beta-Carotene downregulates the steady-state and heregulin-alpha-induced COX-2 pathways in colon cancer cells.
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 micromol/L) decreased COX-2 expression (P < 0.05) and prostaglandin E(2) (PGE(2)) 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.
Palozza
Paola
P
Institute of General Pathology, Catholic University, Rome, Italy.
Serini
Simona
S
Maggiano
Nicola
N
Tringali
Giuseppe
G
Navarra
Pierluigi
P
Ranelletti
Franco O
FO
Calviello
Gabriella
G
D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins; D020890:Neuregulin-1 / Q000235:genetics / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019207:beta Carotene / Q000494:pharmacology*
D007527:Isoenzymes; D008565:Membrane Proteins; D020890:Neuregulin-1; D017382:Reactive Oxygen Species; C117463:heregulin alpha; D019207:beta Carotene; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015232:Dinoprostone