HT-29 colorectal cancer cells undergoing apoptosis overexpress COX-2 to delay ursolic acid-induced cell death.
Colorectal cancer is one of the most common cancer types and the third leading cause of cancer-related death in the western world. Generally, colorectal cancers are resistant to anticancer drugs. Several lines of evidence support a critical role for cyclooxygenase-2 (COX-2) during colorectal tumorigenesis and its role in chemoresistance. In this study, we focused our interest on the role played by COX-2 in apoptosis induced in HT-29 human colorectal cancer cells by ursolic acid (UA), a triterpenoid found in a large variety of plants. We showed that UA-induced apoptosis and that COX-2 was overexpressed only in apoptotic cells. We demonstrated that this overexpression was mediated by the p38 MAP kinase pathway as inhibiting its activation using a p38-specific inhibitor, SB 203580, abrogated COX-2 expression. Inhibiting COX-2 expression either by using a p38-specific inhibitor or COX-2-specific siRNA increased apoptosis. These results demonstrated that COX-2 was involved in a resistance mechanism to UA-induced apoptosis in HT-29 cells. Cells undergoing apoptosis were able to trigger a resistance mechanism by overexpressing a protein such as COX-2 to delay their death. Furthermore, we demonstrated that this resistance mechanism was independent of PGE(2) production as the addition of the specific COX-2 activity inhibitor, NS-398, did not affect apoptosis in UA-treated cells.
Université de Limoges, Institut GEIST, EA 4021, Biomolécules et thérapies anti-tumorales, Faculté de Pharmacie, Limoges, France.
Youness
Y
Limami
Aline
A
Pinon
David Yannick
DY
Leger
Yoanne
Y
Mousseau
Jeanne
J
Cook-Moreau
Jean-Louis
JL
Beneytout
Christiane
C
Delage
Bertrand
B
Liagre
Alain
A
Simon
D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009578:Nitrobenzenes / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097245:Ursolic Acid
D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D034741:RNA, Small Interfering; D013449:Sulfonamides; D014315:Triterpenes; D048051:p38 Mitogen-Activated Protein Kinases; D000097245:Ursolic Acid; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C496540:PTGS2 protein, human