PMID- 17525527
OWN - NLM
STAT- MEDLINE
DCOM- 20070809
LR  - 20200930
IS  - 1551-4005 (Electronic)
IS  - 1551-4005 (Linking)
VI  - 6
IP  - 11
DP  - 2007 Jun 1
TI  - Low dose geldanamycin inhibits hepatocyte growth factor and hypoxia-stimulated 
      invasion of cancer cells.
PG  - 1393-402
AB  - Hepatocyte growth factor (HGF) receptor Met and hypoxia-inducible factor-1 
      (HIF-1) signaling pathways are commonly activated in aggressive tumors and 
      promote progression. Since both Met and HIF-1alpha proteins are heat shock 
      protein (Hsp) 90 clients, Hsp90 inhibitors might be expected to positively impact 
      tumor progression. Here, we systematically evaluated the inhibitory effects of 
      the prototypical Hsp90 inhibitor geldanamycin (GA) on cellular processes involved 
      in invasion and angiogenesis in T24 bladder cancer cells stimulated with HGF and 
      chemical hypoxia. First, we demonstrated the positive feedback loop between Met 
      and HIF-1 pathways, which serves to sustain and amplifies their signaling in T24 
      cells. GA downregulated Met by inhibiting new protein maturation, thereby 
      dampening HGF signaling. HGF and chemical hypoxia with CoCl2 cooperatively 
      promoted in vitro invasion and vascular endothelial growth factor (VEGF) 
      secretion, while CoCl2 but not HGF activated urokinase-type plasminogen activator 
      and matrix metalloproteinase 2, both of which promote invasion and angiogenesis. 
      Low dose GA (100 nmol/L) inhibited these processes by suppressing both HGF and 
      HIF-1 pathways. Notably, brief GA pretreatment inhibited in vitro invasion and 
      VEGF secretion induced by HGF as effectively as did continuous treatment. 
      Moreover, we found that GA inhibited activation of focal adhesion kinase, focal 
      adhesion assembly, and actin reorganization induced by HGF and integrin 
      engagement by extracellular matrix. Thus, GA widely suppresses extrinsic 
      stimuli-induced signaling that contribute to tumor invasion and angiogenesis in 
      this bladder carcinoma model, suggesting the utility of Hsp90 inhibitors in 
      preventing tumor progression and metastasis.
FAU - Koga, Fumitaka
AU  - Koga F
AD  - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 
      Bethesda, Maryland 20892-1107, USA.
FAU - Tsutsumi, Shinji
AU  - Tsutsumi S
FAU - Neckers, Leonard M
AU  - Neckers LM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070613
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Benzoquinones)
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (Fibronectins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Integrin beta3)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 3G0H8C9362 (Cobalt)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EVS87XF13W (cobaltous chloride)
RN  - Z3K3VJ16KU (geldanamycin)
SB  - IM
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Benzoquinones/*pharmacology
MH  - Breast Neoplasms/pathology
MH  - Carcinoma/pathology
MH  - Cell Hypoxia
MH  - Cell Line, Tumor/drug effects/physiology
MH  - Cobalt/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Extracellular Matrix Proteins/metabolism
MH  - Feedback, Physiological
MH  - Female
MH  - Fibronectins/metabolism
MH  - Focal Adhesions/drug effects/physiology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - HSP90 Heat-Shock Proteins/antagonists & inhibitors
MH  - Hepatocyte Growth Factor/*antagonists & inhibitors/pharmacology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/genetics/physiology
MH  - Integrin beta3/genetics/physiology
MH  - Lactams, Macrocyclic/*pharmacology
MH  - *Neoplasm Invasiveness
MH  - Neoplasm Proteins/biosynthesis/genetics/physiology
MH  - Neovascularization, Pathologic/drug therapy/physiopathology
MH  - Proto-Oncogene Proteins c-met/biosynthesis/genetics/physiology
MH  - Stress Fibers/drug effects/ultrastructure
MH  - Urinary Bladder Neoplasms/*pathology
MH  - Vascular Endothelial Growth Factor A/metabolism
EDAT- 2007/05/26 09:00
MHDA- 2007/08/10 09:00
CRDT- 2007/05/26 09:00
PHST- 2007/05/26 09:00 [pubmed]
PHST- 2007/08/10 09:00 [medline]
PHST- 2007/05/26 09:00 [entrez]
AID - 4296 [pii]
AID - 10.4161/cc.6.11.4296 [doi]
PST - ppublish
SO  - Cell Cycle. 2007 Jun 1;6(11):1393-402. doi: 10.4161/cc.6.11.4296. Epub 2007 Jun 
      13.