Hsp90 C-terminal inhibitors exhibit antimigratory activity by disrupting the Hsp90α/Aha1 complex in PC3-MM2 cells.
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.
Department of Medicinal Chemistry, ‡Microscopy and Analytical Imaging Laboratory, ∥Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
Suman
S
Ghosh
Heather E
HE
Shinogle
Gaurav
G
Garg
George A
GA
Vielhauer
Jeffrey M
JM
Holzbeierlein
Rick T
RT
Dobrowsky
Brian S J
BS
Blagg
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009675:Novobiocin / Q000494:pharmacology*; D011485:Protein Binding; D017510:Protein Folding; D020033:Protein Isoforms
C515652:AHSA1 protein, human; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D018832:Molecular Chaperones; D020033:Protein Isoforms; D009675:Novobiocin