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

被引：17

作者：

Futamura, Yushi ^{[1
]}

Muroi, Makoto ^{[1
]}

Aono, Harumi ^{[1
]}

Kawatani, Makoto ^{[1
]}

Hayashida, Marina ^{[1
,2
]}

Sekine, Tomomi ^{[1
]}

Nogawa, Toshihiko ^{[1
]}

Osada, Hiroyuki ^{[1
,2
]}

机构：

[1] RIKEN Ctr Sustainable Resource Sci, Chem Biol Res Grp, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

[2] Saitama Univ, Grad Sch Sci & Engn, Sakura Ku, Shimo Okubo 255, Saitama 3388570, Japan

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS | 2019年 / 1867卷 / 01期

关键词：

Proteomic profilin; Unantimycin A; NPL40330; Cancer metabolism; Phenotypic screening; Respiration inhibition; IDENTIFICATION; MECHANISM; HYPOXIA; CELLS; PYRROLIZILACTONE; GLUTAMINASE; EXPRESSION; BIOLOGY;

D O I：

10.1016/j.bbapap.2018.06.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：28 / 37

页数：10

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