Autophagy induction by xanthoangelol exhibits anti‐metastatic activities in hepatocellular carcinoma
Authors: Kun Fang
Kui Lu
Xianzhou Shi
Xuezhu Lin
Mei Han
Xiaoxiao Liu
Jing Xie
Zhuang Zhang
Hui Gao
Zhi Gong
Zichao Li
Luying Zhang
Xiuwei Yang
Journal: Cell biochemistry and function (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: AMPK/mTOR; HCC; autophagy; metastasis; xanthoangelol.
Affiliations: The Affiliated Hospital of Qingdao University Qingdao China, Medical CollegeQingdao University Qingdao China, College of Life SciencesQingdao University Qingdao China, Qingdao Fifth People's Hoespital (Shandong Qingdao Hospital of Integrated Traditional and Western Medicine) Qingdao China, Department of Pharmacology, School of PharmacyQingdao University Qingdao China, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of BiotechnologyTianjin University of Science and Technology Tianjin China, Northeast Yucai Bilingual School Shenyang China

Abstract:  Xanthoangelol (XAG), a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi, has been reported to exhibit antineoplastic properties. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC), and the relevant mechanisms are not known. Herein, we evaluated the effect of XAG against HCC in vitro and in vivo. Although XAG treatment did not significantly reduce the viability of the Hep3B and Huh7 cell lines, it suppressed cell migration, invasion, and EMT. This anti-metastatic effect of XAG was due to induction of autophagy, because treatment with the autophagy inhibitor 3-methyadenine (3-MA) or knockdown of the pro-autophagy Beclin-1 effectively abrogated the XAG-induced suppression of metastasis. Mechanistically, XAG induced autophagy via activation of the AMPK/mTOR signaling pathway, and XAG treatment dramatically increased the expression of p-AMPK while decreasing p-mTOR expression. In addition, blocking AMPK/mTOR axis with compound C abrogated the autophagy-mediated inhibition of metastasis. The murine model of HCC metastasis also showed that XAG effectively reduced the number of metastatic pulmonary nodules. Taken together, our results revealed that autophagy via the activation of AMPK/mTOR pathway is essential for the anti-metastatic effect of XAG against HCC. These findings not only contribute to our understanding of the anti-tumor activity of XAG but also provide a basis for its clinical application in HCC. Before this study, evidence of XAG on HCC was purely anecdotal; present study provides the first comprehensive assessments of XAG on HCC metastasis and investigates its underlying mechanism. Results suggest that XAG exerts anti-metastatic properties against HCC through inducing autophagy which is mediated by the activation of AMPK/mTOR signaling pathway. This research extends our knowledge about the antineoplastic properties of XAG and suggests that induction autophagy may represent future treatment strategies for metastatic HCC. 

Retracted: No

PubPeer comments:
 Fig 3C.  Autophagy inhibition abrogated the effect of XAG on HCC cell migration and invasion. ... C, Transwell migration (left) and invasion (right) assays of Hep3B and Huh7 cells transfected with Beclinu20101 shRNA or scrambled shRNA, followed by XAG treatment . Panels are shared with (below) Fig 3E and 4D from [Liu et al (2018)] . ![file] These are different cell-lines and different treatments. Could the authors comment? , 
 #1 Further coincidences. As well as 3(c) at top and 3E from [Liu et al (2018)] at lower right, I have added 2B from [Fang et al (2019)] to the mix, at lower left. ![file] Two panels (marked) are nearly mirror images, but with clumps of cells added (or deleted). ,