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

被引:14
|
作者
Tang, Shunan [1 ,2 ]
Cai, Sina [1 ,2 ]
Ji, Shuai [1 ,3 ]
Yan, Xiaojin [1 ,2 ]
Zhang, Weijia [1 ,2 ]
Qiao, Xue [1 ,3 ]
Zhang, Hongquan [1 ,4 ]
Ye, Min [1 ,3 ]
Yu, Siwang [1 ,2 ]
机构
[1] Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
[2] Peking Univ, Dept Mol & Cellular Pharmacol, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
[3] Peking Univ, Dept Nat Med, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
[4] Peking Univ, Dept Anat Histol & Embryol, Sch Basic Med Sci, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
Prenylated flavonoids; Isoangustone A; Autophagy; Apoptosis; AMPK; BIOLOGICAL-ACTIVITIES; ADENOCARCINOMA CELLS; DUAL ROLE; MTOR; INHIBITION; MODULATION; FLAVONOIDS; APOPTOSIS; PROTEIN; TARGET;
D O I
10.1016/j.fitote.2021.104935
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 AMPK alpha 2 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.
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页数:12
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