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

Jing Liu,Ying Liu,Jihong Zhang,Dan Liu,Tao Tang,Tianxing Chen,Ying Luo,Yafeng Bao,Yi Jin,Jun Lin,Jianqiang Zhang

doi:10.1038/s41419-020-03108-2

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 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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common human cancer worldwide and the incidence of HCC has been increasing rapidly, in China[1]
We further showed that ZJQ-24 reduces the tumor growth in a HepG2 xenograft model through suppression of vascular endothelial growth factor (VEGF) and AKT/mammalian target of rapamycin (mTOR) pathways
To clarify the functional role of ZJQ24 in the antiangiogenic effect, we procceded to examine the interaction of ZJQ-24 with mTOR (PDB ID: 4JT6) and AKT (PDB ID: 3O96) proteins

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common human cancer worldwide and the incidence of HCC has been increasing rapidly, in China[1]. Significant progresses in diagnosis and treatment of HCC (including target therapy) has been made, few drugs have been approved effective for HCC2. Not to mention almost all of them have side effects and quickly patients drug resistance[3]. Identification of novel molecular therapeutic targets and development of novel treatments are critical for HCC. HCC is highly vascular tumor with a strong angiogenesis-inducing ability[4]. It has been reported that the expression of vascular endothelial growth factor (VEGF) was increased in HCC tumors and patients sera[5], Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion