Parthenolide inhibits ubiquitin-specific peptidase 7 (USP7), Wnt signaling, and colorectal cancer cell growth
Li, Xue1,2; Kong, Lingmei1,3; Yang, Qihong1,2; Duan, Aizhu1,2; Ju, Xiaoman1,2; Cai, Bicheng1; Chen, Lin1,2; An, Tao1,3; Li, Yan1,3
Corresponding AuthorAn, Tao(antao@mail.kib.ac.cn) ; Li, Yan(liyanb@mail.kib.ac.cn)
2020-03-13
Source PublicationJOURNAL OF BIOLOGICAL CHEMISTRY
ISSN0021-9258
Volume295Issue:11Pages:3576-3589
AbstractIt has been well-established that the deubiquitinating enzyme ubiquitin-specific peptidase 7 (USP7) supports cancer growth by up-regulating multiple cellular pathways, including Wnt/?-catenin signaling. Therefore, considerable efforts are directed at identifying and developing USP7 inhibitors. Here, we report that sesquiterpene lactone parthenolide (PTL) inhibits USP7 activity, assessed with deubiquitinating enzyme activity assays, including fluorogenic Ub-AMC/Ub-Rho110, Ub-VME/PA labeling, and Di-Ub hydrolysis assays. Further investigations using cellular thermal shift (CETSA), surface plasmon resonance (SPR), and mass spectrum (MS) assays revealed that PTL directly interacts with USP7. Consistent with the role of USP7 in stimulating Wnt signaling and carcinogenesis, PTL treatment inhibited the activity of Wnt signaling partly by destabilizing ?-catenin. Moreover, using cell viability assays, we found that PTL suppresses the proliferation of colorectal cancer cells and induces apoptosis in these cells. Additionally, we examined the effects of two other sesquiterpene lactones (costunolide and ?-santonin) on USP7 and Wnt signaling and found that ?-methylene-?-butyrolactone may provide a scaffold for future USP7 inhibitors. In summary, our findings reveal that PTL inhibits USP7 activity, identifying a potential mechanism by which PTL suppresses Wnt/?-catenin signaling. We further suggest that sesquiterpene lactones might represent a suitable scaffold for developing USP7 inhibitors and indicate that PTL holds promise as an anticancer agent targeting aberrant USP7/Wnt signaling.
Keywordsmall molecule deubiquitylation (deubiquitination) Wnt signaling pharmacology enzyme inhibitor ?-catenin parthenolide ubiquitination USP7 Wnt signaling ubiquitin-specific peptidase 7 colorectal cancer proteasome system protein homeostasis deubiquitinating activity
DOI10.1074/jbc.RA119.011396
Indexed BySCI ; SCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000527725300017
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/71623
Collection植物化学与西部植物资源持续利用国家重点实验室
Corresponding AuthorAn, Tao; Li, Yan
Affiliation1.Chinese Acad Sci, State Key Lab Phytochem & Plant Resources West Ch, Kunming Inst Bot, Kunming 650201, Yunnan, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Yunnan Key Lab Nat Med Chem, Kunming Inst Bot, Kunming 650201, Yunnan, Peoples R China
Recommended Citation
GB/T 7714
Li, Xue,Kong, Lingmei,Yang, Qihong,et al. Parthenolide inhibits ubiquitin-specific peptidase 7 (USP7), Wnt signaling, and colorectal cancer cell growth[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2020,295(11):3576-3589.
APA Li, Xue.,Kong, Lingmei.,Yang, Qihong.,Duan, Aizhu.,Ju, Xiaoman.,...&Li, Yan.(2020).Parthenolide inhibits ubiquitin-specific peptidase 7 (USP7), Wnt signaling, and colorectal cancer cell growth.JOURNAL OF BIOLOGICAL CHEMISTRY,295(11),3576-3589.
MLA Li, Xue,et al."Parthenolide inhibits ubiquitin-specific peptidase 7 (USP7), Wnt signaling, and colorectal cancer cell growth".JOURNAL OF BIOLOGICAL CHEMISTRY 295.11(2020):3576-3589.
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