PMID- 10667586
OWN - NLM
STAT- MEDLINE
DCOM- 20000228
LR  - 20121115
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 60
IP  - 2
DP  - 2000 Jan 15
TI  - The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter 
      factor-met-urokinase plasminogen activator-plasmin proteolytic network.
PG  - 342-9
AB  - The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter 
      factor (HGF/SF), have been implicated in human tumor development and metastasis. 
      HGF/SF induces the expression of urokinase plasminogen activator (uPA) and the 
      uPA receptor (uPAR), important mediators of cell invasion and metastasis. We have 
      developed a cell-based assay to screen for inhibitors of this signaling system 
      using the induction of endogenous uPA and uPAR and the subsequent conversion of 
      plasminogen to plasmin as the biological end point. Assay validation was 
      established using a neutralizing antiserum to HGF/SF and a uPA inhibitor (B428), 
      as well as inhibitors of the MKK-MAPK1/2 pathway, shown previously to be 
      important in the induction of uPA and uPAR. Using this assay, we found several 
      classes of molecules that exhibited inhibition of HGF/SF-dependent plasmin 
      activation. However, we discovered that certain members of the geldanamycin 
      family of anisamycin antibiotics are potent inhibitors of HGF/SF-mediated plasmin 
      activation, displaying inhibitory properties at femtomolar concentrations and 
      nine orders of magnitude below their growth inhibitory concentrations. At 
      nanomolar concentrations, the geldanamycins down-regulate Met protein expression, 
      inhibit HGF/SF-mediated cell motility and invasion, and also revert the phenotype 
      of both autocrine HGF/SF-Met transformed cells as well as those transformed by 
      Met proteins with activating mutations. Thus, the geldanamycins may have 
      important therapeutic potential for the treatment of cancers in which Met 
      activity contributes to the invasive/metastatic phenotype.
FAU - Webb, C P
AU  - Webb CP
AD  - Advanced Bioscience Laboratories-Basic Research Program, National Cancer 
      Institute-Frederick Cancer Research Developmental Center, Frederick, Maryland 
      21702, USA. craig.webb@vai.org
FAU - Hose, C D
AU  - Hose CD
FAU - Koochekpour, S
AU  - Koochekpour S
FAU - Jeffers, M
AU  - Jeffers M
FAU - Oskarsson, M
AU  - Oskarsson M
FAU - Sausville, E
AU  - Sausville E
FAU - Monks, A
AU  - Monks A
FAU - Vande Woude, G F
AU  - Vande Woude GF
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Benzoquinones)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (PLAUR protein, human)
RN  - 0 (Plaur protein, mouse)
RN  - 0 (Quinones)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Urokinase Plasminogen Activator)
RN  - 0 (Recombinant Proteins)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 3.4.21.7 (Fibrinolysin)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
RN  - Z3K3VJ16KU (geldanamycin)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - Antibiotics, Antineoplastic/*toxicity
MH  - Benzoquinones
MH  - Cell Division/drug effects
MH  - Cell Line
MH  - Cell Line, Transformed
MH  - Fibrinolysin/*metabolism
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Lactams, Macrocyclic
MH  - Mice
MH  - Proto-Oncogene Proteins c-met/*physiology
MH  - Quinones/*toxicity
MH  - Receptors, Cell Surface/*metabolism
MH  - Receptors, Urokinase Plasminogen Activator
MH  - Recombinant Proteins/metabolism
MH  - Signal Transduction
MH  - Structure-Activity Relationship
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Urokinase-Type Plasminogen Activator/*metabolism
EDAT- 2000/02/10 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/02/10 09:00
PHST- 2000/02/10 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/02/10 09:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2000 Jan 15;60(2):342-9.