?-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 ?-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 ?-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 ?-amanitin to disrupt transcriptional machinery, including TAF15.

SUBMITTER: Kume K 

PROVIDER: S-EPMC4867652 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature