Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae.

Abstract	Cyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane.
Authors	Sophie Martin, Darren C Phillips, Kinga Szekely-Szucs, Lynda Elghazi, Fabienne Desmots, Janet A Houghton
Journal	Cancer research (Cancer Res) Vol. 65 Issue 24 Pg. 11447-58 (Dec 15 2005) ISSN: 0008-5472 [Print] United States
PMID	16357153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins Ceramides Cyclooxygenase 2 Inhibitors FADD protein, human Fas-Associated Death Domain Protein Membrane Glycoproteins Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor TNF-Related Apoptosis-Inducing Ligand TNFRSF10B protein, human TNFSF10 protein, human Tumor Necrosis Factor-alpha Arachidonic Acid Cholesterol Cyclooxygenase 2 acid sphingomyelinase-1 Sphingomyelin Phosphodiesterase CASP8 protein, human Caspase 8 Caspases
Topics	Adaptor Proteins, Signal Transducing (metabolism) Apoptosis (drug effects) Apoptosis Regulatory Proteins (pharmacology) Arachidonic Acid (metabolism) Caspase 8 Caspases (metabolism) Caveolae (metabolism) Cell Membrane (metabolism) Ceramides (metabolism) Cholesterol (metabolism) Colonic Neoplasms (metabolism, pathology, therapy) Cyclooxygenase 2 (metabolism) Cyclooxygenase 2 Inhibitors (pharmacology) Drug Resistance, Neoplasm Fas-Associated Death Domain Protein Humans Membrane Glycoproteins (pharmacology) Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor (metabolism) Signal Transduction Sphingomyelin Phosphodiesterase (metabolism) TNF-Related Apoptosis-Inducing Ligand Tumor Cells, Cultured Tumor Necrosis Factor-alpha (pharmacology)

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