Role of Nuclear Receptors PXR and CAR in Xenobiotic-Induced Hepatocyte Proliferation and Chemical Carcinogenesis

Yoshinari, Kouichi

doi:10.1248/bpb.b19-00267

Cited by 31 publications

(29 citation statements)

References 73 publications

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“…PXR is associated with the regulation of hepatic energy metabolism through crosstalk with insulin response transcription factors, such as forkhead box protein O1 (FOXO1), cAMP response element-binding protein (CREB), and serine/threonine-protein kinase 2 (SGK2) [ 2 , 3 , 4 ]. PXR has been also reported to regulate the sensitivity of hepatocytes to proliferating signals by interacting with FOXO3 and yes-associated protein (YAP) [ 5 , 6 , 7 , 8 , 9 ]. Additionally, PXR is reported to regulate inflammatory signals.…”

Section: Introductionmentioning

confidence: 99%

PXR Functionally Interacts with NF-κB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice

Okamura

Shizu

Abe

et al. 2020

Cells

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Pregnane X receptor (PXR) is a liver-enriched xenobiotic-responsive transcription factor. Although recent studies suggest that PXR shows anti-inflammatory effects by suppressing nuclear factor kappa B (NF-κB), the detailed mechanism remains unclear. In this study, we aimed to elucidate this mechanism. Mice were treated intraperitoneally with the PXR agonist pregnenolone 16α-carbonitrile (PCN) and/or carbon tetrachloride (CCl4). Liver injury was evaluated, and hepatic mRNA levels were determined via quantitative reverse transcription polymerase chain reaction. Reporter assays with wild-type and mutated mouse Cxcl2 promoter-containing reporter plasmids were conducted in 293T cells. Results showed that the hepatic expression of inflammation-related genes was upregulated in CCl4-treated mice, and PCN treatment repressed the induced expression of chemokine-encoding Ccl2 and Cxcl2 among the genes investigated. Consistently, PCN treatment suppressed the increased plasma transaminase activity and neutrophil infiltration in the liver. In reporter assays, tumor necrosis factor-α-induced Cxcl2 expression was suppressed by PXR. Although an NF-κB inhibitor or the mutation of an NF-κB-binding motif partly reduced PXR-dependent suppression, the mutation of both NF-κB and activator protein 1 (AP-1) sites abolished it. Consistently, AP-1-dependent gene transcription was suppressed by PXR with a construct containing AP-1 binding motifs. In conclusion, the present results suggest that PXR exerts anti-inflammatory effects by suppressing both NF-κB- and AP-1-dependent chemokine expression in mouse liver.

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Section: Introductionmentioning

confidence: 99%

PXR Functionally Interacts with NF-κB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice

Okamura

Shizu

Abe

et al. 2020

Cells

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“…This is particularly true for pharmaceuticals and anticancer drugs such as paclitaxel, flutamide or tamoxifen, which can activate hPXR and hCAR [3][4][5]. Chemoresistance to these agents is often associated with activation of hPXR and hCAR and the expression of their target genes in various cancer cell types such as ovary, prostate, liver, intestinal and colon [6][7][8][9][10][11][12][13]. Other compounds that are routinely co-administrated with anticancer agents such as corticosteroids, anticoagulants, analgesics, antibiotics, antiemetics, anticonvulsants or antiepileptics were also shown to activate hPXR and hCAR [4,14].…”

Section: Introductionmentioning

confidence: 99%

The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor

Creusot

Gassiot

Alaterre

et al. 2020

Cells

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The human pregnane X receptor (hPXR) is activated by a large set of endogenous and exogenous compounds and plays a critical role in the control of detoxifying enzymes and transporters regulating liver and gastrointestinal drug metabolism and clearance. hPXR is also involved in both the development of multidrug resistance and enhanced cancer cells aggressiveness. Moreover, its unintentional activation by pharmaceutical drugs can mediate drug–drug interactions and cause severe adverse events. In that context, the potential of the anticancer BRAF inhibitor dabrafenib suspected to activate hPXR and the human constitutive androstane receptor (hCAR) has not been thoroughly investigated yet. Using different reporter cellular assays, we demonstrate that dabrafenib can activate hPXR as efficiently as its reference agonist SR12813, whereas it does not activate mouse or zebrafish PXR nor hCAR. We also showed that dabrafenib binds to recombinant hPXR, induces the expression of hPXR responsive genes in colon LS174T-hPXR cancer cells and human hepatocytes and finally increases the proliferation in LS174T-hPXR cells. Our study reveals that by using a panel of different cellular techniques it is possible to improve the assessment of hPXR agonist activity for new developed drugs.

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“…There is evidence that CAR-mediated activation of the Akt pathway causes redistribution of β-catenin from the cytoplasm to the nucleus in dividing hepatocytes [71]. CAR activates yes-associated protein (YAP) signaling, which may also be involved in CAR-mediated liver carcinogenesis [72,73]. The question of how liver tumors are promoted upon activation of CAR remains open.…”

Section: Noncanonical Car Signaling In Hepatocyte Proliferationmentioning

confidence: 99%

Noncanonical Constitutive Androstane Receptor Signaling in Gene Regulation

Pustylnyak

Gulyaeva

Pustylnyak

2020

IJMS

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The constitutive androstane receptor (CAR, NR1I3) is extremely important for the regulation of many physiological processes, especially xenobiotic (drug) metabolism and transporters. CAR differs from steroid hormone receptors in that it can be activated using structurally unrelated chemicals, both through direct ligand-binding and ligand-independent (indirect) mechanisms. By binding to specific responsive elements on DNA, CAR increases the expression of its target genes encoding drug-metabolizing enzymes and transporters. Therefore, CAR is mainly characterized as a ligand-dependent or ligand-independent transcription factor, and the induction of gene expression is considered the canonical mode of CAR action. Consistent with its central role in xenobiotic metabolism, CAR signaling includes a collection of mechanisms that are employed alongside the core transcriptional machinery of the receptor. These so-called noncanonical CAR pathways allow the receptor to coordinate the regulation of many aspects of cell biology. In this mini-review, we review noncanonical CAR signaling, paying special attention to the role of CAR in energy homeostasis and cell proliferation.

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Role of Nuclear Receptors PXR and CAR in Xenobiotic-Induced Hepatocyte Proliferation and Chemical Carcinogenesis

Cited by 31 publications

References 73 publications

PXR Functionally Interacts with NF-κB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice

PXR Functionally Interacts with NF-κB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice

The Anti-Cancer Drug Dabrafenib Is a Potent Activator of the Human Pregnane X Receptor

Noncanonical Constitutive Androstane Receptor Signaling in Gene Regulation

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