Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

Wang, Hongwei; Venkatesh, Madhukumar; Li, Hao; Goetz, Regina; Mukherjee, Subhajit; Biswas, Arunima; Zhu, Liang; Kaubisch, Andreas; Wang, Lei; Pullman, James; Whitney, Kathleen D.; Kuro-o, Makoto; Roig, Andres I.; Shay, Jerry W.; Mohammadi, Moosa; Mani, Sridhar

doi:10.1172/jci41514

Cited by 132 publications

(128 citation statements)

References 66 publications

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“…Activation of PXR upregulated the antiapoptotic signaling molecules BAG3, BIRC2, and MCL-1, and downregulated the proapoptotic factors BAK1 and p53 (Zhou et al, 2008;Habano et al, 2011). Others showed that activation of PXR induced tumor aggressiveness in mice and humans in a fibroblast growth factor 19-dependent manner (Wang et al, 2011). Based on these studies, the role of PXR in colon cancer remains unclear, thus the need for further investigation.…”

Section: Discussionmentioning

confidence: 99%

Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer

Cheng

Fang

Nagaoka

et al. 2014

J Pharmacol Exp Ther

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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.

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Section: Discussionmentioning

confidence: 99%

Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer

Cheng

Fang

Nagaoka

et al. 2014

J Pharmacol Exp Ther

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“…It also interacts with transcription factors such as the small heterodimer partner, pregnane X receptor (PXR), hepatocyte nuclear factor 4a, and peroxisome proliferatoractivated receptor, which disturb the expression of their target genes thereafter (Prieur et al, 2005;Kim et al, 2008;Krausova et al, 2011;Sozio et al, 2011). In particular, the antagonistic effects of metformin on PXR may partly contribute to its speculated anticancer activity (Krausova et al, 2011;Wang et al, 2011b).…”

Section: Introductionmentioning

confidence: 99%

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

et al. 2013

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Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein kinases in addition to the traditional ligand binding. We show that metformin could suppress drug-induced expression of CYP2B6 (a typical target gene of CAR) by modulating the phosphorylation status of CAR. In human hepatocytes, metformin robustly suppressed the expression of CYP2B6 induced by both indirect (phenobarbital) and direct CITCO [6-(4-chlorophenyl)imidazo[2,1-b]1,3thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] activators of human CAR. Mechanistic investigation revealed that metformin specifically enhanced the phosphorylation of threonine-38 of CAR, which blocks CAR nuclear translocation and activation. Moreover, we showed that phosphorylation of CAR by metformin was primarily an AMP-activated protein kinase-and extracellular signal-regulated kinase 1/2-dependent event. Additional two-hybrid and coimmunoprecipitation assays demonstrated that metformin could also disrupt CITCO-mediated interaction between CAR and the steroid receptor coactivator 1 or the glucocorticoid receptorinteracting protein 1. Our results suggest that metformin is a potent repressor of drug-induced CYP2B6 expression through specific inhibition of human CAR activation. Thus, metformin may affect the metabolism and clearance of drugs that are CYP2B6 substrates.

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“…PXR has been reported to specifically activate the fibroblast growth factor 19 signal only in colon tumor cells, but not in normal intestinal cells, thereby enhancing their neoplastic characteristics (Wang et al, 2011). Our recent study has demonstrated that PXR immediately elicits the p38 MAPK signaling pathways after ligand treatment to stimulate morphological changes and migration in well differentiated HepG2 cells.…”

Section: Discussionmentioning

confidence: 81%

Pregnane X Receptor RepressesHNF4αGene to Induce Insulin-Like Growth Factor–Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells

2015

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Upon treatment with the pregnane X receptor (PXR) activator rifampicin (RIF), human hepatocellular carcinoma HepG2-derived ShP51 cells that stably express PXR showed epithelialmesenchymal transition (EMT)-like morphological changes and migration. Our recent DNA microarrays have identified hepatocyte nuclear factor (HNF) 4a and insulin-like growth factorbinding protein (IGFBP) 1 mRNAs to be downregulated and upregulated, respectively, in RIF-treated ShP51 cells, and these regulations were confirmed by the subsequent real-time polymerase chain reaction and Western blot analyses. Using this cell system, we demonstrated here that the PXR-HNF4a-IGFBP1 pathway is an essential signal for PXR-induced morphological changes and migration. First, we characterized the molecular mechanism underlying the PXR-mediated repression of the HNF4a gene. Chromatin conformation capture and chromatin immunoprecipitation (ChIP) assays revealed that PXR activation by RIF disrupted enhancer-promoter communication and prompted deacetylation of histone H3 in the HNF4a P1 promoter. Cell-based reporter and ChIP assays showed that PXR targeted the distal enhancer of the HNF4a P1 promoter and stimulated dissociation of HNF3b from the distal enhancer. Subsequently, small interfering RNA knockdown of HNF4a connected PXR-mediated gene regulation with the PXRinduced cellular responses, showing that the knockdown resulted in the upregulation of IGFBP1 and EMT-like morphological changes without RIF treatment. Moreover, recombinant IGFBP1 augmented migration, whereas an anti-IGFBP1 antibody attenuated both PXR-induced morphological changes and migration in ShP51 cells. PXR indirectly activated the IGFBP1 gene by repressing the HNF4a gene, thus enabling upregulation of IGFBP1 to change the morphology of ShP51 cells and cause migration. These results provide new insights into PXR-mediated cellular responses toward xenobiotics including therapeutics.

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Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

Cited by 132 publications

References 66 publications

Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer

Activation of Intestinal Human Pregnane X Receptor Protects against Azoxymethane/Dextran Sulfate Sodium–Induced Colon Cancer

Metformin Represses Drug-Induced Expression of CYP2B6 by Modulating the Constitutive Androstane Receptor Signaling

Pregnane X Receptor RepressesHNF4αGene to Induce Insulin-Like Growth Factor–Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells

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