Bioenergetic and proteomic profiling to screen small molecule inhibitors that target cancer metabolisms

Yushi Futamura, Makoto Muroi, Harumi Aono, Makoto Kawatani, Marina Hayashida, Tomomi Sekine, Toshihiko Nogawa, Hiroyuki Osada*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Cancer cells can reprogram their metabolic machinery to survive. This altered metabolism, which is distinct from the metabolism of normal cells, is thought to be a possible target for the development of new cancer therapies. In this study, we constructed a screening system that focuses on bioenergetic profiles (specifically oxygen consumption rate and extracellular acidification rate) and characteristic proteomic changes. Thus, small molecules that target cancer-specific metabolism were investigated. We screened the chemical library of RIKEN Natural Products Depository (NPDepo) and found that unantimycin A, which was recently isolated from the fraction library of microbial metabolites, and NPL40330, which is derived from a chemical library, inhibit mitochondrial respiration. Furthermore, we developed an in vitro reconstitution assay method for mitochondrial electron transport chain using semi-intact cells with specific substrates for each complex of the mitochondrial electron transport chain. Our findings revealed that NPL40330 and unantimycin A target mitochondrial complexes I and III, respectively.

Original languageEnglish
Pages (from-to)28-37
Number of pages10
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1867
Issue number1
DOIs
Publication statusPublished - 2019 Jan
Externally publishedYes

Keywords

  • Cancer metabolism
  • NPL40330
  • Phenotypic screening
  • Proteomic profilin
  • Respiration inhibition
  • Unantimycin A

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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