Targeting ubiquitin conjugating enzyme UbcH5b by a triterpenoid PC3-15 from Schisandra plants sensitizes triple-negative breast cancer cells to lapatinib PMID: 33607208

ADC Targets in Oncology

2026-04-10

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

Cancer Lett. 2021 Apr 28;504:125-136. doi: 10.1016/j.canlet.2021.02.009.

Maobo Huang ¹ , Yuanfei Zhou ² , Dongzhu Duan ³ , Chuanyu Yang ⁴ , Zhongmei Zhou ⁴ , Fubing Li ⁵ , Yanjie Kong ⁶ , Yi-Ching Hsieh ⁷ , Ruihan Zhang ⁸ , Wenping Ding ⁹ , Weilie Xiao ⁸ , PemaTenzin Puno ¹⁰ , Ceshi Chen ¹¹

Affiliations

1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, Yunnan, China.
2. Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, Yunnan, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
3. Shaanxi Key Laboratory of Phytochemistry and College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, 721013, China.
4. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
5. Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.
6. Biobank, Shenzhen Second People's Hospital/ the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518035, China.
7. The Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave, Albany, NY, 12208, USA.
8. Key Laboratory of Medicinal Chemistry for Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of Education and Yunnan Province), State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Chemical Science and Technology, Yunnan University, 2 North Cuihu Road, Kunming, 650091, China.
9. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
10. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China. Electronic address: [email protected].
11. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China; KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China. Electronic address: [email protected].

Abstract

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.

Keywords

Autophagy; HECTD3; Schisandraceae triterpenoid; UbcH5b; Ubiquitination.