PMID- 15782129
OWN - NLM
STAT- MEDLINE
DCOM- 20050609
LR  - 20121115
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 24
IP  - 23
DP  - 2005 May 26
TI  - Geldanamycins exquisitely inhibit HGF/SF-mediated tumor cell invasion.
PG  - 3697-707
AB  - 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.
FAU - Xie, Qian
AU  - Xie Q
AD  - Laboratory of Molecular Oncology, Van Andel Research Institute, 333 Bostwick NE, 
      Grand Rapids, MI 49503, USA.
FAU - Gao, Chong-Feng
AU  - Gao CF
FAU - Shinomiya, Nariyoshi
AU  - Shinomiya N
FAU - Sausville, Edward
AU  - Sausville E
FAU - Hay, Rick
AU  - Hay R
FAU - Gustafson, Margaret
AU  - Gustafson M
FAU - Shen, Yuehai
AU  - Shen Y
FAU - Wenkert, David
AU  - Wenkert D
FAU - Vande Woude, George F
AU  - Vande Woude GF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Benzoquinones)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Quinones)
RN  - 0 (Receptors, Growth Factor)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 73341-73-8 (macbecin II)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
RN  - Z3K3VJ16KU (geldanamycin)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Benzoquinones
MH  - Cell Line
MH  - Dogs
MH  - HSP90 Heat-Shock Proteins/metabolism
MH  - Hepatocyte Growth Factor/*antagonists & inhibitors
MH  - Humans
MH  - Lactams, Macrocyclic
MH  - Neoplasm Invasiveness
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-met
MH  - Quinones/*pharmacology
MH  - Receptors, Growth Factor/metabolism
MH  - Urokinase-Type Plasminogen Activator/*antagonists & inhibitors
EDAT- 2005/03/23 09:00
MHDA- 2005/06/10 09:00
CRDT- 2005/03/23 09:00
PHST- 2005/03/23 09:00 [pubmed]
PHST- 2005/06/10 09:00 [medline]
PHST- 2005/03/23 09:00 [entrez]
AID - 1208499 [pii]
AID - 10.1038/sj.onc.1208499 [doi]
PST - ppublish
SO  - Oncogene. 2005 May 26;24(23):3697-707. doi: 10.1038/sj.onc.1208499.