Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy

Stem Cell Reports. 2022 Apr 12;17(4):835-848. doi: 10.1016/j.stemcr.2022.02.005. Epub 2022 Mar 10.

Abstract

Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer.

Keywords: Niclosamide; PXR; cancer stem cell; colorectal cancer; high-content screen; miR-148a; tumor recurrence.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / genetics
  • Colonic Neoplasms* / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Neoplastic Stem Cells / metabolism
  • Niclosamide / metabolism
  • Niclosamide / pharmacology
  • Niclosamide / therapeutic use
  • Pregnane X Receptor / genetics
  • Pregnane X Receptor / metabolism

Substances

  • MicroRNAs
  • Pregnane X Receptor
  • Niclosamide