Elaiophylin is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity
| Autor: | Tiina A. Salminen, Farid Ahmad Siddiqui, Vladimir R. Vukić, Daniel Abankwa |
|---|---|
| Přispěvatelé: | Academy of Finland (#304638) and the Jane and Aatos Erkko Foundation, Finland [sponsor] |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Chaperonins
Cell Cycle Proteins Hsp90 Nanoconjugates Biochemistry biophysics & molecular biology [F05] [Life sciences] Biochemistry Microbiology Chorioallantoic Membrane Article Proto-Oncogene Proteins p21(ras) 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cancer stem cell Animals Humans cancer biochemistry HSP90 Heat-Shock Proteins Biochimie biophysique & biologie moléculaire [F05] [Sciences du vivant] Molecular Biology IC50 Transcription factor 030304 developmental biology 0303 health sciences Natural product biology drug development QR1-502 Cdc37 nanoclustering Chorioallantoic membrane HEK293 Cells chemistry CDC37 030220 oncology & carcinogenesis biology.protein Biophysics Macrolides Selectivity Chickens K-Ras |
| Zdroj: | Biomolecules Volume 11 Issue 6 Biomolecules, Vol 11, Iss 836, p 836 (2021) |
| Popis: | The natural product elaiophylin is a macrodiolide with a broad range of biological activities. However, no direct target of elaiophylin in eukaryotes has been described so far, which hinders a systematic explanation of its astonishing activity range. We recently showed that the related conglobatin A, a protein–protein interface inhibitor of the interaction between the N-terminus of Hsp90 and its cochaperone Cdc37, blocks cancer stem cell properties by selectively inhibiting K-Ras4B but not H-Ras. Here, we elaborated that elaiophylin likewise disrupts the Hsp90/ Cdc37 interaction, without affecting the ATP-pocket of Hsp90. Similarly to conglobatin A, elaiophylin decreased expression levels of the Hsp90 client HIF1α, a transcription factor with various downstream targets, including galectin-3. Galectin-3 is a nanocluster scaffold of K-Ras, which explains the K-Ras selectivity of Hsp90 inhibitors. In agreement with this K-Ras targeting and the potent effect on other Hsp90 clients, we observed with elaiophylin treatment a submicromolar IC50 for MDA-MB-231 and MIA-PaCa-2 3D spheroid formation. Finally, a strong inhibition of MDA-MB-231 cells grown in the chorioallantoic membrane (CAM) microtumor model was determined. These results suggest that several other macrodiolides may have the Hsp90/ Cdc37 interface as a target site. |
| Databáze: | OpenAIRE |
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