Evidence that the pregnane <scp>X</scp> and retinoid receptors <scp>PXR</scp>,<scp> RAR</scp> and <scp>RXR</scp> may regulate transcription of the transporter <i>h<scp>OCT</scp>1</i> in chronic myeloid leukaemia cells

Austin, Gemma; Holcroft, Alison; Rinne, Natasha; Wang, Lihui; Clark, Richard E.

doi:10.1111/ejh.12409

Cited by 16 publications

(16 citation statements)

References 19 publications

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“…Therefore, the authors hypothesize that rifampicin induces OCT1 in hepatocytes, which subsequently increases the uptake of metformin into hepatocytes, resulting in the increased effect of metformin (Cho et al, 2011). Similarly, agonists of PXR induced OCT1 mRNA in the chronic myeloid leukaemia (CML) cell line and primary CML cells (Austin et al, 2015). However, contradictory data have been also published indicating the downregulation of OCT1 mRNA in human hepatocytes after treatment with rifampicin Badolo et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The pregnane X receptor down‐regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for (“squelching”) SRC‐1 coactivator

Hyršová

Smutný

Carazo

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEThe organic cation transporter 1 (OCT1) transports cationic drugs into hepatocytes. The high hepatic expression of OCT1 is controlled by the HNF4α and USF transcription factors. Pregnane X receptor (PXR) mediates induction of the principal xenobiotic metabolizing enzymes and transporters in the liver. Here, we have assessed the down-regulation of OCT1 expression by PXR activation. EXPERIMENTAL APPROACHWe used primary human hepatocytes and related cell lines to measure OCT1 expression and activity, by assaying MPP + accumulation. Western blotting, qRT-PCR, the OCT1 promoter gene reporter constructs and chromatin immunoprecipitation assays were also used. KEY RESULTSOCT1 mRNA in human hepatocytes was down-regulated along with reduced [ 3 H]MPP + accumulation in differentiated HepaRG cells after treatment with rifampicin. Rifampicin and hyperforin as well as the constitutively active PXR mutant T248D suppressed activity of the 1.8 kb OCT1 promoter construct in gene reporter assays. Silencing of both PXR and HNF4α in HepaRG cells blocked the PXR ligand-mediated down-regulation of OCT1 expression. The mutation of HNF4α and USF1 (E-box) responsive elements reversed the PXR-mediated inhibition in gene reporter assays. Chromatin immunoprecipitation assays indicated that PXR activation sequestrates the SRC-1 coactivator from the HNF4α response element and E-box of the OCT1 promoter. Consistent with these findings, exogenous overexpression of the SRC-1, but not the PGC1α coactivator, relieved the PXR-mediated repression of OCT1 transactivation. CONCLUSIONS AND IMPLICATIONSPXR ligands reduced the HNF4α-mediated and USF-mediated transactivation of OCT1 gene expression by competing for SRC-1 and decreased delivery of a model OCT1 substrate into hepatocytes. AbbreviationsCAR, constitutive androstane receptor; ChiP , chromatin immunoprecipitation assay; CML, chronic myeloid leukaemia; DR-2, direct repeat separated by two nucleotides; HNF4α, hepatocyte nuclear factor-4-α; OCT1, organic cation transporter 1; PXR, pregnane X receptor; SRC-1, steroid receptor coactivator; PGC1α, PPARγ coactivator 1α; USFs, upstream stimulating factors

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Section: Introductionmentioning

confidence: 99%

The pregnane X receptor down‐regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for (“squelching”) SRC‐1 coactivator

Hyršová

Smutný

Carazo

et al. 2016

British J Pharmacology

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“…Initially, it was demonstrated that PXR-null mice developed B cell lymphoma in an age-dependent manner, suggesting a tumor suppressor role for PXR in B-1 cells (Casey et al, 2011). In chronic myeloid leukemia (CML) patients, it is known that the expression and activity of the uptake transporter human organic cation transporter 1 (hOCT1) positively determines the favorable outcome to Imatinib treatment (Austin et al, 2015). Pharmacologic activation of PXR with rifampicin or SR12813 in KCL22 CML cell line and CML primary cells resulted in up-regulation of hOCT1 expression, suggesting that PXR agonists may be potentially used to improve the efficacy of Imatinib in patients with CML (Austin et al, 2015).…”

