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Isoangustone A induces autophagic cell death in colorectal cancer cells by activating AMPK signaling.

Authors
  • Tang, Shunan1
  • Cai, Sina1
  • Ji, Shuai2
  • Yan, Xiaojin1
  • Zhang, Weijia1
  • Qiao, Xue2
  • Zhang, Hongquan3
  • Ye, Min4
  • Yu, Siwang5
  • 1 State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China; Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China. , (China)
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China; Department of Natural Medicines, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China. , (China)
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China; Department of Anatomy, Histology and Embryology, Peking University School of Basic Medicinal Sciences, PR China. , (China)
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China; Department of Natural Medicines, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China. Electronic address: [email protected] , (China)
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China; Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing 100191, PR China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Fitoterapia
Publication Date
May 15, 2021
Volume
152
Pages
104935–104935
Identifiers
DOI: 10.1016/j.fitote.2021.104935
PMID: 34004245
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Phytochemicals, especially flavonoids, have been widely investigated for their diversified pharmacological activities including anticancer activities. Previously we identified isoangustone A from licorice-derived compounds as a potent inducer of cell death. In the present study, the exact mechanism by which isoangustone A induced cell death was further investigated, with autophagy as an indispensible part of this process. Isoangustone A treatment activated autophagic signaling and induced a complete autophagic flux in colorectal cancer cells. Knockdown of ATG5 or pre-treatment with autophagy inhibitors significantly reversed isoangustone A-induced apoptotic signaling and loss of cell viability, suggesting autophagy plays an important role in isoangustone A-induced cell death. Isoangustone A inhibited Akt/mTOR signaling, and overexpressing of a constitutively activated Akt mildly suppressed isoangustone A-induced cell death. More importantly, isoangustone A inhibited cellular ATP level and activated AMPK, and pre-treatment with AMPK inhibitor or overexpression of dominant negative AMPKα2 significantly reversed isoangustone A-induced autophagy and cell death. Further study shows isoangustone A dose-dependently inhibited mitochondrial respiration, which could be responsible for isoangustone A-induced activation of AMPK. Finally, isoangustone A at a dosage of 10 mg/kg potently activated AMPK and autophagic signaling in and inhibited the growth of SW480 human colorectal xenograft in vivo. Taken together, induction of autophagy through activation of AMPK is an important mechanism by which isoangustone A inhibits tumor growth, and isoangustone A deserves further investigation as a promising anti-cancer agent. Copyright © 2021 Elsevier B.V. All rights reserved.

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