A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion.
Heat shock protein 90 (Hsp90) is a molecular chaperone that maintains function of numerous intracellular signaling nodes utilized by cancer cells for proliferation and survival. Hsp90 is also detected on the plasma membrane of tumor cells and its expression has been suggested to correlate with metastatic potential. Given the abundance and diverse functions of the intracellular pool of this protein, the precise contribution of cell surface Hsp90 to cell motility and tumor metastasis remains to be determined. In this study we utilized the small molecule DMAG-N-oxide, a novel cell-impermeable Hsp90 inhibitor, to specifically examine the role of cell surface Hsp90 in cell motility. We observed that, while not affecting intracellular Hsp90 function, DMAG-N-oxide significantly retarded tumor cell migration and integrin/extracellular matrix-dependent cytoskeletal reorganization. Concomitant with these findings, targeting cell surface Hsp90 significantly inhibited tumor cell motility and invasion in vitro, and had a dramatic impact on melanoma cell lung colonization in vivo. These data indicate that cell surface Hsp90 plays an important role in modulating cancer cell migration that is independent of the function of the intracellular Hsp90 pool, and that small molecule inhibitors of surface Hsp90 may provide a new approach to targeting the metastatic phenotype.
Tsutsumi
S
S
Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1107, USA.
Scroggins
B
B
Koga
F
F
Lee
M-J
MJ
Trepel
J
J
Felts
S
S
Carreras
C
C
Neckers
L
L
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002465:Cell Movement / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control
D016227:Benzoquinones; C528386:DMAG-N-oxide; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic