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Nitric Oxide, a Mediator of Inflammation, Suppresses Tumorigenesis

¹ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ² Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina; ³ Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland; ⁴ Laboratory Animal Science Program, Science Applications International Corporation–Frederick, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland; and ⁵ Department of Surgery, University of Virginia Health Science Center, Charlottesville, Virginia

Inflammation influences the development of cancer. The nitric oxide synthase (NOS2) is induced by inflammatory cytokines, e.g., tumor necrosis factor and interleukin 1ß, and produces nitric oxide (NO^·), a critical mediator of the inflammatory response. Because p53 governs NO^· production by transcriptionally transrepressing NOS2, we used a genetic strategy to determine whether NO^· and p53 cooperatively regulate tumorigenesis. Lymphomas developed more rapidly in p53–/–NOS2–/– or p53–/–NOS2+/– mice than in p53–/–NOS2+/+ mice that were cross-bred into a >95% C57BL6 background and maintained in a pathogen-free condition. Likewise, sarcomas and lymphomas developed faster in p53+/–NOS2–/– or p53+/–NOS2+/– than in p53+/–NOS2+/+ mice. When compared with the double knockout mice, p53–/–NOS2+/+ mice showed a higher apoptotic index and a decreased proliferation index with an increased expression of death receptor ligands, CD95-L and tumor necrosis factor-related apoptosis-inducing ligand, and the cell cycle checkpoint protein, p21^waf1, in the spleen and thymus before tumor development. Furthermore, mice deficient in both p53 and NOS2 produced a high level of anti-inflammatory interleukin 10 when compared with p53-deficient mice. These studies provide genetic and mechanistic evidence that NO^· can suppress tumorigenesis.

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