NOS-2 signaling and cancer therapy.
The role of NO and cGMP signaling in tumor biology has been extensively studied during the past three decades. However, whether the pathway is beneficial or detrimental in cancer is still open to question. We suggest several reasons for this ambiguity: first, although NO participates in normal signaling (e.g., vasodilation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric-oxide synthase (iNOS or NOS-2). In addition, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP-independent (NO oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumors contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and inflammatory cells) with different NO biology. Thus, the NO/sGC/cGMP signaling molecules in tumors as well as the surrounding tissue must be further characterized before targeting this signaling pathway for tumor therapy. In this review, we focus on the NOS-2 expression in tumor and surrounding cells and summarized research outcome in terms of cancer therapy. We propose that a normal function of the sGC-cGMP signaling axis may be important for the prevention and/or treatment of malignant tumors. Inhibiting NOS-2 overexpression and the tumor inflammatory microenvironment, combined with normalization of the sGC/cGMP signaling may be a favorable alternative to chemotherapy and radiotherapy for malignant tumors.
Department of Biochemistry and Molecular Biology, George Washington University, School of Medicine, Washington, DC, USA. bcmfxm@gwu.edu
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Bian
Farshid
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Ghassemi
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Sotolongo
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Siu
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Shauger
Alex
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Kots
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Murad
D000818:Animals; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000378:metabolism* / Q000627:therapeutic use; D006162:Guanylate Cyclase / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000627:therapeutic use; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP