Prostaglandin-independent effects of aspirin on cell cycle and putrescine synthesis in human colon carcinoma cells.
Aspirin consumption has been reported to be able to reduce colorectal cancer risk in humans and in animal models of colon carcinogenesis. Although the mechanism involved in such an effect is not yet clear, both prostaglandin-dependent and -independent effects have been proposed. Using HT-29 Glc(-/+)cells, which originate from a human colon adenocarcinoma, we demonstrated in this study a dose-dependent effect of millimolar concentration of aspirin on cell growth that was concomitant with a rapid accumulation of the cells in the G0/G1 phase, followed by an accumulation in the G2/M phase and by a minor increase in the proportion of cells undergoing nuclear condensation. Cell membrane integrity and cell release into the culture medium were not affected by this treatment. The aspirin effects were apparently unrelated to prostaglandin biosynthesis inhibition, since although these cells were found to express high levels of cyclooxygenase 1 (COX-1) and low levels of COX-2 proteins, they did not produce any measurable net amounts of prostaglandins, based on both utilization of radiolabelled arachidonic acid and the radioimmunoassay of prostaglandins E2 and F2 alpha. In contrast, we identified polyamine biosynthesis as a cellular target of aspirin, since the treatment of HT-29 Glc(-/+) cells with aspirin reduced the flux of L-ornithine through ornithine decarboxylase, an effect that could not be explained by an acute action of the drug on the ornithine decarboxylase catalytic activity. Since polyamine biosynthesis is strictly necessary for HT-29 cell growth, our data suggest that reduced flux through ornithine decarboxylase may participate in the antiproliferative activity of aspirin towards colonic tumoral cells. It is concluded that in HT-29 Glc(-/+) cells that are not functional for prostaglandin production, aspirin can affect cell growth, cell cycle, and polyamine biosynthesis without affecting cell membrane integrity.
Eklou-Kalonji
E
E
Laboratoire de Nutrition et Sécurité Alimentaire, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France.
Andriamihaja
M
M
Reinaud
P
P
Mayeur
C
C
Camous
S
S
Robert
V
V
Charpigny
G
G
Blachier
F
F
D000230:Adenocarcinoma; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D018938:Caco-2 Cells; D002453:Cell Cycle / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D003110:Colonic Neoplasms; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008565:Membrane Proteins; D009952:Ornithine / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011453:Prostaglandins / Q000378:metabolism*; D011700:Putrescine / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D011073:Polyamines; D011453:Prostaglandins; D009952:Ornithine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D011700:Putrescine