A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion

Abstract

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.

Heat shock protein 90 (HSP90) contributes to cytosolic translocation of extracellular antigen for cross-presentation by dendritic cells

“…Another inhibitor, geldanamycin (GA), when conjugated with FITC (GA-FITC) is cell-membrane impermeable, binding only cell surface HSP90 (Fig. 1B, Left) and inhibiting its functions but having no effect on cytosolic HSP90 (21,22). We found that GA but not GA-FITC blocked cross-presentation (Fig.…”

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

“…Inhibition of Hop may have affected MMP-2 expression and activity through altering the activity of extracellular Hsp90. A study by Tsutsumi et al [22] using the non cell-permeable Hsp90 inhibitor, DMAG-N-oxide, reduced in vitro tumour cell invasion and migration and decreased melanoma lung metastasis in vivo. The monoclonal antibody (mAb) directed against Hsp90, mAb 4C5, inhibited melanoma cell invasion and significantly reduced metastasis in vivo by binding to surface Hsp90 as it is not internalised, further indicating an extracellular role for Hsp90 [23].…”

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

“…42 DMGA-N-oxide, a novel cell-impermeable Hsp90 inhibitor, was reported to show a dramatic impact on the metastatic phenotype of the lung colonization of melanoma cells and be related to the hepatotoxic property of benzoquinone ansamycins. 43 The O-carbamoylmethyloxime derivative of radicicol, KF25706, inhibits v-Src-and k-Ras-activated signaling. 44,45 Macbecin 46 and its non-quinone compound that target Hsp90 have been reported, 47 indicating that the quinone moiety of macbecin is not a prerequisite for Hsp90 inhibition.…”