Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications
Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/4/616 |
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| author | Nuria Vilaboa Juan Antonio Lopez Marco de Mesa Clara Escudero-Duch Natalie Winfield Melanie Bayford Richard Voellmy |
| author_facet | Nuria Vilaboa Juan Antonio Lopez Marco de Mesa Clara Escudero-Duch Natalie Winfield Melanie Bayford Richard Voellmy |
| author_sort | Nuria Vilaboa |
| collection | DOAJ |
| description | Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested. |
| first_indexed | 2024-03-11T04:38:47Z |
| format | Article |
| id | doaj.art-eac5edeb43a34020b0c80b3e4e682788 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T04:38:47Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-eac5edeb43a34020b0c80b3e4e6827882023-11-17T20:51:27ZengMDPI AGPharmaceuticals1424-82472023-04-0116461610.3390/ph16040616Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic ImplicationsNuria Vilaboa0Juan Antonio Lopez1Marco de Mesa2Clara Escudero-Duch3Natalie Winfield4Melanie Bayford5Richard Voellmy6Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares, CNIC, 28029 Madrid, SpainHospital Universitario La Paz-IdiPAZ, 28046 Madrid, SpainHospital Universitario La Paz-IdiPAZ, 28046 Madrid, SpainDomainex Ltd., Chesterford Research Park, Little Chesterford, Essex, Saffron Walden CB10 1XL, UKDomainex Ltd., Chesterford Research Park, Little Chesterford, Essex, Saffron Walden CB10 1XL, UKHSF Pharmaceuticals SA, 1814 La Tour-de-Peilz, SwitzerlandExposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested.https://www.mdpi.com/1424-8247/16/4/616proteostasis inhibitionproteostasis disruptionprotein unfoldingprotein aggregationIHSFcelastrol |
| spellingShingle | Nuria Vilaboa Juan Antonio Lopez Marco de Mesa Clara Escudero-Duch Natalie Winfield Melanie Bayford Richard Voellmy Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications Pharmaceuticals proteostasis inhibition proteostasis disruption protein unfolding protein aggregation IHSF celastrol |
| title | Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications |
| title_full | Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications |
| title_fullStr | Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications |
| title_full_unstemmed | Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications |
| title_short | Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications |
| title_sort | disruption of proteostasis by natural products and synthetic compounds that induce pervasive unfolding of proteins therapeutic implications |
| topic | proteostasis inhibition proteostasis disruption protein unfolding protein aggregation IHSF celastrol |
| url | https://www.mdpi.com/1424-8247/16/4/616 |
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