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, 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 (sGCα1β1 Cys105) in athymic mice increased the survival time by 4-fold over the control. Histological analysis of xenografts overexpressing α1β1 Cys105 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.

Original languageEnglish (US)
Pages (from-to)1076-1084
Number of pages9
JournalMolecular Pharmacology
Volume80
Issue number6
DOIs
StatePublished - Dec 1 2011

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Glioma
Phosphoric Diester Hydrolases
Soluble Guanylyl Cyclase
1-Methyl-3-isobutylxanthine
National Cancer Institute (U.S.)
Guanylate Cyclase
Atrial Natriuretic Factor
Heterografts
Nude Mice
Radiotherapy
Databases
Drug Therapy
Cell Line
Membranes
Survival

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Zhu, H., Li, J. T., Zheng, F., Martin, E., Kots, A. Y., Krumenacker, J. S., ... Bian, K. (2011). Restoring soluble guanylyl cyclase expression and function blocks the aggressive course of glioma. Molecular Pharmacology, 80(6), 1076-1084. https://doi.org/10.1124/mol.111.073585

Restoring soluble guanylyl cyclase expression and function blocks the aggressive course of glioma. / Zhu, Haifeng; Li, Jessica Tao; Zheng, Fang; Martin, Emil; Kots, Alexander Y.; Krumenacker, Joshua S.; Choi, Byung Kwon; McCutcheon, Ian E.; Weisbrodt, Norman; Bögler, Oliver; Murad, Ferid; Bian, Ka.

In: Molecular Pharmacology, Vol. 80, No. 6, 01.12.2011, p. 1076-1084.

Research output: Contribution to journalArticle

Zhu, H, Li, JT, Zheng, F, Martin, E, Kots, AY, Krumenacker, JS, Choi, BK, McCutcheon, IE, Weisbrodt, N, Bögler, O, Murad, F & Bian, K 2011, 'Restoring soluble guanylyl cyclase expression and function blocks the aggressive course of glioma', Molecular Pharmacology, vol. 80, no. 6, pp. 1076-1084. https://doi.org/10.1124/mol.111.073585
Zhu, Haifeng ; Li, Jessica Tao ; Zheng, Fang ; Martin, Emil ; Kots, Alexander Y. ; Krumenacker, Joshua S. ; Choi, Byung Kwon ; McCutcheon, Ian E. ; Weisbrodt, Norman ; Bögler, Oliver ; Murad, Ferid ; Bian, Ka. / Restoring soluble guanylyl cyclase expression and function blocks the aggressive course of glioma. In: Molecular Pharmacology. 2011 ; Vol. 80, No. 6. pp. 1076-1084.
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