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Nutrition and Cancer

ß-Carotene Downregulates the Steady-State and Heregulin-–Induced COX-2 Pathways in Colon Cancer Cells¹

Paola Palozza², Simona Serini, Nicola Maggiano^*, Giuseppe Tringali, Pierluigi Navarra, Franco O. Ranelletti^** and Gabriella Calviello

Institute of General Pathology, ^* Institute of Pathology, Institute of Pharmacology, and ^** Institute of Histology, Catholic University, 00168 Rome, Italy

²To whom correspondence should be addressed. E-mail: p.palozza{at}rm.unicatt.it.

Experimental studies have shown that ß-carotene inhibited the growth of colon cancer cells, and human trials have demonstrated that the carotenoid reduces colon cell proliferation of adenomatous polyps; however, molecular mechanisms underlying this chemopreventive activity remain unclear. Because COX-2 has been implicated as a causative factor in colon carcinogenesis, the present study was designed to investigate the relation between the growth-inhibitory effect of the carotenoid and COX-2 expression in colon cancer cells. We evaluated the effects of ß-carotene on the growth of human colon adenocarcinoma cells overexpressing (LS-174, HT-29, WiDr) or not expressing (HCT116) COX-2. We also studied COX-2 expression induced by heregulin-, apoptosis induction, reactive oxygen species (ROS) production, and extracellular signal–regulated kinase 1/2 (ERK1/2) activation. ß-Carotene (0.5–2.0 µmol/L) decreased COX-2 expression (P < 0.05) and prostaglandin E₂ (PGE₂) production (P < 0.05) in colon cancer cells. This effect was not observed in cells treated with retinoic acid or retinol. The downregulation of COX-2 by the carotenoid occurred in both untreated and heregulin-treated cells. It was accompanied by an increased ability of cells to undergo apoptosis and by a decrease in intracellular ROS production and in the activation of ERK1/2. Moreover, cells not expressing COX-2 were insensitive to the growth-inhibitory and proapoptotic effects of the carotenoid. Here, we report that the suppression of COX-2 by ß-carotene may represent a molecular mechanism by which this compound acts as an antitumor agent in colon carcinogenesis.

KEY WORDS: • ß-carotene • COX-2 expression • cell growth • apoptosis • colon cancer cells

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