Prostaglandin A2 activates intrinsic apoptotic pathway by direct interaction with mitochondria in HL-60 cells |
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| Authors: | Sun-Young Lee Ji-Hyun Ahn Kyoung Won Ko Jaetaek Kim Seong Whan Jeong In-Kyung Kim Jin Kim Ho-Shik Kim |
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| Institution: | 1. Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea;2. Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 156-755, Republic of Korea;3. Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea;1. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, United States;2. Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States;3. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States;1. Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States;2. Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States;3. The Bert W. Strassburger Lipid Center, Tel Aviv University, 52621 Hashomer Tel, Israel;4. Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, 52621 Hashomer Tel, Israel;5. Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, United States;1. Laboratory of Veterinary Physiology, Kitasato University School of Veterinary Medicine, Towada, Aomori 034-8628, Japan;2. Department of Nutrition, Koshien University, Takarazuka, Hyogo 665-0006, Japan;1. Department of Pharmaceutical Health Chemistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Shomachi, Tokushima 770-8505, Japan;2. Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Shomachi, Tokushima 770-8505, Japan;3. Faculty of Pharmacy, Yasuda Women’s University, Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan;4. Department of Obstetrics and Gynecology, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramotocho, Tokushima 770-8503, Japan;1. Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China;2. Department of Thoracic Surgery, First Hospital of Jilin University, Changchun 130021, China;3. Department of Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China;4. Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, China |
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| Abstract: | HL-60 cells treated by prostaglandin (PG) A2 showed characteristics of apoptosis such as accumulation of hypodiploid and annexin V positive cells, condensed and fragmented nuclei, cytochrome c (Cyt C) release from mitochondria and activation of caspase-1, -2, -3, -7 and -9. PGA2-induced cell death was rescued by inhibitors of caspase-9 and -3, but PGA2-induced Cyt C release was not prevented by caspase inhibitors. During Cyt C release by PGA2, mitochondrial transmembrane potential was maintained and mitochondrial permeability transition pore was not formed. In addition, anti-apoptotic BCL-2 family proteins like BCL-2 and BCL-XL, and ROS scavengers including ascorbic acid and 2,2,6,6-tetramethyl-1-piperidinyloxy were not able to inhibit Cyt C release as well as apoptosis by PGA2. Finally, it was shown that PGA2-induced Cyt C release in vitro from purified mitochondria in the absence of cytosolic components. Furthermore, thiol-containing compounds such as N-acetylcysteine, l-cysteine and monothioglycerol prevented Cyt C release, and hence induction of apoptosis. Taken together, these results suggest that PGA2 activates intrinsic apoptotic pathway by directly stimulating mitochondrial outer membrane permeabilization to release Cyt C, in which thiol-reactivity of PGA2 plays a pivotal role. |
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