Characterization of PMI-5011 on the Regulation of Deubiquitinating Enzyme Activity in Multiple Myeloma Cell Extracts
Autor: | Yongmei Yu, Adam T. Melvin, Z. Elizabeth Floyd, Ted J. Gauthier, Nora Safa, Dong Liu, Manibarathi Vaithiyanathan, Alireza Rahnama, Jacob H. Pettigrew |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0106 biological sciences
Environmental Engineering Cell Biomedical Engineering Bioengineering Protein degradation 01 natural sciences Article Deubiquitinating enzyme 03 medical and health sciences 010608 biotechnology medicine 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Enzyme medicine.anatomical_structure chemistry Proteasome Biochemistry Cell culture Cancer cell biology.protein Function (biology) Biotechnology |
Zdroj: | Biochem Eng J |
Popis: | Deubiquitinating enzyme (DUB)-targeted therapeutics have shown promise in recent years as alternative cancer therapeutics, especially when coupled with proteasome-based inhibitors. While a majority of DUB-based therapeutics function by inhibiting DUB enzymes, studies show that positive regulation of these enzymes can stabilize levels of protein degradation. Unfortunately, there are currently no clinically available therapeutics for this purpose. The goal of this work was to understand the effect of a botanical extract from Artemisia dracunculus L called PMI-5011 on DUB activity in cancer cells. Through a series of kinetic analyses and mathematical modeling, it was found that PMI-5011 positively regulated DUB activity in two model multiple myeloma cells line (OPM2 and MM.1S). This suggests that PMI-5011 interacts with the active domains of DUBs to enhance their activity directly or indirectly, without apparently affecting cellular viability. Similar kinetic profiles of DUB activity were observed with three bioactive compounds in PMI-5011 (DMC-1, DMC-2, davidigenin). Interestingly, a differential cell line-independent trend was observed at higher concentrations which suggested variances in inherent gene expressions of UCHL1, UCHL5, USP7, USP15, USP14, and Rpn11 in OPM2 and MM.1S cell lines. These findings highlight the therapeutic potential of PMI-5011 and its selected bioactive compounds in cancer. |
Databáze: | OpenAIRE |
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