Metarhizin A suppresses cell proliferation by inhibiting cytochrome c oxidase activity

Yasuhiro Katou, Naoya Endo, Toshiyuki Suzuki, Jiang Yu, Haruhisa Kikuchi, Yoshiteru Oshima, Yoshimi Homma

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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 IC50 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.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalLife Sciences
Volume103
Issue number1
DOIs
Publication statusPublished - 2014 May 8
Externally publishedYes

Keywords

  • Entomopathogenic fungi
  • Mitochondria
  • ROS
  • Toxin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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