title: The 1,2-Diaminocyclohexane Carrier Ligand in Oxaliplatin Induces p53-Dependent Transcriptional Repression of Factors Involved in Thymidylate Biosynthesis.
abstract: Platinum-based chemotherapeutic drugs are widely used as components of combination chemotherapy in the treatment of cancer. One such drug, oxaliplatin, exerts a synergistic effect against advanced colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin. In the p53-proficient colorectal cancer cell line HCT116, oxaliplatin represses the expression of deoxyuridine triphosphatase (dUTPase), a ubiquitous pyrophosphatase that catalyzes the hydrolysis of dUTP to dUMP and inhibits dUTP-mediated cytotoxicity. However, the underlying mechanism of this activity has not been completely elucidated, and it remains unclear whether factors other than downregulation of dUTPase contribute to the synergistic effect of 5-FU and oxaliplatin. In this study, we found that oxaliplatin and dachplatin, platinum-based drugs containing the 1,2-diaminocyclohexane (DACH) carrier ligand, repressed the expression of nuclear isoform of dUTPase (DUT-N), whereas cisplatin and carboplatin did not. Oxaliplatin induced early p53 accumulation, upregulation of primary miR-34a transcript expression, and subsequent downregulation of E2F3 and E2F1. Nutlin-3a, which activates p53 nongenotoxically, had similar effects. Introduction of miR-34a mimic also repressed E2F1 and DUT-N expression, indicating that this miRNA plays a causative role. In addition to DUT-N, oxaliplatin repressed, in a p53-dependent manner, the expression of genes encoding enzymes involved in thymidylate biosynthesis. Consequently, oxaliplatin significantly decreased the level of dTTP in the dNTP pool in a p53-dependent manner. These data indicate that the DACH carrier ligand in oxaliplatin triggers signaling via the p53-miR-34a-E2F axis, leading to transcriptional regulation that ultimately results in accumulation of dUTP and reduced dTTP biosynthesis, potentially enhancing 5-FU cytotoxicity.
authors.affiliation: Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan. Department of Biochemistry, Nagoya University Graduate School of Medicine, Aichi, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kiyonari
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Iimori
authors.affiliation: Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan. Taiho Pharmaceutical Co. Ltd., Tokushima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Matsuoka
authors.affiliation: Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Sugiko
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Metabolic Profiling Research Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Morikawa-Ichinose
authors.affiliation: Metabolic Profiling Research Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miura
authors.affiliation: Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan. Taiho Pharmaceutical Co. Ltd., Tokushima, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Niimi
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saeki
authors.affiliation: Department of Comprehensive Clinical Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Tokunaga
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Aichi, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.affiliation: Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.affiliation: Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Kyushu, Japan. Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan. hkitao@surg2.med.kyushu-u.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitao
mesh_terms: D053898:Biosynthetic Pathways; D004261:DNA Replication; D015536:Down-Regulation; D004357:Drug Synergism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D000077150:Oxaliplatin; D010879:Piperazines / Q000494:pharmacology; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D007093:Imidazoles; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D010879:Piperazines; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D013938:Thymidine Monophosphate; C482205:nutlin 3; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D005472:Fluorouracil