title: α-Amanitin Restrains Cancer Relapse from Drug-Tolerant Cell Subpopulations via TAF15.
abstract: Cancer relapse occurs with substantial frequency even after treatment with curative intent. Here we studied drug-tolerant colonies (DTCs), which are subpopulations of cancer cells that survive in the presence of drugs. Proteomic characterization of DTCs identified stemness- and epithelial-dominant subpopulations, but functional screening suggested that DTC formation was regulated at the transcriptional level independent from protein expression patterns. We consistently found that α-amanitin, an RNA polymerase II (RNAPII) inhibitor, effectively inhibited DTCs by suppressing TAF15 expression, which binds to RNA to modulate transcription and RNA processing. Sequential administration of α-amanitin and cisplatin extended overall survival in a cancer-relapse mouse model, namely peritonitis carcinomatosa. Therefore, post-treatment cancer relapse may occur through non-distinct subpopulations and may be effectively prevented by α-amanitin to disrupt transcriptional machinery, including TAF15.
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.|MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.|Institute of Biomedical Science, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kume
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Miura
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ito
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Kei A
authors.initials: KA
authors.lastname: Sato
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.|MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Ohmori
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Endo
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Hirokatsu
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ishida
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Ito
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwaya
authors.affiliation: Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.|MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.|Institute of Biomedical Science, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
authors.forename: Satoshi S
authors.initials: SS
authors.lastname: Nishizuka
mesh_terms: D053959:Alpha-Amanitin / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D015536:Down-Regulation; D004351:Drug Resistance / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D055502:Secondary Prevention; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D053959:Alpha-Amanitin; D004791:Enzyme Inhibitors; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors; D002945:Cisplatin