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Food Science and Human Wellness 2024, 13(3): 1453-1464 https://doi.org/10.26599/FSHW.2022.9250122
Research Article | Open Access | Issue | Published: 08 February 2024

3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) induces autophagy by activation of AMP-activated protein kinase in hepatocellular carcinoma

Show Author's Information Mengjie Liua,1,,  Xuqiang Liub,1( ),  Kaiyue Hea,  Yongping Jiana,  Yujia Lia,  Jinrong Guoa,  Jingyu Yanga,  Zhixiang Xua( ),  Wenyi Kangb,c,d( )
School of Life Sciences, Henan University, Kaifeng 475004, China
National R & D Center for Edible Fungus Processing Technology, Henan University, Kaifeng 475004, China
Joint International Research Laboratory of Food & Medicine Resource Function, Kaifeng 475004, China
Shenzhen Research Institute of Henan University, Shenzhen 518000, China

1 These authors contributed equally to this work.

Peer review under responsibility of Tsinghua University Press.

Keywords:
Autophagy, Hepatocellular carcinoma, ATP, AMPK, eBAG
Cite this article:
Liu M, Liu X, He K, et al. 3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) induces autophagy by activation of AMP-activated protein kinase in hepatocellular carcinoma. Food Science and Human Wellness, 2024, 13(3): 1453-1464. https://doi.org/10.26599/FSHW.2022.9250122
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Abstract Full text Electronic supplementary material About this article

3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) is a pentacyclic triterpene mainly distributed in food and medicinal plants, which exhibits various pharmacological properties. However, whether these functions are attributed to eBAG or additional components in these plants remain unknown. Herein, we report that eBAG exerted an inhibitory activity against hepatocellular carcinoma and esophageal cancer cells. EBAG induced non-apoptotic cell death in hepatocellular carcinoma cells. The eBAG-induced cell death was inhibited by knock-down of autophagy related gene (ATG) 5 and ATG7, by administration of 3-methyladenine, a selective autophagy inhibitor that suppresses phosphoinositide 3-kinase (PI3K), and by chloroquine, a classic autophagy f lux inhibitor. We demonstrated that eBAG induced an autophagy-mediated cell death. Application of eBAG mimicked cellular bioenergetics depletion leading to the reduction of intracellular ATP, activation of AMP-activated protein kinase (AMPK), and inhibition of mTOR. Co-treatment with compound C, an AMPK inhibitor, abrogated cell death induced by eBAG. We further validated the anti-tumor effect of eBAG in the murine xenograft model of hepatocellular carcinoma and found that eBAG treatment promoted the induction of autophagy and reduction of tumor growth in mice. As a functional food ingredient, eBAG is a potential therapeutic agent for the treatment of hepatocellular carcinoma and esophageal cancer.


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About this article

3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) induces autophagy by activation of AMP-activated protein kinase in hepatocellular carcinoma

Show Author's information Mengjie Liua,1,, Xuqiang Liub,1( ), Kaiyue Hea, Yongping Jiana, Yujia Lia, Jinrong Guoa, Jingyu Yanga, Zhixiang Xua( ), Wenyi Kangb,c,d( )
School of Life Sciences, Henan University, Kaifeng 475004, China
National R & D Center for Edible Fungus Processing Technology, Henan University, Kaifeng 475004, China
Joint International Research Laboratory of Food & Medicine Resource Function, Kaifeng 475004, China
Shenzhen Research Institute of Henan University, Shenzhen 518000, China

1 These authors contributed equally to this work.

Peer review under responsibility of Tsinghua University Press.

Abstract

3-Epi-betulinic acid 3-O-β-D-glucopyranoside (eBAG) is a pentacyclic triterpene mainly distributed in food and medicinal plants, which exhibits various pharmacological properties. However, whether these functions are attributed to eBAG or additional components in these plants remain unknown. Herein, we report that eBAG exerted an inhibitory activity against hepatocellular carcinoma and esophageal cancer cells. EBAG induced non-apoptotic cell death in hepatocellular carcinoma cells. The eBAG-induced cell death was inhibited by knock-down of autophagy related gene (ATG) 5 and ATG7, by administration of 3-methyladenine, a selective autophagy inhibitor that suppresses phosphoinositide 3-kinase (PI3K), and by chloroquine, a classic autophagy f lux inhibitor. We demonstrated that eBAG induced an autophagy-mediated cell death. Application of eBAG mimicked cellular bioenergetics depletion leading to the reduction of intracellular ATP, activation of AMP-activated protein kinase (AMPK), and inhibition of mTOR. Co-treatment with compound C, an AMPK inhibitor, abrogated cell death induced by eBAG. We further validated the anti-tumor effect of eBAG in the murine xenograft model of hepatocellular carcinoma and found that eBAG treatment promoted the induction of autophagy and reduction of tumor growth in mice. As a functional food ingredient, eBAG is a potential therapeutic agent for the treatment of hepatocellular carcinoma and esophageal cancer.

Keywords: Autophagy, Hepatocellular carcinoma, ATP, AMPK, eBAG

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Publication history

Received: 25 September 2022
Revised: 11 October 2022
Accepted: 14 November 2022
Published: 08 February 2024
Issue date: May 2024

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© 2024 Beijing Academy of Food Sciences. Publishing services by Tsinghua University Press.

Acknowledgements

Acknowledgment

This work was supported by Henan Provincial Science and Technology Research Project (212102310355) and the National Natural Science Foundation of China (82020108024 and 32161143021).

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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