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

10 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
Externally publishedYes

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rifaximin
Azoxymethane
Dextran Sulfate
Colonic Neoplasms
Apoptosis
Therapeutics
Chemoprevention
pregnane X receptor
Cell Cycle
Colon
B-Lymphocytes
Cell Proliferation
Inflammation
Light

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Activation of intestinal human pregnane X receptor protects against azoxymethane/dextran sulfate sodium-induced colon cancer. / Cheng, Jie; Fang, Zhong Ze; Nagaoka, Kenjiro; Okamoto, Minoru; Qu, Aijuan; Tanaka, Naoki; Kimura, Shioko; Gonzalez, Frank J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 351, No. 3, 01.12.2014, p. 559-567.

Research output: Contribution to journalArticle

Cheng, Jie ; Fang, Zhong Ze ; Nagaoka, Kenjiro ; Okamoto, Minoru ; Qu, Aijuan ; Tanaka, Naoki ; Kimura, Shioko ; Gonzalez, Frank J. / Activation of intestinal human pregnane X receptor protects against azoxymethane/dextran sulfate sodium-induced colon cancer. In: Journal of Pharmacology and Experimental Therapeutics. 2014 ; Vol. 351, No. 3. pp. 559-567.
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