Section: Differential Role Of Pxr In Cancermentioning

confidence: 99%

“…In chronic myeloid leukemia (CML) patients, it is known that the expression and activity of the uptake transporter human organic cation transporter 1 (hOCT1) positively determines the favorable outcome to Imatinib treatment (Austin et al, 2015). Pharmacologic activation of PXR with rifampicin or SR12813 in KCL22 CML cell line and CML primary cells resulted in up-regulation of hOCT1 expression, suggesting that PXR agonists may be potentially used to improve the efficacy of Imatinib in patients with CML (Austin et al, 2015). In another study of multiple myeloma, gene expression of uptake carriers, xenobiotic receptors, phase I and II drug metabolizing enzymes, and efflux transporters was examined in multiple myeloma cells of newly-diagnosed patients (Hassen et al, 2014).…”

Section: Differential Role Of Pxr In Cancermentioning

confidence: 99%

“…PXR activation induces hepatic proliferation and/or inhibits apoptosis through several mechanisms (Elcombe et al, 2012a; Elcombe et al, 2012b; Elcombe et al, 2010; Luisier et al, 2014; Xie et al, 2000). However, PXR activation also induces differentiation of osteoblasts and apoptosis of osteoclasts and certain leukemia cells (Austin et al, 2015; Hassen et al, 2014; Igarashi et al, 2007; Kameda et al, 1996; Tabb et al, 2003), suggesting that control of cell proliferation by PXR is likely tissue and cell-specific. A similar theme plays out in cancer cells, in which, PXR differentially regulates cell growth through multiple mechanisms in a variety of cancers, including liver, prostate, breast, ovarian, endometrial, cervical, and colon (Braeuning et al, 2014; Kakehashi et al, 2013; Koutsounas et al, 2013; Luisier et al, 2014; Ma et al, 2015; Niu et al, 2014; Pondugula and Mani, 2013; Qiao et al, 2013; Ross et al, 2010; Rouquie et al, 2014; Shizu et al, 2013; Tinwell et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula

Pávek

Mani

2016

Nuclear Receptor Research

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Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.

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“…Therefore, it was hypothesized that rifampicin may induce OCT1 in hepatocytes and thus increase the uptake of metformin into hepatocytes (Cho et al, 2011). In other studies, agonists of PXR have been found to mildly induce OCT1 mRNA in the chronic myeloid leukemia (CML) cell line KCL22 and primary CML cells (Austin et al, 2015). Rat Slc22a1 gen has been clearly demonstrated as a target of rat Pxr and pregnenolone16a-carbonitrile (PCN), a prototype rodent Pxr ligand, significantly induced Oct1 in the rat liver (Maeda et al, 2007).…”

Section: Ligand-dependent Nuclear Receptor-mediated Regulationmentioning

confidence: 99%

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

Hyršová

Smutný

Trejtnar

et al. 2016

Drug Metabolism Reviews

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The organic cation transporter 1 (OCT1) is the dominant carrier of organic cationic drugs and some positively charged endogenous compounds into hepatocytes. OCT1 has unique expression pattern. It has the highest expression among drug transporters in normal human hepatocytes with large interindividual variability, but it has negligible expression in other tissues or their tumors. Nowadays, it is clear that the regulation of SLC22A1 gene encoding OCT1 transporter is rather complex and that transactivation with hepatocyte nuclear factor 4α (HNF4α) and CCAAT-enhancer-binding protein (C/EBPs) transcription factors as well as epigenetic regulation contribute to its unique hepatocyte-specific expression pattern. Unfortunately, species- and tissue-specific regulation of OCT1 and its orthologs as well as significant down-regulation in most immortalized cell lines hamper the study of SLC22A1 gene regulation. In the current review, we summarize our current understanding of human OCT1 transporter hepatic gene regulation and we propose potential post-transcriptional regulation by predicted miRNAs. We also discuss in detail recent findings on indirect regulation of the transporter via farnesoid X receptor (FXR), glucocorticoid receptor and pregnane X (PXR) receptor, which point out to potential novel mechanisms of xenobiotic-transporting and drug-metabolizing proteins regulation in the human liver as well as to potentially novel drug-drug interaction mechanisms. We also propose that comprehensive understanding of mechanisms of SLC22A1 gene regulation could direct research for other drug transporters and drug-metabolizing enzymes highly expressed in hepatocytes and controlled by HNF4α or other liver-enriched transcription factors.

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Evidence that the pregnane X and retinoid receptors PXR, RAR and RXR may regulate transcription of the transporter hOCT1 in chronic myeloid leukaemia cells

Cited by 16 publications

References 19 publications

The pregnane X receptor down‐regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for (“squelching”) SRC‐1 coactivator

The pregnane X receptor down‐regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for (“squelching”) SRC‐1 coactivator

Pregnane X Receptor and Cancer: Context-Specificity is Key

Expression of organic cation transporter 1 (OCT1): unique patterns of indirect regulation by nuclear receptors and hepatospecific gene regulation

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