Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression
Abstract
:1. Introduction
2. Results
2.1. Identification of Putative Selective Hakai Inhibitors
2.2. Effect of Hakin-1 on Hakai-Induced Ubiquitination
2.3. Hakin-1 Activates Epithelial Cell Differentiation in Tumour Cells
2.4. Hakin-1 Inhibits Proliferation, Oncogenic Potential and Invasiveness of Epithelial Tumour Cells
2.5. Antitumour Effect of Hakin-1 in Tumour Xenografts In Vivo
2.6. Hakin-1 Treatment Reduces N-Cadherin Mesenchymal Marker in Tumour Xenografts and Initiation of Lung Metastases
3. Discussion
4. Materials and Methods
4.1. Protein and Ligands Models
4.2. Virtual Screening
4.3. Binding Pocket Analysis
4.4. Plasmids, Inhibitors and Antibodies
4.5. Cell Culture
4.6. Ubiquitination Assays
4.7. Immunoprecipitation
4.8. Viability Assays
4.9. Western Blotting and Immunofluorescence
4.10. Real-Time Quantitative PCR (qRT-PCR)
4.11. Proliferation Assays
4.12. Soft Agar-Colony Formation Assay
4.13. Migration and Invasion Assay
4.14. Tumour Xenograft Model
4.15. Histology and Immunohistochemistry
4.16. Quantification of Lung Metastasis from In Vivo Mouse Model
4.17. Statistical Analysis
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Martinez-Iglesias, O.; Casas-Pais, A.; Castosa, R.; Díaz-Díaz, A.; Roca-Lema, D.; Concha, Á.; Cortés, Á.; Gago, F.; Figueroa, A. Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression. Cancers 2020, 12, 1340. https://doi.org/10.3390/cancers12051340
Martinez-Iglesias O, Casas-Pais A, Castosa R, Díaz-Díaz A, Roca-Lema D, Concha Á, Cortés Á, Gago F, Figueroa A. Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression. Cancers. 2020; 12(5):1340. https://doi.org/10.3390/cancers12051340
Chicago/Turabian StyleMartinez-Iglesias, Olaia, Alba Casas-Pais, Raquel Castosa, Andrea Díaz-Díaz, Daniel Roca-Lema, Ángel Concha, Álvaro Cortés, Federico Gago, and Angélica Figueroa. 2020. "Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression" Cancers 12, no. 5: 1340. https://doi.org/10.3390/cancers12051340