Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3
Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3
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DOI：
10.3389/fonc.2019.00743
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发表时间：
2019-08-08
影响因子：
4.7
通讯作者：
Iratni, Rabah
中科院分区：
文献类型：
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作者：
Alsamri, Halima;El Hasasna, Hussain;Iratni, Rabah
我们以前已经证明，鼠尾草酚，一种天然存在的二萜，抑制体外细胞活力和集落生长，以及诱导细胞周期停滞，自噬和凋亡的人三阴性乳腺癌（TNBC）细胞。在本研究中，我们评估了鼠尾草酚在体内抑制肿瘤生长和转移的能力。我们发现，非细胞毒性浓度的鼠尾草酚抑制MDA-MB-231细胞在伤口愈合和基质胶侵袭测定中的迁移和侵袭。明胶酶谱法、ELISA和RT-PCR检测结果显示鼠尾草酚抑制了MMP-9的活性，下调了MMP-9的表达。从机制上讲，我们证明了鼠尾草酚通过ROS依赖性靶向乳腺癌细胞（MDA-MB-231，Hs 578 T，MCF-7和T47 D）中的STAT 3蛋白酶体降解来抑制STAT 3信号通路的激活。我们发现，通过MG-132和硼替佐米阻断蛋白酶体活性，或通过N-乙酰半胱氨酸（NAC）阻断ROS积累，恢复了STAT 3蛋白的水平。此外，通过鸡胚肿瘤生长实验，我们发现鼠尾草酚显著地抑制了乳腺癌移植瘤的生长和转移。据我们所知，这是第一个报告，表明鼠尾草酚特异性靶向信号转导和转录激活因子3（STAT 3）的蛋白酶体降解乳腺癌。我们的研究进一步提供了证据，鼠尾草酚可能代表一个有前途的治疗候选人，可以调节乳腺癌的生长和转移。
We have previously demonstrated that carnosol, a naturally occurring diterpene, inhibited in vitro cell viability and colony growth, as well as induced cell cycle arrest, autophagy and apoptosis in human triple negative breast cancer (TNBC) cells. In the present study, we evaluated the ability of carnosol to inhibit tumor growth and metastasis in vivo. We found that non-cytotoxic concentrations of carnosol inhibited the migration and invasion of MDA-MB-231 cells in wound healing and matrigel invasion assays. Furthermore, gelatin zymography, ELISA, and RT-PCR assays revealed that carnosol inhibited the activity and downregulation the expression of MMP-9. Mechanistically, we demonstrated that carnosol suppressed the activation of STAT3 signaling pathway through a ROS-dependent targeting of STAT3 to proteasome-degradation in breast cancer cells (MDA-MB-231, Hs578T, MCF-7, and T47D). We show that blockade of proteasome activity, by MG-132 and bortezomib, or ROS accumulation, by N-acetylcysteine (NAC), restored the level of STAT3 protein. In addition, using chick embryo tumor growth assay, we showed that carnosol significantly and markedly suppressed tumor growth and metastasis of breast cancer xenografts. To the best of our knowledge, this is the first report which shows that carnosol specifically targets signal transducer and activator of transcription 3 (STAT3) for proteasome degradation in breast cancer. Our study further provide evidence that carnosol may represent a promising therapeutic candidate that can modulate breast cancer growth and metastasis.