Molecular mechanisms for discrete nitric oxide levels in cancer

doi:10.1016/j.niox.2008.04.006

Nitric Oxide

Volume 19, Issue 2, September 2008, Pages 73-76

https://doi.org/10.1016/j.niox.2008.04.006 Get rights and content

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.

Section snippets

NO signaling and concentration dependence

Characterizing steady state NO is of particular importance when assessing its effects at the cellular level [9], [10]. MCF-7 breast cancer cells were found to activate specific signaling pathways in response to distinct fluxes of NO. Levels below 50 nM NO were associated with increased cGMP-mediated ERK phosphorylation, intermediate levels (>100 nM) lead to HIF-1α stabilization, and high NO (>300 nM) was associated with p53-P(ser-15), which persisted even after dissipation of NO [10]. These

Inflammation and wound healing in cancer therapy

While it is clear that NO elicits direct radiosensitizing effects on DNA within a tumor, modulation of wound responses by NO is an additional mechanism for the potentiation of chemo and radiation therapies. Although molecular mechanisms regulating growth differ among cancer types, exposure to radiation, surgery, and/or chemotherapy enhances cell death followed by the onset of inflammation and wound healing. These processes are similar to that of a wound response in normal tissue where

Summary

When NO effects in mammalian cells are grouped according to the concentration of NO, a pro- and anti-tumorigenic response emerges (Fig. 1). Increased cGMP promotes angiogenesis and proliferation of endothelial cells and occurs between 1 and 30 nM [14]. At this level, ERK phosphorylation stimulates proliferation of endothelial cells while suppressing the anti-angiogenic factor TSP-1 [14]. At NO concentrations of 30–100 nM, a marked increase in Akt and ERK signals a proliferative and anti-apoptotic

Acknowledgment

This work is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research.

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ReviewMolecular mechanisms for discrete nitric oxide levels in cancer

Abstract

Section snippets

NO signaling and concentration dependence

Inflammation and wound healing in cancer therapy

Summary

Acknowledgment

Res. Immunol.

Free Radic. Biol. Med.

Free Rad. Biol. Med.

J. Biol. Chem.

J. Biol. Chem.

Lancet

Nitric Oxide

Mol. Cell

Eur. J. Cancer

J. Biol. Chem.

Blood

J. Biol. Chem.

A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells

J. Exp. Med.

Nitric oxide, a mediator of inflammation, suppresses tumorigenesis

Cancer Res.

Inflammation and IGF-I activate the Akt pathway in breast cancer

Int. J. Cancer

Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival

Clin. Cancer Res.

Tumor iNOS predicts poor survival for stage III melanoma patients

Int. J. Cancer

Review
Molecular mechanisms for discrete nitric oxide levels in cancer