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土木香内酯通过抑制三阴性乳腺癌细胞系和小鼠模型中的 TrxR1 促进 ER 应激介导的细胞凋亡。

Alantolactone promotes ER stress-mediated apoptosis by inhibition of TrxR1 in triple-negative breast cancer cell lines and in a mouse model.

机构信息

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

出版信息

J Cell Mol Med. 2019 Mar;23(3):2194-2206. doi: 10.1111/jcmm.14139. Epub 2019 Jan 4.

DOI:10.1111/jcmm.14139
PMID:30609207
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6378194/
Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome and currently no effective targeted therapies are available. Alantolactone (ATL), a sesquiterpene lactone, has been shown to have potential anti-tumour activity against various cancer cells. However, the underlying mechanism and therapeutic effect of ATL in the TNBC are largely unknown. In the present study, we found that ATL suppresses TNBC cell viability by reactive oxygen species (ROS) accumulation and subsequent ROS-dependent endoplasmic reticulum (ER) stress both in vitro and in vivo. Thioredoxin reductase 1 (TrxR1) expression and activity of were significantly up-regulated in the TNBC tissue specimens compare to the normal adjacent tissues. Further analyses showed that ATL inhibits the activity of TrxR1 both in vitro and in vivo in TNBC and knockdown of TrxR1 in TNBC cells sensitized ATL-induced cell apoptosis and ROS increase. These results will provide pre-clinical evidences that ATL could be a potential therapeutic agent against TNBC by promoting ROS-ER stress-mediated apoptosis through partly targeting TrxR1.

摘要

三阴性乳腺癌（TNBC）是一种临床预后较差的乳腺癌亚型，目前尚无有效的靶向治疗方法。土木香内酯（ATL），一种倍半萜内酯，已被证明对各种癌细胞具有潜在的抗肿瘤活性。然而，ATL 在 TNBC 中的作用机制和治疗效果在很大程度上尚不清楚。在本研究中，我们发现 ATL 通过在体外和体内积累活性氧（ROS）并随后引发 ROS 依赖性内质网（ER）应激来抑制 TNBC 细胞活力。与正常相邻组织相比，TNBC 组织标本中硫氧还蛋白还原酶 1（TrxR1）的表达和活性显著上调。进一步分析表明，ATL 在体外和体内均抑制 TNBC 中的 TrxR1 活性，并且在 TNBC 细胞中敲低 TrxR1 可使 ATL 诱导的细胞凋亡和 ROS 增加敏感化。这些结果将提供临床前证据，表明 ATL 可能通过部分靶向 TrxR1 促进 ROS-ER 应激介导的凋亡而成为治疗 TNBC 的潜在治疗剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f4a2/6378194/c4303d2eeed9/JCMM-23-2194-g007.jpg
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