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Carcinogenesis Advance Access originally published online on September 9, 2004
Carcinogenesis 2004 25(12):2303-2310; doi:10.1093/carcin/bgh265
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Carcinogenesis vol.25 no.12 © Oxford University Press 2004; all rights reserved.

ARTICLE

n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and -2 and HIF-1{alpha} induction pathway

Gabriella Calviello1,4,5, Fiorella Di Nicuolo1, Simona Gragnoli1, Elisabetta Piccioni1, Simona Serini1, Nicola Maggiano2, Giuseppe Tringali3, Pierluigi Navarra3, Franco O. Ranelletti4 and Paola Palozza1

1 Institute of General Pathology, 2 Institute of Pathology, 3 Institute of Pharmacology and 4 Institute of Histology, Catholic University, L.go F. Vito, 1, 00168 Rome, Italy

5 To whom correspondence should be addressed Email: g.calviello{at}rm.unicatt.it

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-{alpha} (HIF-1{alpha}) 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-1{alpha} 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.


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