Atractylenolide I inhibits colorectal cancer cell proliferation by affecting metabolism and stemness via AKT/mTOR signaling

• Published in: Phytomedicine (Stuttgart) Vol. 68; p. 153191
• Main Authors: Wang, Kuilong, Huang, Wei, Sang, Xianan, Wu, Xin, Shan, Qiyuan, Tang, Dongxin, Xu, Xiaofen, Cao, Gang
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.03.2020
• Subjects: AKT/mTOR signaling; Apoptosis; Cell behavior; Gastrointestinal; Glucose metabolism; Traditional Chinese medicine; S6; Cell behavior; Gastrointestinal; MTT; HK2; RIPA; OCT4; SOX2; Glucose metabolism; LDH; SD; AKT/mTOR signaling; CSC; FITC; PI3K; ANOVA; FBS; mTOR; PBS; GLUT1; eIF4E; HIF; PKM2; Traditional Chinese medicine; S6K; AKT; DCFH-DA; CRC; PBST; ROS; ATL; Cyt-C; GAPDH; Apoptosis; TCM
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2020.153191

Atractylenolide I (ATL-1) is a natural herbal compound used in traditional Chinese medicine that has exhibited anti-cancer properties. The anti-tumorigenic activity of ATL-1 against colorectal cancer (CRC) and the underlying signaling pathways involved in its mechanisms are examined here. ATL-1 exerts therapeutic effect against CRC by disrupting glucose metabolism and cancer stem cell maintenance via AKT/mTOR pathway regulation. In vitro studies were performed in COLO205 and HCT116 CRC cell lines and in vivo studies were conducted in a mouse xenograft model of CRC tumor. CRC cells were treated with ATL-1 at various concentrations, with or without inhibitors of AKT or mTOR. Cell proliferation, apoptosis, invasion, stemness maintenance, glucose metabolism, and AKT/mTOR signaling were evaluated. CRC tumor-xenografted mice were treated with an AKT inhibitor and/or ATL-1, and glucose metabolism and stemness maintenance were examined in tumor tissues. ATL-1 significantly inhibited the invasion of CRC cells by inducing their apoptosis, possibly via the excessive production of reactive oxygen species. Glucose metabolism (Warburg effect) was also altered and stem-like traits were suppressed by ATL-1. In addition, ATL-1 effectively acted as an inhibitor or AKT/mTOR by downregulating the phosphorylation of proteins related to the AKT/mTOR pathway. In vivo studies showed that tumor weight and volume were reduced by ATL-1 and that aerobic glycolysis, stemness maintenance, and AKT/mTOR activation were impaired by ATL-1 in colorectal tumors. ATL-1 acts as an effective agent to suppress colorectal tumor progression, mainly by inhibiting CRC cell proliferation through altering apoptosis, glucose metabolism, and stem-like behavior. These processes were mediated by the AKT/mTOR signaling pathway both in vitro and in vivo. ATL-1 may be a potential agent to be used in molecular-targeted strategies for cancer treatment. [Display omitted]