5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation

Yong-Hee Cho, Eun Ji Ro, Jeong-Su Yoon, Tomohiro Mizutani, Dong-Woo Kang, Jong-Chan Park, Tae Il Kim, Hans Clevers, Kang-Yell Choi

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.

Original languageEnglish
Pages (from-to)5321
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 21 Oct 2020

Keywords

  • Animals
  • Antineoplastic Agents/administration & dosage
  • Cell Line, Tumor
  • Colorectal Neoplasms/drug therapy
  • Fluorouracil/pharmacology
  • HCT116 Cells
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Mice, Transgenic
  • Neoplastic Stem Cells/drug effects
  • Organoids/drug effects
  • Pyrazines/administration & dosage
  • Pyridines/administration & dosage
  • Receptors, G-Protein-Coupled/genetics
  • Tumor Suppressor Protein p53/metabolism
  • Wnt Signaling Pathway/drug effects
  • Wnt3 Protein/genetics
  • Xenograft Model Antitumor Assays
  • beta Catenin/metabolism

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