Eupalinolide J Suppresses the Growth of Triple-Negative Breast Cancer Cells via Targeting STAT3 Signaling Pathway
Eupalinolide J Suppresses the Growth of Triple-Negative Breast Cancer Cells via Targeting STAT3 Signaling Pathway
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Eupalinolide J 通过靶向 STAT3 信号通路抑制三阴性乳腺癌细胞的生长
DOI：
10.3389/fphar.2019.01071
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发表时间：
2019-09-19
影响因子：
5.6
通讯作者：
Zhao, Huajun
中科院分区：
文献类型：
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作者：
Lou, Chenghua;Chen, Yan;Zhao, Huajun
STAT3的持续激活在三阴性乳腺癌的发生发展中起着重要作用，抑制STAT3被认为是肿瘤治疗的新途径。在本项目中，我们旨在研究Eupalinolide J(EJ)在TNBC细胞中的抗癌活性及其分子机制。结果表明，EJ对人TNBC细胞(MDA-MB-231和MDA-MB-468)的生长有明显的抑制作用。IC50值分别为3.74±0.58和4.30±0.39亩M。进一步的研究表明，EJ主要通过诱导细胞凋亡、破坏线粒体膜电位和细胞周期停滞来抑制TNBC细胞的增殖。同时，EJ处理的TNBC细胞中的STAT3和p-STAT3明显受到抑制。重要的是，STAT3-shRNA沉默STAT3显著减弱了EJ在TNBC细胞中的抗癌活性，提示EJ通过靶向STAT3途径抑制癌细胞的增殖。值得注意的是，进一步的研究表明，EJ显著促进了STAT3在TNBC细胞中的降解。最后，EJ在体内对MDA-MB-231细胞显示出有效的抗肿瘤活性。总之，我们发现EJ通过靶向STAT3信号通路抑制了TNBC细胞的生长。这些结果有力地支持了EJ是一种很有前途的治疗TNBC的药物。
Persistent activation of STAT3 plays an important role in the development of triple-negative breast cancer (TNBC), and suppression of STAT3 is considered as a novel approach for cancer therapy. In this project, we aimed to examine the anticancer activity and molecular mechanism of eupalinolide J (EJ) in TNBC cells. The presented results demonstrated that the growth of human TNBC cells (MDA-MB-231 and MDA-MB-468 cells) was obviously inhibited by EJ. The IC50 values were 3.74 +/- 0.58 and 4.30 +/- 0.39 mu M, respectively. Further study demonstrated that EJ suppressed the proliferation of TNBC cells mainly through cell apoptosis induction, mitochondrial membrane potential (MMP) disruption, and cell cycle arrest. Meanwhile, the STAT3 and p-STAT3 in EJ-treated TNBC cells were remarkably suppressed. Importantly, silencing of STAT3 by STAT3-shRNA significantly blunted the anticancer activities of EJ in TNBC cells, suggesting that EJ suppressed cancer cell proliferation via targeting the STAT3 pathway. Notably, further study demonstrated that EJ significantly promoted the degradation of STAT3 in TNBC cells. Finally, EJ exhibited an effective antitumor activity against MDA-MB-231 cells in vivo. In conclusion, we identified that EJ suppressed the growth of TNBC cells via targeting the STAT3 signaling pathway. These results strongly support that EJ is a promising therapeutic agent for TNBC.