Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 62; no. 17; pp. 4903 - 4908
• Main Authors: XIMING TANG, YUN JIE SUN, HALF, Elizabeth, KUO, M. Tien, SINICROPE, Frank
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2002
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins; Biological and medical sciences; Caspases - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Cyclooxygenase 2; Drug Resistance, Neoplasm; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Humans; Isoenzymes - biosynthesis; Isoenzymes - genetics; Isoenzymes - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - pharmacology; Membrane Proteins; Molecular and cellular biology; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - antagonists & inhibitors; Receptors, Tumor Necrosis Factor - biosynthesis; Receptors, Tumor Necrosis Factor - metabolism; TNF-Related Apoptosis-Inducing Ligand; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - pharmacology; Human; Prostaglandin-endoperoxide synthase; Enzyme; Isozyme; Gene overexpression; Malignant tumor; Gene expression; In vitro; Colonic disease; Resistance; Cell death; Death receptor; Established cell line; Digestive diseases; Intestinal disease; TNF related apoptosis inducing ligand; Oxidoreductases; Colon; Mechanism of action; Tumor cell; Apoptosis; Biological receptor
• ISSN: 0008-5472; 1538-7445

The inducible cyclooxygenase-2 (COX-2) gene regulates prostaglandin biosynthesis,is up-regulated in colorectal cancers, and can influence apoptotic susceptibility. We determined whether forced COX-2 expression modulates apoptosis induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of tumor necrosis factor ligand family, and examined determinants of the apoptotic pathway, including membrane death receptors (DR-4 and DR-5). HCT-15 colon cancer cells lacking endogenous COX-2 proteins were stably transfected with the COX-2 cDNA and incubated with TRAIL. Forced COX-2 expression significantly attenuated TRAIL-induced apoptosis and was associated with transcriptional repression of DR-5 and up-regulation of Bcl-2. COX-2 transfectants showed reduced DR-5 mRNA and protein expression as well as reduced caspase-8, caspase-3, and caspase-9 activation relative to parental cells. Sulindac sulfide treatment restored DR-5 expression and, when combined with TRAIL, reduced cell viability to a greater extent than did either drug alone. In summary, modulation of DR-5 and Bcl-2 levels by COX-2 attenuates TRAIL-induced apoptosis and represents a novel mechanism of intrinsic drug resistance in human colon cancer cells.