Metarhizin A suppresses cell proliferation by inhibiting cytochrome c oxidase activity
| Autor: | Jiang Yu, Naoya Endo, Yoshiteru Oshima, Yasuhiro Katou, Yoshimi Homma, Haruhisa Kikuchi, Toshiyuki Suzuki |
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| Rok vydání: | 2014 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Metarhizium Cell signaling Programmed cell death Cell Mitochondria Liver Mitochondrion General Biochemistry Genetics and Molecular Biology S Phase Electron Transport Complex IV Lactones Mice Oxygen Consumption medicine Animals Humans Cytochrome c oxidase RNA Messenger Enzyme Inhibitors General Pharmacology Toxicology and Pharmaceutics Cell Proliferation chemistry.chemical_classification Reactive oxygen species biology Cell growth G1 Phase General Medicine Cell cycle Cell biology Enzyme Activation medicine.anatomical_structure chemistry MCF-7 Cells biology.protein Diterpenes Mitogen-Activated Protein Kinases Reactive Oxygen Species |
| Zdroj: | Life Sciences. 103:1-7 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2014.03.023 |
| Popis: | Aims Metarhizin A was originally isolated from Metarhizium flavoviride as a potent inhibitor of the growth of insect and mammalian cells. In this study, we aimed to understand the molecular targets of metarhizin A involved in its anti-proliferative activity against human cells. Main methods Cell cycle regulators and signaling molecules were examined by immunoblotting using specific antibodies. A mitochondria-enriched fraction was prepared from mouse liver, and mitochondrial activity was monitored using an oxygen electrode. Enzyme activity was measured using purified cytochrome c oxidase and permeabilized cells. Key findings Metarhizin A inhibits the growth of MCF-7 cells with an IC 50 value of ~ 0.2 μM and other cells in a similar manner; a cell cycle-dependent kinase inhibitor, p21, is selectively induced. Significant amounts of reactive oxygen species (ROS) are generated and ERK1/2 is activated in cells treated with metarhizin A. Metarhizin A completely suppresses oxygen consumption by mitochondria, and potently inhibits the activity of cytochrome c oxidase. It induces cell death when MCF-7 cells are cultured under limiting conditions. Significance Metarhizin A is a potent inhibitor of cytochrome c oxidase and activates the MAPK pathway through the generation of ROS, which induces growth arrest of cells, and, under some conditions, enhances cell death. The cytochrome c oxidase system is a possible molecular target of metarhizin A. |
| Databáze: | OpenAIRE |
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