Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Mol Sci. 2021 Mar 25;22(7):3354. doi: 10.3390/ijms22073354.
The aberrant activation of a signal transducer and activator of transcription 3 (STAT3) restrains type I interferon (IFN) α/β-induced antiviral responses and is associated with the development of cancer. Designing specific STAT3 inhibitors will thus provide new options for use as IFN therapy. Herein, we identified a novel small molecule, dimethyl 2-(4-(2-(methyl(phenyl(p-tolyl)methyl)amino)ethoxy)benzyl)malonate (CIB-6), which can inhibit the IFN-α-induced interferon stimulated response element (ISRE) luciferase reporter (IC value = 6.4 μM) and potentiate the antiproliferative effect of IFN-α in human hepatocellular carcinoma (HCC) cells. CIB-6 was found to bind to the STAT3 Src homology 2 (SH2) domain, thereby selectively inhibiting STAT3 phosphorylation without affecting Janus kinases and STAT1/2. CIB-6 also inhibited the migration and invasion of HCC cells by inhibiting the epithelial-mesenchymal transition (EMT) process. Mechanistically, CIB-6 reduced the expression of β-catenin (an EMT key protein) via upregulating β-transducin repeat-containing protein (β-TrCP) and curbed nuclear factor kappa-B (NF-κB) activation through restricting the phosphorylation of the inhibitor of NF-κB (IκB) kinase (IKK) via STAT3 inhibition. Treatment with CIB-6 significantly retarded tumor growth in nude mice with SK-HEP-1 xenografts. In addition, clinical sample analysis revealed that lower β-TrCP and higher β-catenin expression could affect the median survival time of HCC patients. Our findings suggest that CIB-6 could be a new therapeutic strategy for HCC therapy through STAT3-mediated β-TrCP/β-catenin/NF-κB axis.
信号转导子和转录激活子 3（STAT3）的异常激活抑制了 I 型干扰素（IFN）α/β诱导的抗病毒反应，与癌症的发展有关。因此，设计特异性 STAT3 抑制剂将为 IFN 治疗提供新的选择。在此，我们鉴定了一种新型小分子，二甲基 2-（4-（2-（甲基（苯基（对甲苯基）甲基）氨基）乙氧基）苄基）丙二酸盐（CIB-6），它可以抑制 IFN-α诱导的干扰素刺激反应元件（ISRE）荧光素酶报告（IC 值=6.4μM），并增强 IFN-α在人肝癌（HCC）细胞中的增殖抑制作用。CIB-6 被发现与 STAT3 Src 同源 2（SH2）结构域结合，从而选择性地抑制 STAT3 磷酸化，而不影响 Janus 激酶和 STAT1/2。CIB-6 还通过抑制上皮-间质转化（EMT）过程抑制 HCC 细胞的迁移和侵袭。机制上，CIB-6 通过上调 β-转导重复蛋白（β-TrCP）降低 EMT 关键蛋白β-连环蛋白（β-catenin）的表达，并通过抑制 STAT3 抑制抑制 NF-κB 激酶（IKK）的磷酸化来抑制核因子 kappa-B（NF-κB）的激活。用 CIB-6 治疗可显著抑制裸鼠 SK-HEP-1 异种移植瘤的生长。此外，临床样本分析显示，较低的 β-TrCP 和较高的 β-catenin 表达可能会影响 HCC 患者的中位生存时间。我们的研究结果表明，通过 STAT3 介导的 β-TrCP/β-catenin/NF-κB 轴，CIB-6 可能成为 HCC 治疗的一种新的治疗策略。
