title: Mitochondrial localization of cyclooxygenase-2 and calcium-independent phospholipase A2 in human cancer cells: implication in apoptosis resistance.
abstract: Cyclooxygenase-2 (COX-2) is inducible by myriad stimuli. The inducible COX-2 in primary cultured human cells has been reported to localize to nuclear envelope, endoplasmic reticulum, nucleus and caveolae. As COX-2 plays an important role in tumor growth, we were interested in its subcellular location in cancer cells. We examined COX-2 localization in several cancer cell lines by confocal microscopy. A majority of COX-2 was colocalized with heat shock protein 60, a mitochondrial protein, in colon cancer (HT-29, HCT-15 and DLD-1), breast cancer (MCF7), hepatocellular cancer (HepG2) and lung cancer cells (A549) with a similar distribution pattern. By contrast, COX-2 was not localized to mitochondria in human foreskin fibroblasts or endothelial cells. Immunoblot analysis of COX-2 in mitochondrial and cytosolic fractions confirmed localization of COX-2 to mitochondria in HT-29 and DLD-1 cells but not in fibroblasts. Calcium-independent phospholipase A2 was colocalized with heat shock protein 60 to mitochondria not only in cancer cells (HT-29 and DLD-1) but also in fibroblasts. HT-29 which expressed more abundant mitochondrial COX-2 than DLD-1 was highly resistant to arachidonic acid and H2O2-induced apoptosis whereas DLD-1 was less resistant and human fibroblasts were highly susceptible. Treatment of HT-29 cells with sulindac or SC-236, a selective COX-2 inhibitor, resulted in loss of resistance to apoptosis. These results suggest that mitochondrial COX-2 in cancer cells confer resistance to apoptosis by reducing the proapoptotic arachidonic acid.
authors.affiliation: Vascular Biology Research Center and Division of Hematology, Institute of, Molecular Medicine and Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030-1503, USA.
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
authors.forename: Nena
authors.initials: N
authors.lastname: Aleksic
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Chen
authors.forename: Tsai-Jung
authors.initials: TJ
authors.lastname: Han
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016718:Arachidonic Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000032:analysis / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D054522:Group VI Phospholipases A2; D019073:HT29 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D010741:Phospholipases A / Q000032:analysis / Q000378:metabolism*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D016718:Arachidonic Acid; D018834:Chaperonin 60; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D045304:Cytochromes c; D054522:Group VI Phospholipases A2; D006861:Hydrogen Peroxide; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010741:Phospholipases A; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D013467:Sulindac; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human; C516475:PLA2G6 protein, human