Targeting ubiquitin conjugating enzyme UbcH5b by a triterpenoid PC3-15 from Schisandra plants sensitizes triple-negative breast cancer cells to lapatinib

• Published in: Cancer letters 2021-04, Vol.504, p.125-136
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Amino acids; Antifungal agents; Autophagy; Binding sites; Breast cancer; Cancer therapies; Drug dosages; Enzymes; Fluorescence resonance energy transfer; HECTD3; Inhibitor drugs; Kinases; Phagocytosis; Schisandraceae; Schisandraceae triterpenoid; Targeted cancer therapy; Triterpenoids; UbcH5b; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.02.009

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. •The UbcH5b-p62 axis confers TNBC cells resistance to lapatinib by promoting autophagy.•PC3-15 directly binds to UbcH5b and inhibits UbcH5b mediated HECTD3 autoubiquitination.•PC3-15 inhibits lapatinib induced autophagy in TNBC cells.•PC3-15 partly restores lapatinib sensitivity in vitro and vivo.