α-Amanitin Restrains Cancer Relapse from Drug-Tolerant Cell Subpopulations via TAF15

  • Sci Rep. 2016 May 16;6:25895. doi: 10.1038/srep25895.
Kohei Kume  1  2  3 ,  Miyuki Ikeda  1 ,  Sawako Miura  1 ,  Kohei Ito  1 ,  Kei A Sato  1 ,  Yukimi Ohmori  1  2 ,  Fumitaka Endo  1 ,  Hirokatsu Katagiri  1 ,  Kaoru Ishida  1 ,  Chie Ito  1 ,  Takeshi Iwaya  1 ,  Satoshi S Nishizuka  1  2  3
Affiliations
  • 1. Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
  • 2. MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.
  • 3. Institute of Biomedical Science, Iwate Medical University, Yahaba, Iwate 028-3694, Japan.
PMID: 27181033 DOI: 10.1038/srep25895
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.

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