5-Fluorouracil enhances the chemosensitivity of gastric cancer to TRAIL via inhibition of the MAPK pathway

• Published in: Biochemical and biophysical research communications 2021-02, Vol.540, p.108-115
• Main Authors: Li, Hui, Lv, Jing, Guo, Jing, Wang, Shasha, Liu, Shihai, Ma, Yingji, Liang, Zhiwei, Wang, Yunyun, Qi, Weiwei, Qiu, Wensheng
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Caspases - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Combinational therapy; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gastric cancer; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Nude; Stomach Neoplasms - drug therapy; Stomach Neoplasms - enzymology; Stomach Neoplasms - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.01.006

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to selectively trigger cancer cell apoptosis and can be used as a target for tumor therapy. However, gastric cancer cells are usually insensitive to TRAIL so reducing this drug resistance may improve the treatment of gastric cancer. In this study, we used Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) experiments to determine the effects of 5-fluorouracil (5-FU) and TRAIL on the proliferation of gastric cancer cells. An Annexin V/propidium iodide (PI) staining experiment was used to detect apoptosis, and Western blotting was used to analyze the expression levels of apoptosis-related proteins and mitogen-activated protein kinase (MAPK) pathway proteins. The antitumor effects of 5-FU and TRAIL were verified in vivo using a nude mouse tumorigenesis experiment, and a TUNEL assay was performed to evaluate apoptosis in tumor tissue from the nude mice. We found the combination of 5-FU and TRAIL had a greater inhibitory effect on the proliferation of gastric cancer cells than 5-FU or TRAIL alone both in vivo and in vitro. 5-FU enhanced TRAIL-induced gastric cancer cell apoptosis by inactivating the MAPK pathway. Overall, our analysis firstly provided new insights into the role of 5-FU in increasing sensitivity to TRAIL. 5-FU can be used as a sensitizer for TRAIL, and its administration is a potential strategy for the treatment of gastric cancer. •The combination of TRAIL and 5-Fluorouracil (5-FU) can inhibit gastric cancer cell proliferation and induce cell apoptosis in vivo and in vitro to a large extent.•The MAPK pathway may be involved in the sensitization to TRAIL induced by 5-FU.•These findings provide a theoretical basis for the synergistic antitumor effect of 5-FU as a sensitizer of TRAIL.