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Molecular mechanisms for discrete nitric oxide levels in cancer.

Abstract
Nitric oxide (NO) has been invoked in nearly every normal and pathological condition associated with human physiology. In tumor biology, nitrogen oxides have both positive and negative affects as they have been implicated in both promoting and preventing cancer. Our work has focused on NO chemistry and how it correlates with cytotoxicity and cancer. Toward this end, we have studied both concentration- and time-dependent NO regulation of specific signaling pathways in response to defined nitrosative stress levels that may occur within the tumor microenvironment. Threshold levels of NO required for activation and stabilization of key proteins involved in carcinogenesis including p53, ERK, Akt and HIF have been identified. Importantly, threshold NO levels are further influenced by reactive oxygen species (ROS) including superoxide, which can shift or attenuate NO-mediated signaling as observed in both tumor and endothelial cells. Our studies have been extended to determine levels of NO that are critical during angiogenic response through regulation of the anti-angiogenic agent thrombospondin-1 (TSP-1) and pro-angiogenic agent matrix metalloproteinase-9 (MMP-9). The quantification of redox events at the cellular level has revealed potential mechanisms that may either limit or potentiate tumor growth, and helped define the positive and negative function of nitric oxide in cancer.
AuthorsLisa A Ridnour, Douglas D Thomas, Christopher Switzer, Wilmarie Flores-Santana, Jeffrey S Isenberg, Stefan Ambs, David D Roberts, David A Wink
JournalNitric oxide : biology and chemistry / official journal of the Nitric Oxide Society (Nitric Oxide) Vol. 19 Issue 2 Pg. 73-6 (Sep 2008) ISSN: 1089-8611 [Electronic] United States
PMID18472020 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Reactive Nitrogen Species
  • Nitric Oxide
Topics
  • Humans
  • Inflammation
  • Neoplasms (metabolism, pathology)
  • Neovascularization, Pathologic
  • Nitric Oxide (metabolism, physiology)
  • Reactive Nitrogen Species

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