title: Proteomic profiling reveals that collismycin A is an iron chelator.
abstract: 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.
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Muroi
authors.affiliation: Nonnatural Amino Acid Technology Team, RIKEN CLST, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Wada
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Engineering, Toyo University, 2100 Kujirai, Kawagoe, Saitama 350-0815, Japan.
authors.forename: Gyo
authors.initials: G
authors.lastname: Inoue
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Futamura
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Aono
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.|Department of Materials Science and Engineering, Graduate School of Engineering, Tokyo Denki University, 5 Senju Asahi-cho, Adachi-ku, Tokyo 120-8551, Japan.
authors.forename: Kenshirou
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Biotechnology Research Center and Department of Biotechnology, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Engineering, Toyo University, 2100 Kujirai, Kawagoe, Saitama 350-0815, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takahashi-Ando
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism; D062126:Databases, Chemical; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D013302:Streptomyces / Q000737:chemistry; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D013882:Thiosemicarbazones; C089907:collismycin A; D015082:2,2'-Dipyridyl; D007501:Iron