| 论文题目: | Targeting Ubiquitin Conjugating Enzyme UbcH5b by a Triterpenoid PC3-15 from Schisandra Plants Sensitizes Triple-negative Breast Cancer Cells to Lapatinib |
| 作者: | Huang, Maobo; Zhou, Yuanfei; Duan, Dongzhu; Yang, Chuanyu; Zhou, Zhongmei; Li, Fubing; Kong, Yanjie; Hsieh, Yi-Ching; Zhang, Ruihan; Ding, Wenping; Xiao, Weilie; Puno, PemaTenzin; Chen, Ceshi |
| 联系作者: | chenc@mail.kiz.ac.cn |
| 发表年度: | 2021 |
| DOI: | 10.1016/j.canlet.2021.02.009 |
| 摘要: | Increasing evidence suggested that a number of ubiquitin enzymes, including ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, E3 ubiquitin ligases and deubiquitination enzymes contribute to therapeutic resistance in triple-negative breast cancer (TNBC) cells. Inhibition of these enzymes with small molecule inhibitors may restore therapeutic sensitivity. Here, we demonstrated ubiquitin conjugating enzyme UbcH5b strongly supports HECTD3 auto-ubiquitination in vitro. Based on this, we developed a Fluorescence Resonance Energy Transfer (FRET) assay and identified three Schisandraceae triterpenoids, including PC3-15, to block HECTD3/UbcH5b auto-ubiquitination. Furthermore, we revealed that PC3-15 directly binds to UbcH5b and also inhibits UbcH5b-mediated p62 ubiquitination. We found that the UbcH5b-p62 axis confers TNBC cells resistance to lapatinib by promoting autophagy. Consistently, PC3-15 inhibits lapatinib-induced autophagy and increases lapatinib sensitivity in TNBC in vitro and in mouse xenografts. These findings suggest that the UbcH5b-p62 axis provides potential therapeutic targets and that Schisandraceae triterpenoids may be used for TNBC treatment in combination with lapatinib |
| 刊物名称: | Cancer Letters |
| 论文出处: | https://www.sciencedirect.com/science/article/pii/S0304383521000744?via%3Dihub |
| 影响因子: | 7.360(2019年） |
