Activation of intestinal human pregnane X receptor protects against azoxymethane/dextran sulfate sodium-induced colon cancer

Jie Cheng, Zhong Ze Fang, Kenjiro Nagaoka, Minoru Okamoto, Aijuan Qu, Naoki Tanaka, Shioko Kimura, Frank J. Gonzalez

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The role of intestinal human pregnane X receptor (PXR) in colon cancer was determined through investigation of the chemopreventive role of rifaximin, a specific agonist of intestinal human PXR, toward azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer. Rifaximin treatment significantly decreased the number of colon tumors induced by AOM/DSS treatment in PXR-humanized mice, but not wild-type or Pxr-null mice. Additionally, rifaximin treatment markedly increased the survival rate of PXR-humanized mice, but not wild-type or Pxr-null mice. These data indicated a human PXR-dependent therapeutic chemoprevention of rifaximin toward AOM/DSS-induced colon cancer. Nuclear factor k-light-chain-enhancer of activated B cells -mediated inflammatory signaling was upregulated in AOM/DSS-treated mice, and inhibited by rifaximin in PXRhumanized mice. Cell proliferation and apoptosis were also modulated by rifaximin treatment in the AOM/DSS model. In vitro cell-based assays further revealed that rifaximin regulated cell apoptosis and cell cycle in a human PXR-dependent manner. These results suggested that specific activation of intestinal human PXR exhibited a chemopreventive role toward AOM/DSS-induced colon cancer by mediating anti-inflammation, antiproliferation, and proapoptotic events.

Original languageEnglish
Pages (from-to)559-567
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume351
Issue number3
DOIs
Publication statusPublished - Dec 1 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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