TY - JOUR
T1 - Proteomic profiling reveals that collismycin A is an iron chelator
AU - Kawatani, Makoto
AU - Muroi, Makoto
AU - Wada, Akira
AU - Inoue, Gyo
AU - Futamura, Yushi
AU - Aono, Harumi
AU - Shimizu, Kenshirou
AU - Shimizu, Takeshi
AU - Igarashi, Yasuhiro
AU - Takahashi-Ando, Naoko
AU - Osada, Hiroyuki
N1 - Funding Information:
This work was supported by the JSPS KAKENHI Grant Number 25350981 (to M.K.), the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry, and the Project for Cancer Research And Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development, AMED.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/12/6
Y1 - 2016/12/6
N2 - Collismycin A (CMA), a microbial product, has anti-proliferative activity against cancer cells, but the mechanism of its action remains unknown. Here, we report the identification of the molecular target of CMA by ChemProteoBase, a proteome-based approach for drug target identification. ChemProteoBase profiling showed that CMA is closely clustered with di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, an iron chelator. CMA bound to both Fe(II) and Fe(III) ions and formed a 2:1 chelator-iron complex with a redox-inactive center. CMA-induced cell growth inhibition was completely canceled by Fe(II) and Fe(III) ions, but not by other metal ions such as Zn(II) or Cu(II). Proteomic and transcriptomic analyses showed that CMA affects the glycolytic pathway due to the accumulation of HIF-1α. These results suggest that CMA acts as a specific iron chelator, leading to the inhibition of cancer cell growth.
AB - Collismycin A (CMA), a microbial product, has anti-proliferative activity against cancer cells, but the mechanism of its action remains unknown. Here, we report the identification of the molecular target of CMA by ChemProteoBase, a proteome-based approach for drug target identification. ChemProteoBase profiling showed that CMA is closely clustered with di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, an iron chelator. CMA bound to both Fe(II) and Fe(III) ions and formed a 2:1 chelator-iron complex with a redox-inactive center. CMA-induced cell growth inhibition was completely canceled by Fe(II) and Fe(III) ions, but not by other metal ions such as Zn(II) or Cu(II). Proteomic and transcriptomic analyses showed that CMA affects the glycolytic pathway due to the accumulation of HIF-1α. These results suggest that CMA acts as a specific iron chelator, leading to the inhibition of cancer cell growth.
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U2 - 10.1038/srep38385
DO - 10.1038/srep38385
M3 - Article
C2 - 27922079
AN - SCOPUS:85002194669
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 38385
ER -