Journal Article

n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE<sub>2</sub> induced ERK-1 and -2 and HIF-1α induction pathway

Gabriella Calviello, Fiorella Di Nicuolo, Simona Gragnoli, Elisabetta Piccioni, Simona Serini, Nicola Maggiano, Giuseppe Tringali, Pierluigi Navarra, Franco O. Ranelletti and Paola Palozza

in Carcinogenesis

Volume 25, issue 12, pages 2303-2310
Published in print December 2004 | ISSN: 0143-3334
Published online December 2004 | e-ISSN: 1460-2180 | DOI:
n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and -2 and HIF-1α induction pathway

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n-3 Polyunsaturated fatty acids (PUFAs) inhibit the development of microvessels in mammary tumors growing in mice. Human colorectal tumors produce vascular endothelial growth factor (VEGF) whose expression is up-regulated in tumor cells by both cyclooxygenase-2 (COX-2) and PGE2 and directly correlated to neoangiogenesis and clinical outcome. The goal of this study was to examine the capability of n-3 PUFAs to regulate VEGF expression in HT-29 human colorectal cells in vitro and in vivo. Constitutive VEGF expression was augmented in cultured HT-29 cells by serum starvation and the effects of eicosapentaenoic (EPA) or docosahexaenoic acid (DHA) on VEGF, COX-2, phosphorylated extracellular signal-regulated kinase (ERK)-1 and -2 and hypoxia-inducible-factor 1-α (HIF-1α) expression and PGE2 levels were assessed. Tumor growth, VEGF, COX and PGE2 analysis were carried out in tumors derived from HT-29 cells transplanted in nude mice fed with either EPA or DHA. Both EPA and DHA reduced VEGF and COX-2 expression and PGE2 levels in HT-29 cells cultured in vitro. Moreover, they inhibited ERK-1 and -2 phosphorylation and HIF-1α protein over-expression, critical steps in the PGE2-induced signaling pathway leading to the augmented expression of VEGF in colon cancer cells. EPA always showed higher efficacy than DHA in vitro. Both fatty acids decreased the growth of the tumors obtained by inoculating HT-29 cells in nude mice, microvessel formation and the levels of VEGF, COX-2 and PGE2 in tumors. The data provide evidence that these n-3 PUFAs are able to inhibit VEGF expression in colon cancer cells and suggest that one possible mechanism involved may be the negative regulation of the COX-2/PGE2 pathway. Their potential clinical application as anti-angiogenic compounds in colon cancer therapy is proposed.

Keywords: COX-2, cyclooxygenase-2; DHA, docosahexaenoic acid; EPA, eicosapentaenoic; ERK, extracellular signal-regulated kinase; HIF1-α, hypoxia-inducible factor 1-α; LI %, Labeling Index; PUFAs, polyunsaturated fatty acids; RIA, radioimmunoassay; VEGF, vascular endothelial growth factor

Journal Article.  6246 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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