Indole hydrazide compound ZJQ-24 inhibits angiogenesis and induces apoptosis cell death through abrogation of AKT/mTOR pathway in hepatocellular carcinoma

作者：Jing Liu, Ying Liu, Jianqiang Zhang, Jianqiang Zhang, Dan Liu, Yafeng Bao, Tianxing Chen, Tao Tang, Jun Lin, Ying Luo, Yi Jin, Jihong Zhang, Jihong Zhang · 发表于：Cell Death and Disease · 年份：2020 · DOI：10.1038/s41419-020-03108-2 · 被引用次数：25 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Cancer Mechanisms and Therapy、14-3-3 protein interactions

Abstract 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 G 2 /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 (Thr 389 ) and phospho-4EBP-1 (Ser65, Thr 37/46 , Thr 70 ) and phospho-AKT (Ser 473 ) 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 th...