Identification of an annonaceous acetogenin mimetic, AA005, as an AMPK activator and autophagy inducer in colon cancer cells.
Identification of an annonaceous acetogenin mimetic, AA005, as an AMPK activator and autophagy inducer in colon cancer cells.
复制标题
鉴定 Annonaceous Acetogenin 模拟物 AA005，作为结肠癌细胞中的 AMPK 激活剂和自噬诱导剂
DOI：
10.1371/journal.pone.0047049
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhou GB
中科院分区：
文献类型：
--
作者：
Liu YQ;Cheng X;Guo LX;Mao C;Chen YJ;Liu HX;Xiao QC;Jiang S;Yao ZJ;Zhou GB
已发现番荔枝内酯（Annonaceous acetogenins）是从番荔枝科（Annonaceae）植物属的各种物种中分离的天然存在的聚酮化合物的大家族，其对多种癌细胞表现出显著的细胞毒性。研究表明，这些化合物可作用于线粒体复合物I，阻断相应的电子传递链，终止ATP的产生。然而，作用机制的更多细节仍然不明确。在这项研究中，我们测试了番荔枝内酯的一组模拟物对一些癌细胞系的影响，并报告其中AA 005表现出最强的抗肿瘤活性。AA 005消耗ATP，激活AMP活化蛋白激酶（AMPK），抑制mTOR复合物1（mTORC 1）信号通路，导致结肠癌细胞生长抑制和自噬。AMPK抑制剂化合物C和肌苷抑制，而AMPK激活剂AICAR增强，AA 005引起的结肠癌细胞的增殖抑制和随后的自噬。AA 005增强由2-脱氧葡萄糖（线粒体呼吸和糖酵解的抑制剂）引起的ATP消耗和AMPK活化。AA 005还抑制化疗剂顺铂触发的mTOR上调，并与该药物协同抑制结肠癌细胞的增殖和诱导凋亡。这些数据表明AA 005是一种新的代谢抑制剂，在结肠癌中显示出治疗潜力。
Annonaceous acetogenins, a large family of naturally occurring polyketides isolated from various species of the plant genus Annonaceae, have been found to exhibit significant cytotoxicity against a variety of cancer cells. Previous studies showed that these compounds could act on the mitochondria complex-I and block the corresponding electron transport chain and terminate ATP production. However, more details of the mechanisms of action remain ambiguous. In this study we tested the effects of a set of mimetics of annonaceous acetogenin on some cancer cell lines, and report that among them AA005 exhibits the most potent antitumor activity. AA005 depletes ATP, activates AMP-activated protein kinase (AMPK) and inhibits mTOR complex 1 (mTORC1) signal pathway, leading to growth inhibition and autophagy of colon cancer cells. AMPK inhibitors compound C and inosine repress, while AMPK activator AICAR enhances, AA005-caused proliferation suppression and subsequent autophagy of colon cancer cells. AA005 enhances the ATP depletion and AMPK activation caused by 2-deoxyglucose, an inhibitor of mitochondrial respiration and glycolysis. AA005 also inhibits chemotherapeutic agent cisplatin-triggered up-regulation of mTOR and synergizes with this drug in suppression of proliferation and induction of apoptosis of colon cancer cells. These data indicate that AA005 is a new metabolic inhibitor which exhibits therapeutic potentials in colon cancer.
登录
查看更多内容
影响因子：
56.9
作者：
Dennis, PB;Jaeschke, A;Thomas, G
通讯作者：
Thomas, G
影响因子：
3.6
作者：
Jiang, S;Liu, ZH;Yao, ZJ
通讯作者：
Yao, ZJ
影响因子：
64.8
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
DOI：
10.1006/bbrc.2001.5627
发表时间：
2001-09-21
影响因子：
3.1
作者：
Imamura, K;Ogura, T;Esumi, H
通讯作者：
Esumi, H
影响因子：
11.2
作者：
Buzzai, Monica;Jones, Russell G.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.