Weiming Xu

Nitric oxide and gene expression in cancer cells

Nitric oxide (NO) is a pleiotropic regulator which has an important role in many biological processes including vasodilatation, neurotransmission, and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Various studies have shown that all three isoforms can be implicated in promotion or inhibition of the development of human cancer. High amounts of iNOS expression - eg, those generated by activated macrophages - might be cytostatic or cytotoxic for tumour cells, whereas low activity could have the opposite effect and promote tumour growth.

NO has both genotoxic and angiogenic properties, so increased NO production could select mutant p53 cells and contribute to tumour angiogenesis by upregulation of vascular endothelial growth factor and provide radiation and multidrug resistance by upregulation of DNA-dependent protein kinase catalytic subunit (1). These dual functions can be partly explained by the dose-dependency of NO in physiological and pathological conditions. In order to investigate the effects of different concentrations of NO we have developed two recombinant iNOS cell expression systems with promoters regulated by either insect hormone ecdysone (figure) or tetracycline (2,3). These cell lines can generate NO in a dose-dependent and time-dependent manner at concentrations found in human cancer cells. We are currently using several cDNA microarray systems and proteomic approaches to dissect NO-mediated inhibition of the mitochondrial respiration pathway, which could have an important role in cytotoxicity and hypoxia adaptation in tumour cells. Our findings could help us to understand the fundamental roles of NO in tumour biology.

Selected publications

1. Xu W, Liu L, Smith GC, Charles IG. Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumour agents. Nat Cell Biol 2000; 2:339-45.
2. Xu W, Liu L, Charles IG. Microencapsulated iNOS-expressing cells cause tumor suppression in mice. FASEB J 2002; 16: 213-15.
3. Xu W, Liu L, Loizidou M, Ahmed M, Charles IG. The role of nitric oxide in cancer. Cell Res. 2002; 12:311-20.
4. Xu W, Liu L, Charles IG & Moncada S. Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nat Cell Biol. 2004; 6:1129-34.

This page last modified 17 August, 2005 by Richard Passey

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