TY - JOUR
T1 - Bioenergetic and proteomic profiling to screen small molecule inhibitors that target cancer metabolisms
AU - Futamura, Yushi
AU - Muroi, Makoto
AU - Aono, Harumi
AU - Kawatani, Makoto
AU - Hayashida, Marina
AU - Sekine, Tomomi
AU - Nogawa, Toshihiko
AU - Osada, Hiroyuki
N1 - Funding Information:
We thank Ms. H. Kondo, Ms. K. Noda, Ms. Y. Nakata, Ms. Y. Hirata, and Ms. M. Tanaka for conducting the proteome analysis; Dr. T. Suzuki and Dr. N Dohmae for their help with the protein identification study; Ms. A. Okano and Dr. C. L. Lim for isolating the natural products; Mr. H. Hirano, Mr. Y. Iwai, and Ms. A. Yoshioka for providing the chemical library and hit compounds; and Dr. J. Otaka and Mr. K. Yamamoto for performing the biological activity tests. This work was supported in part by JSPS KAKENHI Grant Numbers JP17H06412 , JP18H03945 , JP17K07783 , JP17K01970 , JP16K01941 , JP17K07784 , and a Grant-in-Aid for the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Cancer metabolism
KW - NPL40330
KW - Phenotypic screening
KW - Proteomic profilin
KW - Respiration inhibition
KW - Unantimycin A
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U2 - 10.1016/j.bbapap.2018.06.001
DO - 10.1016/j.bbapap.2018.06.001
M3 - Article
C2 - 29883687
AN - SCOPUS:85048198509
SN - 1570-9639
VL - 1867
SP - 28
EP - 37
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
IS - 1
ER -