Cyclooxygenase-2-dependent and -independent inhibition of proliferation of colon cancer cells by 5-aminosalicylic acid.
The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway may have a pathogenic role in colorectal cancer (CRC). Recent studies suggest that 5-aminosalicylic acid (5-ASA) reduces the risk of inflammatory bowel disease-related CRC, but the mechanism by which 5-ASA interferes with CRC cell growth remains unknown. In this study, we have examined whether the negative effect of 5-ASA on CRC cells is dependent on COX-2/PGE2 axis inhibition. We show that 5-ASA down-regulates both constitutive and TNF-alpha or IL-1beta-induced COX-2 in HT-115 and HT-29 cells. Inhibition of COX-2 by 5-ASA occurs at the RNA and protein level, and is associated with a significant decrease in PGE2 synthesis, arrest of growth and enhanced death of CRC cells. However, exogenous PGE2 does not revert the 5-ASA-mediated CRC cell proliferation block. 5-ASA also inhibits the growth of DLD-1, a COX-deficient CRC cell line, thus suggesting that the anti-proliferative effect of 5-ASA on CRC cells is not strictly dependent on the inhibition of COX-2/PGE2. Taken together our data indicate that 5-ASA causes both a COX-2-dependent and -independent inhibition of CRC cell growth.
Stolfi
Carmine
C
Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1-00133 Rome, Italy.
Fina
Daniele
D
Caruso
Roberta
R
Caprioli
Flavio
F
Sarra
Massimiliano
M
Fantini
Massimo Claudio
MC
Rizzo
Angelamaria
A
Pallone
Francesco
F
Monteleone
Giovanni
G
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D019804:Mesalamine / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D016211:Transforming Growth Factor alpha; D019804:Mesalamine; D051546:Cyclooxygenase 2; D015232:Dinoprostone