Indole hydrazide compound ZJQ-24 inhibits angiogenesis and induces apoptosis cell death through abrogation of AKT/mTOR pathway in hepatocellular carcinoma.
Indole hydrazide compound ZJQ-24 inhibits angiogenesis and induces apoptosis cell death through abrogation of AKT/mTOR pathway in hepatocellular carcinoma.
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吲哚酰肼化合物 ZJQ-24 通过消除肝细胞癌中的 AKT/mTOR 通路来抑制血管生成并诱导细胞凋亡。
DOI：
10.1038/s41419-020-03108-2
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发表时间：
2020-10-28
影响因子：
9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Liu J;Liu Y;Zhang J;Liu D;Bao Y;Chen T;Tang T;Lin J;Luo Y;Jin Y;Zhang J
血管生成和AKT/mTOR通路的激活在肝癌的发生发展中起着至关重要的作用，临床肝癌标本中已经证实了mTORC1/2及其相关底物的激活。因此，AKT/mTOR通路是抗癌药物开发的主要靶点。在此，我们研究了ZJQ-24在体内和体外对肝细胞癌的抗增殖活性及其机制。肝细胞癌移植瘤模型显示，ZJQ-24能显著抑制肿瘤生长，且副作用少。四甲基偶氮唑盐比色法、流式细胞仪分析、Western blotting和免疫组织化学分析表明，ZJQ-24通过G2/M期阻滞和caspase依赖的细胞凋亡抑制肝癌细胞的增殖，而对正常细胞无细胞毒作用。此外，ZJQ-24通过下调肝癌细胞中的磷酸化p70S6K(Thr389)、磷酸化4EBP-1(Ser65，Thr37/46，Thr70)和磷酸化AKT(Ser473)等mTORC1分子，显著抑制AKT/mTOR信号转导。很重要的一点是，ZJQ-24没有通过JNK激活诱导依赖mTORC1的PI3K/Akt反馈激活。此外，ZJQ-24通过破坏eIF4E/eIF4G复合体的组装，抑制了帽子依赖的翻译起始。免疫组织化学进一步证实ZJQ-24在体内通过抑制血管内皮生长因子和AKT/mTOR通路抑制肿瘤生长。因此，本研究首次阐明了ZJQ-24通过抑制AKT/mTOR通路而触发肝癌细胞的抗血管生成活性和细胞凋亡，为ZJQ-24作为肝细胞癌血管生成和肿瘤生长抑制因子的潜在作用提供了基本的科学证据。
Angiogenesis and the activation of AKT/mTOR pathway are crucial for hepatocarcinoma development and progression, the activation of mTORC1/2 and relevant substrates have been confirmed in clinical hepatocarcinoma samples. Therefore, AKT/mTOR pathway represents the major targets for anti-cancer drugs development. Here, we investigated the anti-proliferative activity and mechanisms of ZJQ-24 in hepatocellular carcinoma, both in vivo and in vitro. A hepatocellular carcinoma xenograft model showed that ZJQ-24 significantly inhibited tumor growth with few side effects. MTT assays, flow cytometric analysis, Western blotting and immunohistochemistry identified that ZJQ-24 effectively suppressed hepatocellular carcinoma cell proliferation via G2/M phase arrest and caspase-dependent apoptosis but had no cytotoxic on normal cells. Furthermore, ZJQ-24 significantly blocked AKT/mTOR signaling by down-regulation of mTORC1 molecules, including phospho-p70S6K (Thr389) and phospho-4EBP-1 (Ser65, Thr37/46, Thr70) and phospho-AKT (Ser473) in HCC cells. It is very important that the ZJQ-24 did not induce the mTORC1-depdent PI3K/Akt feedback activation through JNK excitation. Moreover, ZJQ-24 inhibited the cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex. Immunohistochemistry further confirmed ZJQ-24 inhibited the tumor growth through suppression of VEGF and AKT/mTOR pathways in vivo. Thus, the present study is the first to illustrate that ZJQ-24 triggers antiangiogenic activity and apoptosis via inhibiting the AKT/mTOR pathway in hepatocellular carcinoma cells, providing basic scientific evidence that ZJQ-24 shows great potential function as inhibitor of angiogenesis and tumor growth in hepatocellular carcinoma.
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影响因子：
16
作者：
Loewith, R;Jacinto, E;Hall, MN
通讯作者：
Hall, MN
影响因子：
7.3
作者：
Pike, Kurt G.;Morris, Jeff;Pearson, Stuart E.
通讯作者：
Pearson, Stuart E.
DOI：
10.1158/1078-0432.ccr-10-0433
发表时间：
2010-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hsieh AC;Ruggero D
通讯作者：
Ruggero D
影响因子：
8.8
作者：
Mateo J;Olmos D;Dumez H;Poondru S;Samberg NL;Barr S;Van Tornout JM;Jie F;Sandhu S;Tan DS;Moreno V;LoRusso PM;Kaye SB;Schöffski P
通讯作者：
Schöffski P
影响因子：
15.9
作者：
Carracedo, Arkaitz;Ma, Li;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo