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Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion

Oncogene volume 24, pages 3697–3707 (2005)Cite this article

Abstract

Induction of the urokinase-type plasminogen activator (uPA) by hepatocyte growth factor/scatter factor (HGF/SF) plays an important role in tumor cell invasion and metastasis that is mediated through the Met receptor tyrosine kinase. Geldanamycins (GA) are antitumor drugs that bind and inhibit HSP90 chaperone activity at nanomolar concentrations (nM-GAi) by preventing proper folding and functioning of certain oncoproteins. Previously, we have shown that a subset of GA derivatives exhibit exquisite potency, inhibiting HGF/SF-induced uPA-plasmin activation at femtomolar concentrations (fM-GAi) in canine MDCK cells. Here, we report that (1) inhibition of HGF/SF-induced uPA activity by fM-GAi is not uncommon, in that several human tumor glioblastoma cell lines (DBTRG, U373 and SNB19), as well as SK-LMS-1 human leiomyosarcoma cells are also sensitive to fM-GAi; (2) fM-GAi drugs only display inhibitory activity against HGF/SF-induced uPA activity (rather than basal activity) and only when the observed magnitude of uPA activity induction by HGF/SF is at least 1.5 times basal uPA activity; and (3) not only do fM-GAi derivatives strongly inhibit uPA activity but they also block MDCK cell scattering and in vitro invasion of human glioblastoma cells at similarly low drug concentrations. These effects of fM-GAi drugs on the Met-activated signaling pathway occur at concentrations well below those required to measurably affect Met expression or cell proliferation. We also examined the effect of Radicicol (RA), a drug with higher affinity than GA for HSP90. RA displays uPA activity inhibition at nanomolar levels, but not at lower concentrations, indicating that HSP90 is not likely the fM-GAi molecular target. Thus, we show that certain GA drugs (fM-GAi) in an HGF/SF-dependent manner block uPA-plasmin activation in tumor cells at femtomolar levels. This inhibition can also be observed in scattering and in vitro invasion assays. Our findings also provide strong circumstantial evidence for a novel non-HSP90 molecular target that is involved in HGF/SF-mediated tumor cell invasion.

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Abbreviations

GA:

geldanamycin

17-ADG:

17-amino-17-demethoxygeldanamycin

17-AAG:

17-allylamino-17-demethoxygeldanamycin

MA:

Macbecin II

RA:

Radicicol

fM-GAi:

GA and derivatives with uPA inhibitory activity in the femtomolar range

nM-GAi:

GA and derivatives with uPA inhibitory activity in the nanomolar range

HGF/SF:

hepatocyte growth factor/scatter factor

uPA:

urokinase-type plasminogen activator

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Acknowledgements

This study was supported by funding from the Robert J Lynch/American Brain Tumor Association Grant (to QX), a grant from the Michigan Life Sciences Corridor (GVW) and by the generosity of the Jay and Betty Van Andel Foundation. We appreciate Dr. Justi Rao providing us with U87 and SNB19 GBM cell lines. We are very grateful to Kyle Furge for helpful discussions and to Michelle Reed for assistance with the paper.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, MI, 49503, USA

    Qian Xie, Chong-Feng Gao, Nariyoshi Shinomiya, Rick Hay, Margaret Gustafson & George F Vande Woude

  2. Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD, USA

    Edward Sausville

  3. Department of Physiology, Biomedical Physical Sciences Building, Michigan State University, East Lansing, MI, USA

    Yuehai Shen & David Wenkert

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  1. Qian Xie
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Xie, Q., Gao, CF., Shinomiya, N. et al. Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion. Oncogene 24, 3697–3707 (2005). https://doi.org/10.1038/sj.onc.1208499

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