Involvement of mTOR/Survivin signaling pathway in TUA(2β, 3β, 23-trihydroxy-urs-12-ene-28-olic acid)-induced apoptosis in human gastric cancer cell line BGC823 cells

• Published in: Journal of ethnopharmacology 2021-03, Vol.267, p.113437-113437, Article 113437
• Main Authors: Cheng, Qilai, Li, Yingchen, Guo, Xiaohua, Li, Hongliang
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; BGC823 cells; Cell Line, Tumor; Cell Proliferation - drug effects; Female; G2 Phase Cell Cycle Checkpoints - drug effects; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; mTOR; Signal Transduction; Stomach Neoplasms - drug therapy; Stomach Neoplasms - enzymology; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Survivin; Survivin - genetics; Survivin - metabolism; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Triterpenes - pharmacology; TUA; Tumor Burden - drug effects
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2020.113437

A natural ursolic compound, 2β,3β,23-trihydroxy-urs-12-ene-28-olic acid (TUA) was isolated from the root of Actinidiafulvicoma Hance. (A.fulvicoma Radix), which is used as a traditional hebal medicine to cure innominate inflammation of unknown origin of the digestive tract in the She nationality. Aim of the study: The aim of present study was to investigate the effects of TUA on gastric cancer and to clarify the potential mechanisms in human gastric cancer cell line BGC823 cells in vitro and in vivo. Cell proliferation, apoptosis, cell cycle, autophagy were all measured by MTS assay, flow cytometry following exposure to TUA. The mRNA expressions of PI3K, AKT, mTOR, P70S6K, Survivin and the protein expressions of p-PI3K, p-AKT, p-mTOR, p-P70S6K, Survivin were determined by qRT-PCR and Western blotting analysis, respectively. In vivo antitumor activity of TUA was assessed in a xenograft model. In vitro studies showed that TUA significantly suppressed the viability of BGC823 cells in a concentration- and time-dependent manner but not GES-1 non-tumorigenic human gastric epithelial cells. TUA also significantly increased the apoptosis rate and the sub G2 population by cell cycle analysis in a concentration dependent manner. Exposure to TUA decreased PI3K, AKT, mTOR, P70S6K, Survivin mRNA, inhibited the phosphorylation of major receptors involved in autophagy and apoptosis, such as PI3K, AKT, mTOR and P70S6K, while reduced the expression of Survivin in BGC cells. In vivo studies showed that TUA decreased tumor volume and tumor weight and also down regulated the autophagy-related proteins expression. TUA occupies underlying antitumor effects, the potential mechanisms may involve the suppression of mTOR/Survivin pathways connected to autophagy and the activation of apoptotic pathways in gastric cancer cells. [Display omitted] •TUA, which isolated from the root of Actinidiafulvicoma Hance. (A.fulvicoma Radix), was a natural ursolic compound.•TUA induced apoptosis of human gastric cancer cell line BGC823 in vitro and in vivo via down-regulation of the mTOR/Survivin signaling pathway.•Inhibition of autophagy promoted apoptosis induced by TUA in BGC823 cells and xenograft model.•TUA will be a potent anticancer candidate for gastric cancer treatment in future.