title: Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression.
abstract: Iron is an important biological catalyst and is critical for DNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding to RNA stem-loop structures known as iron-response elements. We also found thatIrp2mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(Δ19) tumors expressing the clock-mutant protein (CLOCK(Δ19)) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCK(Δ19)expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor.
authors.affiliation: From the Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, the Department of Pharmaceutics and.
authors.forename: Fumiyasu
authors.initials: F
authors.lastname: Okazaki
authors.affiliation: the Department of Pharmaceutics and.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: the Department of Molecular Biology and.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okazaki
authors.affiliation: the Department of Pharmaceutics and.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Azuma
authors.affiliation: the Department of Molecular Biology and.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hamamura
authors.affiliation: the Department of Pharmaceutics and.
authors.forename: Akito
authors.initials: A
authors.lastname: Tsuruta
authors.affiliation: the Department of Pharmaceutics and.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Tsurudome
authors.affiliation: the Department of Pharmaceutics and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogino
authors.affiliation: the Department of Pharmaceutics and.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Hara
authors.affiliation: the Formulation Research, Pharmaceutical Science & Technology Core Function Unit and.
authors.forename: Takuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: the Formulation Research, Pharmaceutical Science & Technology Core Function Unit and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hyodo
authors.affiliation: the Formulation Research, Pharmaceutical Science & Technology Core Function Unit and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishihara
authors.affiliation: Chief Innovation Officer Group, Eisai Product Creation Systems, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: From the Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194.
authors.forename: Hideto
authors.initials: H
authors.lastname: To
authors.affiliation: the Department of Molecular Biology and Drug Innovation Research Center, Daiichi University of Pharmacy, Fukuoka 815-8511, and.
authors.forename: Hironori
authors.initials: H
authors.lastname: Aramaki
authors.affiliation: the Department of Global Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: the Department of Pharmaceutics and ohdo@phar.kyushu-u.ac.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000172:deficiency / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000235:genetics*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D056930:ARNTL Transcription Factors; D056926:CLOCK Proteins; D027682:Cation Transport Proteins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D000099236:Solute Carrier Family 11, Member 2; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse; C480029:Tfrc protein, mouse; C538944:Clock protein, mouse
keywords: circadian; circadian rhythm; iron; iron metabolism; pharmacology