PMID- 18566226
OWN - NLM
STAT- MEDLINE
DCOM- 20080822
LR  - 20200930
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 7
IP  - 6
DP  - 2008 Jun
TI  - Fasudil-induced hypoxia-inducible factor-1alpha degradation disrupts a 
      hypoxia-driven vascular endothelial growth factor autocrine mechanism in 
      endothelial cells.
PG  - 1551-61
LID - 10.1158/1535-7163.MCT-07-0428 [doi]
AB  - Hypoxic response of endothelial cells (EC) is an important component of tumor 
      angiogenesis. Especially, hypoxia-inducible factor-1 (HIF-1)-dependent 
      EC-specific mechanism is an essential component of tumor angiogenesis. Recently, 
      the Rho/Rho-associated kinase (ROCK) signaling has been shown to play a key role 
      in HIF-1alpha induction in renal cell carcinoma and trophoblast. The present 
      study was designed to investigate whether low oxygen conditions might modulate 
      HIF-1alpha expression through the Rho/ROCK signaling in human umbilical vascular 
      ECs (HUVEC). Pull-down assay showed that hypoxia stimulated RhoA activity. Under 
      hypoxic conditions, HUVECs transfected with small interfering RNA of RhoA and 
      ROCK2 exhibited decreased levels of HIF-1alpha protein compared with nontargeted 
      small interfering RNA transfectants, whereas HIF-1alpha mRNA levels were not 
      altered. One of ROCK inhibitors, fasudil, inhibited hypoxia-induced HIF-1alpha 
      expression without altering HIF-1alpha mRNA expression. Furthermore, proteasome 
      inhibitor prevented the effect of fasudil on HIF-1alpha expression, and 
      polyubiquitination was enhanced by fasudil. These results suggested that 
      hypoxia-induced HIF-1alpha expression is through preventing HIF-1alpha 
      degradation by activating the Rho/ROCK signaling in ECs. Furthermore, hypoxia 
      induced both vascular endothelial growth factor (VEGF) and VEGF receptor-2 
      expression through the Rho/ROCK/HIF-1alpha signaling in HUVECs. Thus, augmented 
      VEGF/VEGF receptor-2 autocrine mechanism stimulated HUVEC migration under hypoxic 
      conditions. In summary, the Rho/ROCK/HIF-1alpha signaling is an essential 
      mechanism for hypoxia-driven, VEGF-mediated autocrine loop in ECs. Therefore, 
      fasudil might have the antimigratory effect against ECs in tumor angiogenesis.
FAU - Takata, Keiko
AU  - Takata K
AD  - Department of Obstetrics and Gynecology, Osaka University Graduate School of 
      Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Morishige, Ken-Ichirou
AU  - Morishige K
FAU - Takahashi, Toshifumi
AU  - Takahashi T
FAU - Hashimoto, Kae
AU  - Hashimoto K
FAU - Tsutsumi, Seiji
AU  - Tsutsumi S
FAU - Yin, Limei
AU  - Yin L
FAU - Ohta, Tsuyoshi
AU  - Ohta T
FAU - Kawagoe, Jun
AU  - Kawagoe J
FAU - Takahashi, Kazuhiro
AU  - Takahashi K
FAU - Kurachi, Hirohisa
AU  - Kurachi H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Amides)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Leupeptins)
RN  - 0 (Myosin Light Chains)
RN  - 0 (Pyridines)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 138381-45-0 (Y 27632)
RN  - 84477-87-2 (1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
RN  - EC 2.7.11.1 (rho-Associated Kinases)
RN  - Q0CH43PGXS (fasudil)
RN  - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde)
SB  - IM
MH  - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs & derivatives/pharmacology
MH  - Amides/pharmacology
MH  - Autocrine Communication/*drug effects
MH  - Cell Hypoxia/drug effects
MH  - Cell Movement/drug effects
MH  - Cell Nucleus/drug effects/metabolism
MH  - Drug Screening Assays, Antitumor
MH  - Endothelial Cells/*drug effects/enzymology/*metabolism/pathology
MH  - Enzyme Activation/drug effects
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Leupeptins/pharmacology
MH  - Myosin Light Chains/metabolism
MH  - Neovascularization, Pathologic/pathology
MH  - Phosphorylation/drug effects
MH  - Protein Processing, Post-Translational/*drug effects
MH  - Protein Transport/drug effects
MH  - Pyridines/pharmacology
MH  - Ubiquitination/drug effects
MH  - Vascular Endothelial Growth Factor A/*metabolism
MH  - Vascular Endothelial Growth Factor Receptor-2/metabolism
MH  - rho-Associated Kinases/metabolism
EDAT- 2008/06/21 09:00
MHDA- 2008/08/23 09:00
CRDT- 2008/06/21 09:00
PHST- 2008/06/21 09:00 [pubmed]
PHST- 2008/08/23 09:00 [medline]
PHST- 2008/06/21 09:00 [entrez]
AID - 7/6/1551 [pii]
AID - 10.1158/1535-7163.MCT-07-0428 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2008 Jun;7(6):1551-61. doi: 10.1158/1535-7163.MCT-07-0428.