Abstract
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.
Highlights
Published: 4 June 2021The C2 -symmetric 16-member macrodiolide elaiophylin was isolated from Streptomyces melanosporus, an actinomycete strain, in 1959 as azalomycin [1]
We recently described the mechanism of how the Hsp90/ Cdc37 interface inhibitor conglobatin A selectively targets K-Ras nanoclustering [15]
Both elaiophylin and conglobatin A treatment reduced the amount of co-precipitated Cdc37 (Figure 1B)
Summary
The C2 -symmetric 16-member macrodiolide elaiophylin was isolated from Streptomyces melanosporus, an actinomycete strain, in 1959 as azalomycin [1]. Elaiophylins have an astonishingly broad spectrum of biological activities, including antibiotic, antiviral, antifungal, antiprotozoan, anthelmintic, immunosuppressive, and anticancer activities [1,4,5,6]. While their antibacterial activity might be attributed to their ionophoric activity, i.e., they are able to form cation-selective ion channels in membranes [7], their mechanism of action in eukaryotes is likely different and may include several targets. Treatment of SKOV3 cells was found to inhibit late stages of autophagy, to the established inhibitor chloroquine, blocking autophagic
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