Beta-carotene downregulates the steady-state and heregulin-alpha-induced COX-2 pathways in colon cancer cells
2005
Palozza, P. | Serini, S. | Maggiano, N. | Tringali, G. | Navarra, P. | Ranelletti, F.O. | Calviello, G.
Experimental studies have shown that [beta]-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 [beta]-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-[alpha], apoptosis induction, reactive oxygen species (ROS) production, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. [beta]-Carotene (0.5-2.0 [micro]mol/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 [beta]-carotene may represent a molecular mechanism by which this compound acts as an antitumor agent in colon carcinogenesis.
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