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Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells.
- Source :
-
Cancer research [Cancer Res] 2002 Nov 01; Vol. 62 (21), pp. 6323-8. - Publication Year :
- 2002
-
Abstract
- The cyclooxygenase-2 (COX-2) gene encodes an inducible enzyme that converts arachidonic acid to prostaglandins and is up-regulated in colorectal neoplasms. Evidence indicates that COX-2 may regulate apoptosis and can influence the malignant phenotype. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzymes and induce apoptosis in colorectal cancer cell lines, which may contribute to their antitumor effects. To determine whether forced COX-2 expression modulates susceptibility to drug-induced apoptosis, HCT-15 colon carcinoma cells were stably transfected with the COX-2 cDNA, and two clones overexpressing COX-2 were isolated. Selective COX-2 (NS398) and nonselective (sulindac sulfide) COX inhibitors, as well as 5-fluorouracil (5-FU), induced apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling in a dosage-dependent manner. Forced COX-2 expression significantly attenuated induction of apoptosis by all three of the drugs compared with parental HCT-15 cells. NSAIDs and 5-FU induced the mitochondrial release of cytochrome c as well as caspase-3 and -9 activation, and to a much lesser extent, caspase-8. COX-2-overexpressing cells showed reduced cytochrome c and caspase activation, relative to parental cells. A specific inhibitor of caspase-3 restored cell survival after drug treatment. COX-2 transfectants were found to overexpress the antiapoptotic Bcl-2 mRNA and protein relative to parental cells. In conclusion, forced COX-2 expression significantly attenuates apoptosis induction by NSAIDs and 5-FU through predominant inhibition of the cytochrome c-dependent apoptotic pathway. COX-2-mediated up-regulation of Bcl-2 suggests a potential mechanism for reduced apoptotic susceptibility.
- Subjects :
- Anti-Inflammatory Agents, Non-Steroidal pharmacology
Apoptosis drug effects
Caspase Inhibitors
Caspases metabolism
Colonic Neoplasms genetics
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors pharmacology
Cytochrome c Group physiology
Dinoprostone biosynthesis
Enzyme Activation
Fluorouracil pharmacology
Humans
Isoenzymes antagonists & inhibitors
Isoenzymes biosynthesis
Isoenzymes genetics
Isoenzymes metabolism
Membrane Proteins
Mitochondria drug effects
Mitochondria physiology
Nitrobenzenes pharmacology
Nucleic Acid Synthesis Inhibitors pharmacology
Prostaglandin-Endoperoxide Synthases biosynthesis
Prostaglandin-Endoperoxide Synthases genetics
Proto-Oncogene Proteins c-bcl-2 biosynthesis
Proto-Oncogene Proteins c-bcl-2 genetics
RNA, Messenger biosynthesis
RNA, Messenger genetics
Sulfonamides pharmacology
Transfection
Tumor Cells, Cultured
Apoptosis physiology
Colonic Neoplasms enzymology
Colonic Neoplasms pathology
Cytochrome c Group antagonists & inhibitors
Isoenzymes physiology
Prostaglandin-Endoperoxide Synthases physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 62
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 12414664