Downregulation of the Arg/N-degron Pathway Sensitizes Cancer Cells to Chemotherapy In Vivo
| Autor: | Daniel G. Anderson, Tatiana Prikazchikova, Timofei S. Zatsepin, Luke H. Rhym, Dominique Leboeuf, Konstantin I. Piatkov, Tatiana O. Abakumova |
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| Rok vydání: | 2019 |
| Předmět: |
Small interfering RNA
Carcinoma Hepatocellular Angiogenesis Cell Survival Ubiquitin-Protein Ligases Down-Regulation 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Ubiquitin Cell Movement Cell Line Tumor Drug Discovery Genetics medicine Animals RNA Small Interfering Molecular Biology 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences biology Cell growth Chemistry Liver Neoplasms Cancer Drug Synergism medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Apoptosis Doxorubicin 030220 oncology & carcinogenesis Cancer cell Liposomes Cancer research biology.protein Molecular Medicine Nanoparticles Calmodulin-Binding Proteins Original Article |
| Zdroj: | Mol Ther Elsevier |
| ISSN: | 1525-0024 |
| Popis: | The N-degron pathway is an emerging target for anti-tumor therapies, because of its capacity to positively regulate many hallmarks of cancer, including angiogenesis, cell proliferation, motility, and survival. Thus, inhibition of the N-degron pathway offers the potential to be a highly effective anti-cancer treatment. With the use of a small interfering RNA (siRNA)-mediated approach for selective downregulation of the four Arg/N-degron-dependent ubiquitin ligases, UBR1, UBR2, UBR4, and UBR5, we demonstrated decreased cell migration and proliferation and increased spontaneous apoptosis in cancer cells. Chronic treatment with lipid nanoparticles (LNPs) loaded with siRNA in mice efficiently downregulates the expression of UBR-ubiquitin ligases in the liver without any significant toxic effects but engages the immune system and causes inflammation. However, when used in a lower dose, in combination with a chemotherapeutic drug, downregulation of the Arg/N-degron pathway E3 ligases successfully reduced tumor load by decreasing proliferation and increasing apoptosis in a mouse model of hepatocellular carcinoma, while avoiding the inflammatory response. Our study demonstrates that UBR-ubiquitin ligases of the Arg/N-degron pathway are promising targets for the development of improved therapies for many cancer types. |
| Databáze: | OpenAIRE |
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