期刊
CANCER LETTERS
卷 504, 期 -, 页码 125-136出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.02.009
关键词
HECTD3; UbcH5b; Ubiquitination; Autophagy; Schisandraceae triterpenoid
类别
资金
- National Key Research and Development Program of China [2020YFA0112300, 2018YFC2000400]
- National Natural Science Foundation of China [82073316, 81830087, 31771516, 81672639, 81903541]
- project of Innovative Research Team of Yunnan Province [2019HC005]
- Yunnan Applicative and Basic Research Program [2018FY001]
- China Postdoctoral Science Foundation [2019M662869]
The study reveals the important role of ubiquitin enzymes in therapeutic resistance in TNBC cells, suggesting that small molecule inhibitors can restore sensitivity to treatment. Specifically, PC3-15 was found to block auto-ubiquitination of HECTD3/UbcH5b and inhibit UbcH5b-mediated p62 ubiquitination, leading to increased sensitivity to lapatinib in TNBC.
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.
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