PMID- 22984202
OWN - NLM
STAT- MEDLINE
DCOM- 20121210
LR  - 20211021
IS  - 1460-2105 (Electronic)
IS  - 0027-8874 (Print)
IS  - 0027-8874 (Linking)
VI  - 104
IP  - 19
DP  - 2012 Oct 3
TI  - Protumorigenic activity of plasminogen activator inhibitor-1 through an 
      antiapoptotic function.
PG  - 1470-84
LID - 10.1093/jnci/djs377 [doi]
AB  - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is a protease inhibitor but 
      is paradoxically associated with poor outcomes in cancer patients. However, the 
      mechanisms of its effects on tumor cells have not been explored. METHODS: 
      Endogenous PAI-1 in human tumor cell lines (HT-1080, A549, HCT-116, and 
      MDA-MB-231) was suppressed by small interfering RNAs (siRNAs) and PAI-039, a 
      small molecule inhibitor of PAI-1, and the effects on apoptosis were examined. 
      Tumorigenicity of PAI-1 knockdown (KD) tumor cells was examined in 
      immunodeficient PAI-1 wild-type and knockout (KO) mice (9-15 per group), and 
      event-free survival was analyzed by the Kaplan-Meier method. The effect of PAI-1 
      suppression on HT-1080 xenotransplanted tumors was evaluated for cell 
      proliferation, apoptosis, and angiogenesis. All statistical tests were two-sided. 
      RESULTS: Genetic and pharmacological inhibition of PAI-1 in the four tumor cell 
      lines increased spontaneous apoptosis (mean fold increase relative to control: 
      HT-1080, siRNA#1, mean = 4.0, 95% CI = 2.6 to 5.3, P < .001; siRNA#2, mean = 2.6, 
      95% CI = 2.4 to 2.9, P < .001, Student t test), which was blocked in the presence 
      of recombinant PAI-1, a caspase-8 inhibitor, or Fas/FasL neutralizing antibodies 
      and was partially attenuated by a plasmin inhibitor-aprotinin. PAI-1 KO mice 
      implanted with PAI-1 KD HT-1080 cells had decreased tumorigenesis and prolonged 
      survival compared with control mice (P = .002, log-rank test), and their tumors 
      exhibited decreased cell proliferation and angiogenesis and increased apoptosis. 
      Furthermore, five of 15 PAI-1 KO mice implanted with PAI-1 KD HT-1080 cells never 
      developed tumors. CONCLUSIONS: These data suggest that PAI-1 exerts a protective 
      effect against tumor cell apoptosis by a mechanism that, in part, involves 
      plasmin activation and inhibition of Fas/Fas-L-mediated apoptosis and may be a 
      promising therapeutic target.
FAU - Fang, Hua
AU  - Fang H
AD  - Division of Hematology-Oncology, Department of Pediatrics, Keck School of 
      Medicine, University of Southern California, Los Angeles, CA, USA.
FAU - Placencio, Veronica R
AU  - Placencio VR
FAU - DeClerck, Yves A
AU  - DeClerck YA
LA  - eng
GR  - R01 CA129377/CA/NCI NIH HHS/United States
GR  - CA129377/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120913
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Fasl protein, mouse)
RN  - 0 (Indoleacetic Acids)
RN  - 0 (Oligopeptides)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl 
      ketone)
RN  - 0 (tiplaxtinin)
RN  - 9001-32-5 (Fibrinogen)
RN  - 9001-91-6 (Plasminogen)
RN  - EC 3.4.21.7 (Fibrinolysin)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Animals
MH  - Antibodies, Neutralizing/pharmacology
MH  - *Apoptosis/drug effects
MH  - Blotting, Western
MH  - Caspase Inhibitors/pharmacology
MH  - Cell Line, Tumor
MH  - *Cell Proliferation/drug effects
MH  - Disease Progression
MH  - Disease-Free Survival
MH  - Down-Regulation
MH  - Fas Ligand Protein/immunology
MH  - Female
MH  - Fibrinogen/metabolism
MH  - Fibrinolysin/metabolism
MH  - Flow Cytometry
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - Indoleacetic Acids
MH  - Kaplan-Meier Estimate
MH  - Mice
MH  - Mice, Knockout
MH  - *Neovascularization, Pathologic/metabolism
MH  - Oligopeptides/pharmacology
MH  - Plasminogen/metabolism
MH  - Plasminogen Activator Inhibitor 1/*genetics/*metabolism
MH  - RNA, Small Interfering
MH  - Transplantation, Heterologous
MH  - Urokinase-Type Plasminogen Activator/metabolism
PMC - PMC3529616
EDAT- 2012/09/18 06:00
MHDA- 2012/12/12 06:00
PMCR- 2013/10/03
CRDT- 2012/09/18 06:00
PHST- 2012/09/18 06:00 [entrez]
PHST- 2012/09/18 06:00 [pubmed]
PHST- 2012/12/12 06:00 [medline]
PHST- 2013/10/03 00:00 [pmc-release]
AID - djs377 [pii]
AID - 10.1093/jnci/djs377 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 2012 Oct 3;104(19):1470-84. doi: 10.1093/jnci/djs377. Epub 
      2012 Sep 13.