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Characterization of the Effects of Migrastatic Inhibitors on 3D Tumor Spheroid Invasion by High-resolution Confocal Microscopy
Published on: September 16, 2019
Hsp90 C-terminal inhibitors exhibit antimigratory activity by disrupting the Hsp90α/Aha1 complex in PC3-MM2 cells
Suman Ghosh1, Heather E Shinogle, Gaurav Garg
1Department of Medicinal Chemistry, ‡Microscopy and Analytical Imaging Laboratory, ∥Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
Abstract:
Human Hsp90 isoforms are molecular chaperones that are often up-regulated in malignances and represent a primary target for Hsp90 inhibitors undergoing clinical evaluation. Hsp90α is a stress-inducible isoform of Hsp90 that plays a significant role in apoptosis and metastasis. Though Hsp90α is secreted into the extracellular space under metastatic conditions, its role in cancer biology is poorly understood. We report that Hsp90α associates with the Aha1 co-chaperone and found this complex to localize in secretory vesicles and at the leading edge of migrating cells. Knockdown of Hsp90α resulted in a defect in cell migration. The functional role of Hsp90α/Aha1 was studied by treating the cells with various novobiocin-based Hsp90 C-terminal inhibitors. These inhibitors disrupted the Hsp90α/Aha1 complex, caused a cytoplasmic redistribution of Hsp90α and Aha1, and decreased cell migration. Structure-function studies determined that disruption of Hsp90α/Aha1 association and inhibition of cell migration correlated with the presence of a benzamide side chain, since an acetamide substituted analog was less effective. Our results show that disruption of Hsp90α/Aha1 interactions with novobiocin-based Hsp90 C-terminal inhibitors may limit the metastatic potential of tumors.
Insights
Heat shock protein 90 alpha (Hsp90α) and its co-chaperone Aha1 are crucial for cancer cell migration. Inhibiting their interaction with novobiocin-based drugs may reduce tumor metastasis.
Area of Science:
- Molecular biology
- Cancer research
- Biochemistry
Background:
- Heat shock protein 90 (Hsp90) is a molecular chaperone often upregulated in cancers.
- Hsp90α, a stress-inducible isoform, is secreted during metastasis, but its role is unclear.
- Hsp90 inhibitors are in clinical trials for cancer treatment.
Purpose of the Study:
- To investigate the role of extracellular Hsp90α in cancer biology.
- To explore the interaction between Hsp90α and its co-chaperone Aha1.
- To evaluate the effect of Hsp90 inhibitors on Hsp90α/Aha1 complex and cell migration.
Main Methods:
- Studied Hsp90α/Aha1 complex localization in secretory vesicles and leading edge of migrating cells.
- Utilized Hsp90α knockdown to assess its role in cell migration.
- Treated cells with novobiocin-based Hsp90 C-terminal inhibitors to disrupt the Hsp90α/Aha1 complex.
Main Results:
- Hsp90α associates with Aha1, localizing to secretory vesicles and the leading edge of migrating cells.
- Hsp90α knockdown impaired cell migration.
- Novobiocin-based inhibitors disrupted the Hsp90α/Aha1 complex, altered protein localization, and reduced cell migration.
- Inhibitor efficacy correlated with a benzamide side chain, suggesting specific structural requirements for disrupting the complex.
Conclusions:
- The Hsp90α/Aha1 complex plays a significant role in cancer cell migration.
- Disrupting Hsp90α/Aha1 interactions with specific inhibitors may represent a therapeutic strategy to limit tumor metastasis.
- Novobiocin-based inhibitors targeting the Hsp90α/Aha1 complex show potential for reducing metastatic activity.
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