Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines

Toporová, Lucia; Grimaldi, Marina; Boulahtouf, Abdelhay; Balaguer, Patrick

doi:10.3389/fphar.2020.01122

Cited by 19 publications

(8 citation statements)

References 45 publications

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“…Unexpectedly, binding of PXR to SLC16A1 promoter in the presence of SR12813 did not translate into a significant increase in SLC16A1 mRNA levels in 22Rv1 clones in which PXR was ectopically expressed. This could be attributed to a marginal effect of the agonist due to a high basal activity of PXR and a level of PXR expression that may be sufficient to sustain its activity, as it was already reported [ 23 , 49 ]. Alternatively, this could also be due to a PXR-mediated negative feedback loop attenuating the expression of SLC16A1, as it was demonstrated for the CYP3A4 target gene in HuH7 liver cancer cells overexpressing PXR [ 50 ].…”

Section: Discussionmentioning

confidence: 78%

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

Matheux

Gassiot

Fromont

et al. 2021

Cancers

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Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.

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Section: Discussionmentioning

confidence: 78%

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

Matheux

Gassiot

Fromont

et al. 2021

Cancers

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“…To validate the results obtained in the nr1h4 mutant, we applied two FXR inhibitors, DY268 and guggulsterone. (35,36) DY268 and guggulsterone treatments notably inhibited liver regeneration after Mtz treatment (Supporting Figs. S9A and S10A).…”

Section: The Bppc-to-hepatocyte Redifferentiation Is Defective In The...mentioning

confidence: 91%

Farnesoid X Receptor Is Required for the Redifferentiation of Bipotential Progenitor Cells During Biliary‐Mediated Zebrafish Liver Regeneration

et al. 2021

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Background and Aims Liver regeneration after extreme hepatocyte loss occurs through transdifferentiation of biliary epithelial cells (BECs), which includes dedifferentiation of BECs into bipotential progenitor cells (BPPCs) and subsequent redifferentiation into nascent hepatocytes and BECs. Although multiple molecules and signaling pathways have been implicated to play roles in the BEC‐mediated liver regeneration, mechanisms underlying the dedifferentiation‐redifferentiation transition and the early phase of BPPC redifferentiation that is pivotal for both hepatocyte and BEC directions remain largely unknown. Approach and Results The zebrafish extreme liver damage model, genetic mutation, pharmacological inhibition, transgenic lines, whole‐mount and fluorescent in situ hybridizations and antibody staining, single‐cell RNA sequencing, quantitative real‐time PCR, and heat shock–inducible overexpression were used to investigate roles and mechanisms of farnesoid X receptor (FXR; encoded by nuclear receptor subfamily 1, group H, member 4 [nr1h4]) in regulating BPPC redifferentiation. The nr1h4 expression was significantly up‐regulated in response to extreme liver injury. Genetic mutation or pharmacological inhibition of FXR was ineffective to BEC‐to‐BPPC dedifferentiation but blocked the redifferentiation of BPPCs to both hepatocytes and BECs, leading to accumulation of undifferentiated or less‐differentiated BPPCs. Mechanistically, induced overexpression of extracellular signal‐related kinase (ERK) 1 (encoded by mitogen‐activated protein kinase 3) rescued the defective BPPC‐to‐hepatocyte redifferentiation in the nr1h4 mutant, and ERK1 itself was necessary for the BPPC‐to‐hepatocyte redifferentiation. The Notch activities in the regenerating liver of nr1h4 mutant attenuated, and induced Notch activation rescued the defective BPPC‐to‐BEC redifferentiation in the nr1h4 mutant. Conclusions FXR regulates BPPC‐to‐hepatocyte and BPPC‐to‐BEC redifferentiations through ERK1 and Notch, respectively. Given recent applications of FXR agonists in the clinical trials for liver diseases, this study proposes potential underpinning mechanisms by characterizing roles of FXR in the stimulation of dedifferentiation‐redifferentiation transition and BPPC redifferentiation.

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“…Ochatoxin A, a mycotoxin, has also been shown to significantly downregulate PXR activity in human primary hepatocytes [46,47]. Other antagonists are clotrimazole, dabrafenib, SR12813, Nelfinavir and SPA70 [48,49]. SPA70 interacts with hPXR LBD, is highly specific for hPXR and has selective downregulating effects [47,[50][51][52].…”

Section: Agonists and Antagonistsmentioning

confidence: 99%

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

2021

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Pregnane X Receptor (PXR) belongs to the nuclear receptors’ superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR’s regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine.

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Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines

Cited by 19 publications

References 45 publications

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

Farnesoid X Receptor Is Required for the Redifferentiation of Bipotential Progenitor Cells During Biliary‐Mediated Zebrafish Liver Regeneration

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

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