTICLE
Konjac glucomannan enhances 5-FU-induced cytotoxicity of hepatocellular carcinoma cells via TLR4/PERK/CHOP signaling to induce endoplasmic reticulum stress
YONGKANG SHI, JUN MA, KE CHEN, BIN CHEN*
Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s
Hospital, Hangzhou Medical College, Hangzhou, 310011, China
* Corresponding Author: Bin Chen,
Oncology Research 2022, 30(4), 201-210. https://doi.org/10.32604/or.2022.027584
Received 04 November 2022; Accepted 12 January 2023; Issue published 31 January 2023
Abstract
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.
Keywords
Cite This Article
SHI, Y., MA, J., CHEN, K., CHEN, B. (2022). Konjac glucomannan enhances 5-FU-induced cytotoxicity of hepatocellular carcinoma cells via TLR4/PERK/CHOP signaling to induce endoplasmic reticulum stress.
Oncology Research, 30(4), 201–210. https://doi.org/10.32604/or.2022.027584