Abstract
Hepatocellular carcinoma is one of the most common primary malignant tumors of the digestive system. Compound 5-chloro-N′-(2,4-dimethoxybenzylidene)-1H-indole-2-carbohydrazide (IHZ-1/ZJQ-24) is a novel indole hydrazide derivative. In a recent study, we demonstrated that IHZ-1 inhibits tumor growth and induces cell apoptosis through inhibiting the kinase activity of mTORC1 without activation of AKT, which is associated with JNK/IRS-1 activation. However, the impact and mechanisms of JNK activation by IHZ-1 in hepatocellular carcinoma remains entirely unknown. Here, we find that IHZ-1 increases the generation of intracellular ROS and enhances autophagy. The phosphorylation of JNK induced by IHZ-1 was reversed by the decreased ROS level. Moreover, inhibition of ROS/JNK or autophagy equally attenuated apoptotic effect induced by IHZ-1. Our findings suggest that the activation of JNK by IHZ-1 treatment is dependent on the generation of ROS that mediates apoptosis and autophagy in hepatocellular carcinoma.
Highlights
Primary carcinoma of the liver [hepatocellular carcinoma (HCC)] is one of the familiar digestive system neoplasms [1]
Our result showed that IHZ-1 increased the expression level of p-Jun Nterminal kinase (JNK) and the upregulation of p-JNK was inhibited by NAC and SP600125 (Figure 2A)
We demonstrated that IHZ-1 caused JNK upregulation in ROSdependent HCC cells, which is required for IHZ-1induced apoptosis
Summary
Primary carcinoma of the liver [hepatocellular carcinoma (HCC)] is one of the familiar digestive system neoplasms [1]. Current treatments for HCC include surgery, radiation therapy, and drug therapy, but the overall outlook for most patients has not improved significantly, with 5-year survival rates below 20% [2]. Our previous study reported that IHZ-1 has been named ZJQ-24 (5-chloro-N′-(2,4dimethoxybenzylidene)-1H-indole-2-carbohydrazide) (Figure 1A) induced cell apoptosis by inhibiting the mTORC1 activity without activation of AKT via phosphorylation of c-Jun Nterminal kinase (JNK) [3]. The inhibition of AKT/mTOR by IHZ-1 has positive correlation with antitumor effect, the mechanisms of JNK activation remain unclear. Whether the activation of JNK by IHZ-1 can result in apoptosis or autophagy has not been investigated yet
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