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  • br Malecka Massalska T Smolen A Zubrzycki

    2020-08-07


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    Contents lists available at ScienceDirect
    BBA - Proteins and Proteomics
    journal homepage: www.elsevier.com/locate/bbapap
    Bioenergetic and proteomic profiling to screen small molecule inhibitors T that target cancer metabolisms
    Yushi Futamuraa,1, Makoto Muroia,1, Harumi Aonoa, Makoto Kawatania, Marina Hayashidaa,b, Tomomi Sekinea, Toshihiko Nogawaa, Hiroyuki Osadaa,b,
    a Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
    b Graduate School of Science and Engineering, Saitama University, Shimo-Okubo 255, Sakura-ku, Saitama 338-8570, Japan
    Keywords: Proteomic profilin
    Unantimycin A
    Cancer metabolism
    Phenotypic screening
    Respiration inhibition 
    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 con-sumption 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.