p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells

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The finding of frequent nitric oxide synthase expression in human cancers indicates that nitric oxide has a pathophysiological role in carcinogenesis. To determine the role of nitric oxide in tumor progression, we generated human carcinoma cell lines that produced nitric oxide constitutively. Cancer cells expressing inducible nitric oxide synthase that had wild-type p53 had reduced tumor growth in athymic nude mice, whereas those with mutated p53 had accelerated tumor growth associated with increased vascular endothelial growth factor expression and neovascularization. Our data indicate that tumor-associated nitric oxide production may promote cancer progression by providing a selective growth advantage to tumor cells with mutant p53, and that inhibitors of inducible nitric oxide synthase may have therapeutic activity in these tumors.

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Figure 1: NOS2 expression and tumor growth. a and b, NO production in human carcinoma cells does not change cell growth in cell culture.
Figure 2: Expression of p21WAF1 protein is higher in tumors of NOS2-expressing LoVo cells than in tumors of the vector controls (BaglacZ).
Figure 3: a, The NOS2 inhibitor aminoguanidine (1% AG) reverses the growth stimulatory effect of NOS2 in tumors of HT-29 colon carcinoma cells.
Figure 4: NO induces tumor microvascularization.
Figure 5: a, Increased VEGF concentration in protein extracts of NOS2-expressing human carcinoma cell lines.
Figure 6: Nitric oxide inhibits pro-apoptotic PARP cleavage.


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We thank D. Dudek for editorial assistance.

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Correspondence to Curtis C. Harris.

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