RRC ID 63531
Author Kume K, Ikeda M, Miura S, Ito K, Sato KA, Ohmori Y, Endo F, Katagiri H, Ishida K, Ito C, Iwaya T, Nishizuka SS.
Title α-Amanitin Restrains Cancer Relapse from Drug-Tolerant Cell Subpopulations via TAF15.
Journal Sci Rep
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.
Volume 6
Pages 25895
Published 2016-5-16
DOI 10.1038/srep25895
PII srep25895
PMID 27181033
PMC PMC4867652
MeSH Alpha-Amanitin / administration & dosage* Alpha-Amanitin / pharmacology Animals Cell Line, Tumor Cisplatin / administration & dosage Cisplatin / therapeutic use Down-Regulation Drug Resistance / drug effects* Enzyme Inhibitors / administration & dosage* Enzyme Inhibitors / pharmacology Gene Expression Regulation, Neoplastic / drug effects HCT116 Cells HT29 Cells HeLa Cells Humans MCF-7 Cells Mice Peritoneal Neoplasms / drug therapy* Peritoneal Neoplasms / genetics Peritoneal Neoplasms / metabolism Proteomics / methods Secondary Prevention TATA-Binding Protein Associated Factors / metabolism* Transcription, Genetic / drug effects Xenograft Model Antitumor Assays
IF 3.998
Human and Animal Cells HCT116(RCB2979) HeLa MCF7(RCB1904) MKN45(RCB1001)