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

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

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].
PMID: 33607208 DOI: 10.1016/j.canlet.2021.02.009
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.

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