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: Jun-Yang Liou, Nena Aleksic, Shu-Fen Chen, Tsai-Jung Han, Song-Kun Shyue, Kenneth K Wu
• Journal: Experimental cell research (Exp Cell Res) Vol. 306 Issue 1 Pg. 75-84 (May 15 2005) ISSN: 0014-4827 [Print] United States
• PMID: 15878334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
• Chaperonin 60
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Membrane Proteins
• Mitochondrial Proteins
• Proto-Oncogene Proteins c-bcl-2
• Pyrazoles
• Sulfonamides
• Sulindac
• Arachidonic Acid
• Cytochromes c
• Hydrogen Peroxide
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Phospholipases A
• Group VI Phospholipases A2
• PLA2G6 protein, human
• Phospholipases A2

Topics

• Apoptosis (drug effects, physiology)
• Arachidonic Acid (pharmacology)
• Cell Line, Tumor
• Cells, Cultured
• Chaperonin 60 (analysis, metabolism)
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• Cytochromes c (metabolism)
• Female
• Fibroblasts (chemistry, drug effects, metabolism)
• Flow Cytometry
• Group VI Phospholipases A2
• HT29 Cells
• Humans
• Hydrogen Peroxide (pharmacology)
• Male
• Membrane Proteins
• Microscopy, Confocal
• Mitochondria (chemistry, metabolism)
• Mitochondrial Proteins (metabolism)
• Phospholipases A (analysis, metabolism)
• Phospholipases A2
• Prostaglandin-Endoperoxide Synthases (analysis, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)
• Sulindac (pharmacology)