Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression
Open accessAbstract
Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival and Akt-mediated glycolysis and triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent antitumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression.
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In human lung and prostate cancer xenografts, the SKP2 inhibitor SKP2 Inhibitor#25 inhibits tumour growth.
“| SKP2 inhibitor | xenografts | | | SKP2 Inhibitor#25 | Tumour growth inhibition | 159 |”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [159]
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- Authors
- Chan, C.-H., Morrow, J. K., Li, C.-F., Gao, Y., Jin, G., Moten, A., Stagg, L. J., Ladbury, J. E., Cai, Z., Xu, D., Logothetis, C. J., Hung, M.-C., Zhang, S., & Lin, H.-K.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- National Health Research Institutes (TW)
- Corresponding author
- Zhang, Shuxing
- Lin, Hui-Kuan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 154
- Issue
- 3
- Pages
- 556-568
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3845452
- OpenAlex
- W2049706724
- Cited by
- 391
- References
- 43
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 22 · 2023: 29 · 2022: 30 · 2021: 37 · 2020: 41 · 2019: 17 · 2018: 21 · 2017: 28 · 2016: 35 · 2015: 37 · 2014: 46 · 2013: 12
- FWCI
- 19.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
- Funders
- National Cancer Institute (CA 016672, P50CA140388, R01CA136787, P30CA016672, R01CA149321)
- National Institute of General Medical Sciences (P41GM079588)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Skp2, E3 ubiquitin ligase, SCF ubiquitin ligase, cancer stem cells, cellular senescence, self-renewal, anticancer activity, chemosensitization, tumor progression, in silico drug screening
- MeSH terms
- Animals, Antineoplastic Agents, Disease Models, Animal, Drug Screening Assays, Antitumor, Glycolysis, Humans, Mice, Nude, Models, Molecular, Multienzyme Complexes, Neoplasm Transplantation, Neoplasms, Structure-Activity Relationship, Transplantation, Heterologous, Neoplastic Stem Cells, Genes, p53, Ubiquitin-Protein Ligases, S-Phase Kinase-Associated Proteins, Mice, Small Molecule Libraries, Drug Discovery
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