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- Open Access
NO-cGMP signalling and cancer therapy
© Bian et al; licensee BioMed Central Ltd. 2013
- Published: 29 August 2013
The nitric oxide (NO) and 3’,5’-cyclic guanosine monophosphate (cGMP) pathway is one of the best characterized signalling cascades that plays a central role in several physiological processes such as vasodilation, neurotransmission, and embryonic development. Soluble guanylyl cyclase (sGC) is the key receptor for NO with α1β1 as predominate heterodimer for the function. Nitric oxide binds to the ferrous heme at histidine 105 of the β1 subunit and leads to at least a 200-fold increase in sGC activity and cGMP production . On the other hand, the effects of NO can be attributed to cGMP-independent pathway which is mainly mediated by reactive oxygen/nitrogen species such as highly reactive peroxynitrite (ONOO-) . The role of NO and cGMP signalling in tumour biology has been extensively studied during the past three decades, however a consensus regarding the precise role that the NO/cGMP signalling axis plays in neoplastic transformation has not been reached. Simple applications of NO or cGMP regulating reagents to various cancer cell lines or animal models has generated controversial results. We suggest several factors are contributing to this ambiguity: First, although the NO participates in normal signalling (e.g., vasodilatation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric oxide synthase (iNOS or NOS-2). Also, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP-independent (NO/oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumours contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and, inflammatory cells) with differing NO biology. Therefore, the NO/sGC/cGMP signalling molecules in tumours as well as the surrounding tissue must be further characterized before targeting this signalling pathway for tumour therapy.
We have performed initial experiments to prove our hypothesis that restoration of normal NO-cGMP signalling blocks the aggressive course of cancer . Pharmacologically manipulating endogenous cGMP generation in glioma cells through either stimulating pGC (NPR1 and NPR2) by ANP/BNP, or blocking PDE-5 by IBMX/ zaprinast caused significant inhibition of proliferation and colony formation of glioma U87 cells. Genetically restoring sGC expression also inversely correlated with glioma cells growth. Orthotopic implantation of glioma cells transfected with an active mutant form of sGC (sGCα1β1cys-105) in athymic mice increased the survival time by 4-fold over the control. Histological analysis of xenografts overexpressing α1β1cys-105 sGC revealed changes in cellular architecture which resemble the morphology of normal cells. In addition, a decrease in angiogenesis contributed to glioma inhibition by sGC/cGMP therapy.
Our study proposes a 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 signalling-targeted therapy may be a favourable alternative to chemotherapy and radiotherapy for glioma and perhaps other tumours such as breast, lung and pancreatic cancers.
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