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Research ArticleDrug Discovery and Translational Medicine

Apolipoprotein A-I Mimetic Peptides Inhibit Expression and Activity of Hypoxia-Inducible Factor-1α in Human Ovarian Cancer Cell Lines and a Mouse Ovarian Cancer Model

Feng Gao, Arnab Chattopadhyay, Mohamad Navab, Victor Grijalva, Feng Su, Alan M. Fogelman, Srinivasa T. Reddy and Robin Farias-Eisner
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 255-262; DOI: https://doi.org/10.1124/jpet.112.191544
Feng Gao
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Arnab Chattopadhyay
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Mohamad Navab
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Victor Grijalva
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Feng Su
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Alan M. Fogelman
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Srinivasa T. Reddy
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Robin Farias-Eisner
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Abstract

Our previous results demonstrated that the apolipoprotein A-I (apoA-I) mimetic peptides L-4F and L-5F inhibit vascular endothelial growth factor production and tumor angiogenesis. The present study was designed to test whether apoA-I mimetic peptides inhibit the expression and activity of hypoxia-inducible factor-1α (HIF-1α), which plays a critical role in the production of angiogenic factors and angiogenesis. Immunohistochemistry staining was used to examine the expression of HIF-1α in tumor tissues. Immunoblotting, real-time polymerase chain reaction, immunofluorescence, and luciferase activity assays were used to determine the expression and activity of HIF-1α in human ovarian cancer cell lines. Immunohistochemistry staining demonstrated that L-4F treatment dramatically decreased HIF-1α expression in mouse ovarian tumor tissues. L-4F inhibited the expression and activity of HIF-1α induced by low oxygen concentration, cobalt chloride (CoCl2, a hypoxia-mimic compound), lysophosphatidic acid, and insulin in two human ovarian cancer cell lines, OV2008 and CAOV-3. L-4F had no effect on the insulin-induced phosphorylation of Akt, but inhibited the activation of extracellular signal-regulated kinase and p70s6 kinase, leading to the inhibition of HIF-1α synthesis. Pretreatment with L-4F dramatically accelerated the proteasome-dependent protein degradation of HIF-1α in both insulin- and CoCl2-treated cells. The inhibitory effect of L-4F on HIF-1α expression is in part mediated by the reactive oxygen species-scavenging effect of L-4F. ApoA-I mimetic peptides inhibit the expression and activity of HIF-1α in both in vivo and in vitro models, suggesting the inhibition of HIF-1α may be a critical mechanism responsible for the suppression of tumor progression by apoA-I mimetic peptides.

Footnotes

  • This work was supported by funds from the Women's Endowment, the Carl and Roberta Deutsch Family Foundation, the Joan English Fund for Women's Cancer Research, a VA Merit I Award (to R.F.-E.), the Ovarian Cancer Coalition, the Helen Beller Foundation, the Wendy Stark Foundation, the Sue and Mel Geleibter Family Foundation, Kelly Day, the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL-30568, HL-082823], and the Laubisch and M. K. Gray funds at the University of California, Los Angeles.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.191544.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    apoA-I
    apolipoprotein A-I
    HIF-1
    hypoxia-inducible factor-1
    CoCl2
    cobalt chloride
    LPA
    lysophosphatidic acid
    ROS
    reactive oxygen species
    VEGF
    vascular endothelial growth factor
    CHX
    cycloheximide
    DAPI
    4,6-diamidino-2-phenylindole
    DCFH-DA
    dichlorofluorescein diacetate
    ERK
    extracellular signal-regulated kinase
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    HRE
    hypoxia response element
    PCR
    polymerase chain reaction
    PBS
    phosphate-buffered saline
    RT
    reverse transcription
    sc-4F
    scrambled 4F
    SOD
    superoxide dismutase
    MG-132
    N-(benzyloxycarbonyl)leucinylleucinylleucinal-Z-Leu-Leu-Leu-al.

  • Received January 31, 2012.
  • Accepted April 24, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleDrug Discovery and Translational Medicine

Inhibition of HIF-1α by ApoA-I Mimetic Peptides

Feng Gao, Arnab Chattopadhyay, Mohamad Navab, Victor Grijalva, Feng Su, Alan M. Fogelman, Srinivasa T. Reddy and Robin Farias-Eisner
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 255-262; DOI: https://doi.org/10.1124/jpet.112.191544

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Research ArticleDrug Discovery and Translational Medicine

Inhibition of HIF-1α by ApoA-I Mimetic Peptides

Feng Gao, Arnab Chattopadhyay, Mohamad Navab, Victor Grijalva, Feng Su, Alan M. Fogelman, Srinivasa T. Reddy and Robin Farias-Eisner
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 255-262; DOI: https://doi.org/10.1124/jpet.112.191544
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