Metarhizin A suppresses cell proliferation by inhibiting cytochrome c oxidase activity

• Published in: Life sciences (1973) Vol. 103; no. 1; pp. 1 - 7
• Main Authors: Katou, Yasuhiro, Endo, Naoya, Suzuki, Toshiyuki, Yu, Jiang, Kikuchi, Haruhisa, Oshima, Yoshiteru, Homma, Yoshimi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 08-05-2014
• Subjects: Animals; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Diterpenes - pharmacology; Electron Transport Complex IV - antagonists & inhibitors; Entomopathogenic fungi; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; G1 Phase - drug effects; Humans; Lactones - pharmacology; MCF-7 Cells; Metarhizium - chemistry; Mice; Mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitogen-Activated Protein Kinases - metabolism; Oxygen Consumption - drug effects; Reactive Oxygen Species - metabolism; RNA, Messenger - analysis; ROS; S Phase; Toxin; Toxin; Mitochondria; Entomopathogenic fungi; ROS
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2014.03.023

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.
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.
Metarhizin A inhibits the growth of MCF-7 cells with an IC50 value of ~0.2μM 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.
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.