Cucurbitacin B inhibits gastric cancer progression by suppressing STAT3 activity
Cucurbitacin B inhibits gastric cancer progression by suppressing STAT3 activity
复制标题
葫芦素 B 通过抑制 STAT3 活性抑制胃癌进展
DOI：
10.1016/j.abb.2020.108314
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发表时间：
2020-05-15
影响因子：
3.9
通讯作者：
Liu, Ying
中科院分区：
文献类型：
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作者：
Xu, Jiaxin;Chen, Yunhe;Liu, Ying
信号转导和转录激活因子 3 (STAT3) 在多种肿瘤中异常表达，包括胃癌 (GC)。 STAT3过度表达和过度激活已被证实在肿瘤发生中发挥重要作用。葫芦素 B (CuB) 是一种天然产物，对实体瘤具有有效的抗癌活性。在这里，我们系统地研究了 CuB 在体外和体内抑制 GC 的潜在分子机制。在 GC 细胞系中，纳摩尔浓度的 CuB 降低了 STAT3 中 TYR-705 的磷酸化，并抑制了 STAT3 靶基因的表达，包括 c-Myc 和 Bcl-xL。计算对接分析表明 CuB 与 STAT3 的 DNA 结合域在几个疏水残基处相互作用。此外，pulldown实验表明CuB是STAT3的直接抑制剂。 CuB 与传统化疗药物顺铂联合使用可增强 GC 细胞的细胞毒性，这可能是由于增强了 STAT3 激活的抑制作用。此外，异种移植小鼠模型证实了 CuB 的体内治疗作用。这些特性使 CuB 成为一种有前途的候选药物，可用于进一步开发治疗 GC 的新型有效 STAT3 抑制剂。
Signal transducer and activator of transcription 3 (STAT3) is expressed aberrantly in multiple tumors, including gastric cancer (GC). STAT3 overexpression and excessive activation have been confirmed to play vital roles in tumorigenesis. Cucurbitacin B (CuB) is a natural product with potent anti-cancer activities in solid tumors. Here, we systematically studied the underlying molecular mechanisms of CuB inhibition of GC both in vitro and in vivo. In GC cell lines, nanomolar concentrations of CuB decreased the phosphorylation of TYR-705 in STAT3 and suppressed STAT3 target gene expression, including c-Myc and Bcl-xL. Computational docking analysis showed that CuB interacts with the DNA-binding domain of STAT3 at several hydrophobic residues. In addition, pulldown experiments showed that CuB is a direct inhibitor of STAT3. CuB in combination with the conventional chemotherapy drug cisplatin exerted enhanced cytotoxicity in GC cells, possibly due to the potentiated inhibition of STAT3 activation. Moreover, a xenograft mouse model confirmed the therapeutic effect of CuB in vivo. These characteristics render CuB a promising candidate drug for further development in the design of new effective STAT3 inhibitors for treating GC.