AUTHOR=Yuan Weiwei , Huang Jinxi , Hou Shanshan , Li Huahua , Bie Liangyu , Chen Beibei , Li Gaofeng , Zhou Yang , Chen Xiaobing 

TITLE=The Antigastric Cancer Effect of Triptolide is Associated With H19/NF-κB/FLIP Axis

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.918588

DOI=10.3389/fphar.2022.918588

ISSN=1663-9812

ABSTRACT=Background and Objective: Triptolide (TP), one of the fat-soluble components extracted from the Chinese medicinal herb Tripterygium wilfordii Hook F. (TWHF), possesses strong anti-tumor bioactivities while its dose-dependent side effects restrict its wide application. This study was designed to investigate whether inflammatory factors increased the anti-tumor effects of the non-toxic dose of TP on gastric cancer cells and tried to explore the possible mechanisms.
Method: AGS and MKN45 cells were treated with different doses of TP and TNF-α. Cell viability and apoptosis were detected in vitro. Additionally, NF-κB mediated pro-survival signals and cytoprotective proteins, especially FLIP, were detected to determine their effects on TP/TNF-α-induced apoptosis. Moreover, the function of lncRNA H19/miR-204-5p/NF-κB/FLIP axis was investigated in vitro and the anti-gastric cancer effect of TP plus TNF-α was proved in the mice xenograft model.
Result: In vitro experimental results showed that TP pre-treatment promoted apoptosis in AGS and MKN45 cells upon TNF-α exposure. TP/TNF-α mediated apoptosis was partly mediated by the inhibitory effect of NF-κB mediated FLIP expression. Oncogene H19 lying in the upstream pathway of NF-κB played a vital role upon TNF-α exposure and bioinformatics analysis proved that H19 participated in TP/TNF-α-induced apoptosis via binding of miR-204-5p. Lastly, low dose of TP and TNF-α inhibited the tumor weight and tumor volume of AGS and MKN45 cells in vivo.
Conclusion: TP pretreatment increased apoptosis in TNF-α stimulated gastric cancer cells, which is dependent on the disruption of H19/miR-204-5p/NF-κB/FLIP axis. Co-treatment of TP and TNF-α is a better option for enhancing the anti-cancer effect and lowering the side effect of TP.