Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, 59 Hudong Road, Ma'anshan, 243002, Anhui, People's Republic of China.
Med Oncol. 2022 Sep 7;39(12):189. doi: 10.1007/s12032-022-01792-y.
The molecular mechanism of anti-metastatic effect of celastrol is not fully understood in breast cancer cells. Herein, we investigated the activity and molecular mechanism of celastrol in triple-negative breast cancer (TNBC) cells, which is a more aggressive subtype of breast cancer. The results of wound healing assay and trans-well assay revealed that celastrol inhibited cell migration and invasion under sub-cytotoxic concentrations in MDA-MB-231 and MDA-MB-468 TNBC cells. Molecular data showed that the effect of celastrol on TNBC cells might be mediated via up-regulation of E-cadherin, a key protein involved in epithelial-mesenchymal transition (EMT). In addition, Hakai, an E3 ligase responsible for E-cadherin complex ubiquitination and degradation, was down-regulated under celastrol treatment. Hakai partially contributed to celastrol-induced anti-invasive effect. In addition, celastrol and docetaxel could synergistically inhibit growth and metastasis of MDA-MB-231 cells. Our results showing anti-migratory/anti-invasive effects of celastrol and associated mechanisms provide new evidence for the development of celastrol as a potential anti-metastatic compound against highly aggressive breast cancer, and celastrol in combination with docetaxel might potentially be used as a novel regimen for the treatment of TNBC.
在乳腺癌细胞中，雷公藤红素抗转移作用的分子机制尚未完全阐明。在此，我们研究了雷公藤红素在三阴性乳腺癌（TNBC）细胞中的活性和分子机制，这是乳腺癌更具侵袭性的亚型。划痕愈合试验和 Trans-well 试验的结果表明，雷公藤红素在亚细胞毒性浓度下抑制 MDA-MB-231 和 MDA-MB-468 TNBC 细胞的迁移和侵袭。分子数据表明，雷公藤红素对 TNBC 细胞的作用可能是通过上调 E-钙黏蛋白介导的，E-钙黏蛋白是参与上皮-间充质转化（EMT）的关键蛋白。此外，Hakai 是一种负责 E-钙黏蛋白复合物泛素化和降解的 E3 连接酶，在雷公藤红素处理下表达下调。Hakai 部分促成了雷公藤红素诱导的抗侵袭作用。此外，雷公藤红素和多西紫杉醇可以协同抑制 MDA-MB-231 细胞的生长和转移。我们的研究结果显示了雷公藤红素的抗迁移/抗侵袭作用及其相关机制，为将雷公藤红素开发为一种针对高度侵袭性乳腺癌的潜在抗转移化合物提供了新的证据，并且雷公藤红素联合多西紫杉醇可能有望成为治疗 TNBC 的新方案。
