PDF(Sci-hub)
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.
摘要：
植物化学品,尤其是类黄酮,已经广泛研究了它们的多种药理活性，包括抗癌活性。以前，我们从甘草衍生的化合物中鉴定出异龙酮A是细胞死亡的有效诱导剂。在本研究中,进一步研究了异龙酮A诱导细胞死亡的确切机制，自噬是这个过程不可或缺的一部分。IsoangestoneA治疗激活了自噬信号并在结直肠癌细胞中诱导了完全的自噬通量。敲低ATG5或用自噬抑制剂预处理可显着逆转异龙骨蛋白A诱导的凋亡信号和细胞活力的丧失，提示自噬在异龙骨蛋白A诱导的细胞死亡中起重要作用。异神酮A抑制Akt/mTOR信号传导，组成型激活的Akt的过表达轻度抑制了异龙骨蛋白A诱导的细胞死亡。更重要的是,异龙酮A抑制细胞ATP水平并激活AMPK，用AMPK抑制剂预处理或过表达显性阴性的AMPKα2可显着逆转异龙骨蛋白A诱导的自噬和细胞死亡。进一步的研究表明异龙酮A剂量依赖性地抑制线粒体呼吸，这可能与异龙骨A诱导的AMPK活化有关。最后,10mg/kg剂量的异族酮A可有效激活AMPK和自噬信号，并抑制体内SW480人结直肠异种移植物的生长。一起来看,通过激活AMPK诱导自噬是异龙珠酮A抑制肿瘤生长的重要机制,和异龙酮A作为一种有前途的抗癌剂值得进一步研究。
