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.
Keywords: Celastrol; Docetaxel; E-cadherin; Hakai; Triple-negative breast cancer.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.