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Molecular Pharmacology

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Research ArticleArticle

Restoring Soluble Guanylyl Cyclase Expression and Function Blocks the Aggressive Course of Glioma

Haifeng Zhu, Jessica Tao Li, Fang Zheng, Emil Martin, Alexander Y. Kots, Joshua S. Krumenacker, Byung-Kwon Choi, Ian E. McCutcheon, Norman Weisbrodt, Oliver Bögler, Ferid Murad and Ka Bian
Molecular Pharmacology December 2011, 80 (6) 1076-1084; DOI: https://doi.org/10.1124/mol.111.073585
Haifeng Zhu
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Jessica Tao Li
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Fang Zheng
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Emil Martin
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Alexander Y. Kots
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Joshua S. Krumenacker
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Byung-Kwon Choi
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Ian E. McCutcheon
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Norman Weisbrodt
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Oliver Bögler
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Ferid Murad
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Ka Bian
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Abstract

The NO and cGMP signaling pathways are of broad physiological and pathological significance. We compared the NO/soluble guanylyl cyclase (sGC)/cGMP pathway in human glioma tissues and cell lines with that of healthy control samples and demonstrated that sGC expression is significantly lower in glioma preparations. Our analysis of GEO databases (National Cancer Institute) further revealed a statistically significant reduction of sGC transcript levels in human glioma specimens. On the other hand, the expression levels of particulate (membrane) guanylyl cyclases (pGC) and cGMP-specific phosphodiesterase (PDE) were intact in the glioma cells that we have tested. Pharmacologically manipulating endogenous cGMP generation in glioma cells through either stimulating pGC by ANP/BNP, or blocking PDE by 3-isobutyl-1-methylxanthine/zaprinast caused significant inhibition of proliferation and colony formation of glioma cells. Genetically restoring sGC expression also correlated inversely with glioma cells growth. Orthotopic implantation of glioma cells transfected with an active mutant form of sGC (sGCα1β1Cys105) in athymic mice increased the survival time by 4-fold over the control. Histological analysis of xenografts overexpressing α1β1Cys105 sGC revealed changes in cellular architecture that resemble the morphology of normal cells. In addition, a decrease in angiogenesis contributed to glioma inhibition by sGC/cGMP therapy. Our study proposes the new concept that suppressed expression of sGC, a key enzyme in the NO/cGMP pathway, may be associated with an aggressive course of glioma. The sGC/cGMP signaling-targeted therapy may be a favorable alternative to chemotherapy and radiotherapy for glioma and perhaps other tumors.

Footnotes

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

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM076695-02]; the John S. Dunn [Grants 74Y-1-9135, 000447] and Robert A. Welch Foundations [Grants AU-1437, L-AU-0002]; The Department of Defense [Grant T5-0004271project]; and The George Washington University. The work was also supported in part by the NHLBI Grant 5R01HL088128 [E.M.]. The authors sincerely thank the supports of Dr. Raymond Sawaya of the Department of Neurosurgery and Brain Tumor Center of The University of Texas M. D. Anderson Cancer Center.

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

    doi:10.1124/mol.111.073585.

  • ABBREVIATIONS:

    cGMP
    cyclic 3′,5′-GMP
    sGC
    soluble guanylyl cyclase
    iNOS
    inducible nitric-oxide synthase
    PCR
    polymerase chain reaction
    IBMX
    3-isobutyl-1-methylxanthine
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
    Bay41-2272
    3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine
    Q-PCR
    quantitative polymerase chain reaction
    GC
    guanylyl cyclase
    pGC
    particulate guanylyl cyclase
    NPR
    natriuretic peptide receptor
    ANP
    atrial natriuretic peptide
    BNP
    brain natriuretic peptide
    PDE
    phosphodiesterase
    PKG
    cGMP-dependent protein kinase.

  • Received May 16, 2011.
  • Accepted September 9, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (6)
Molecular Pharmacology
Vol. 80, Issue 6
1 Dec 2011
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Research ArticleArticle

sGC/cGMP as Molecular Targets for Glioma Therapy

Haifeng Zhu, Jessica Tao Li, Fang Zheng, Emil Martin, Alexander Y. Kots, Joshua S. Krumenacker, Byung-Kwon Choi, Ian E. McCutcheon, Norman Weisbrodt, Oliver Bögler, Ferid Murad and Ka Bian
Molecular Pharmacology December 1, 2011, 80 (6) 1076-1084; DOI: https://doi.org/10.1124/mol.111.073585

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Research ArticleArticle

sGC/cGMP as Molecular Targets for Glioma Therapy

Haifeng Zhu, Jessica Tao Li, Fang Zheng, Emil Martin, Alexander Y. Kots, Joshua S. Krumenacker, Byung-Kwon Choi, Ian E. McCutcheon, Norman Weisbrodt, Oliver Bögler, Ferid Murad and Ka Bian
Molecular Pharmacology December 1, 2011, 80 (6) 1076-1084; DOI: https://doi.org/10.1124/mol.111.073585
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