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.

肝细胞癌是消化系统最常见的原发性恶性肿瘤之一。化合物5-氯-氮'-(2,4-二甲氧基亚苄基)-1H-吲哚-2-碳酰肼 (IHZ-1/ZJQ-24) 是一种新型吲哚酰肼衍生物。在最近的一项研究中，我们证明 IHZ-1 通过抑制 mTORC1 的激酶活性来抑制肿瘤生长并诱导细胞凋亡，而无需激活 AKT，而 AKT 与 JNK/IRS-1 激活相关。然而，IHZ-1 激活 JNK 对肝细胞癌的影响和机制仍完全未知。在这里，我们发现 IHZ-1 增加了细胞内 ROS 的产生并增强了自噬。IHZ-1 诱导的 JNK 磷酸化因 ROS 水平降低而逆转。此外，抑制 ROS/JNK 或自噬同样会减弱 IHZ-1 诱导的细胞凋亡作用。我们的研究结果表明，IHZ-1 治疗对 JNK 的激活依赖于 ROS 的产生，而 ROS 介导肝细胞癌中的细胞凋亡和自噬。