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Pregnane X Receptor (PXR) Polymorphisms and Cancer

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biomolecules Review PregnaneReview X Receptor (PXR) Polymorphisms andPregnane Cancer XTreatment Receptor (PXR) Polymorphisms and Cancer Treatment Aikaterini Skandalaki, Panagiotis Sarantis and Stamatios Theocharis * Aikaterini Skandalaki , Panagiotis Sarantis and Stamatios Theocharis * First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] (A.S.); [email protected] (P.S.) * Correspondence:First Department [email protected]; of Pathology, Medical Tel.: School, +30-210-746-2116 National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] (A.S.); [email protected] (P.S.) * Correspondence: [email protected]; Tel.: +30-210-746-2116 Abstract: 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 Abstract: Pregnane X Receptor (PXR) belongs to the nuclear receptors’ superfamily and mainly and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR’s regula- functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal tion. Antineoplastic agents are of particular interest since cancer patients are characterized by sig- and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR’s regulation. nificant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms Antineoplastic agents are of particular interest since cancer patients are characterized by significant may alter the function of the protein and are linked with significant effects on the pharmacokinetics intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to sum- alter the function of the protein and are linked with significant effects on the pharmacokinetics of marize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemothera- chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize peutic drugs. It is also expected that this review will highlight the importance of PXR polymor- the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. phisms in selection of chemotherapy, prediction of adverse effects and personalized medicine. 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. Keywords: PXR; polymorphisms; SNP; cancer; treatment; pharmacogenomics Keywords: PXR; polymorphisms; SNP; cancer; treatment; pharmacogenomics Citation: Skandalaki, A.; Sarantis, P.; Theocharis, S. Pregnane X Receptor 1. Introduction (PXR)Citation: PolymorphismsSkandalaki, and A.;Cancer Sarantis, P.; Treatment.Theocharis, Biomolecules S. Pregnane 2021, X 11 Receptor, 1.Pregnane Introduction X receptor (PXR), also known as nuclear receptor subfamily 1 group I 1142. https://doi.org/10.3390/ (PXR) Polymorphisms and Cancer memberPregnane 2 (NR1I2) Xand receptor steroid (PXR), and xenobiotic also known receptor as nuclear (SXR), is receptor an orphan subfamily receptor 1 of group the I biom11081142 Treatment. Biomolecules 2021, 11, 1142. nuclearmember receptor 2 (NR1I2) gene andsuperfamily steroid and and xenobiotic plays a key receptor role in (SXR), the metabolism is an orphan of receptorxenobiotics of the https://doi.org/10.3390/ andnuclear endobiotics receptor [1–6]. gene Human superfamily PXR (hPXR), and plays a 49.7 a keykDa role protein in the of metabolism434 amino acids, of xenobiotics is the Academicbiom11081142 Editor: Vladimir N. productand endobiotics of the NR1I2 [1 –gene6]. Human which is PXR located (hPXR), in chromosome a 49.7 kDa protein 3 (3q12-q13.3) of 434 amino and consists acids, isof the Uversky approximatelyproduct of the 40 NR1I2kb [7,8]. gene hPXR which is mostly is located expressed in chromosome in normal liver 3 (3q12-q13.3) tissue, the andsmall consists in- Academic Editor: Vladimir testine and the kidney whereas the PXR expression in tissues like stomach, ovaries, lungs, Received: 30 June 2021 of approximately 40 kb [7,8]. hPXR is mostly expressed in normal liver tissue, the small N. Uversky breast and peripheral blood cells is less frequent [9,10]. PXR expression in neoplastic tis- Accepted: 29 July 2021 intestine and the kidney whereas the PXR expression in tissues like stomach, ovaries, lungs, sues has also been reported, which differs from the expression levels in normal tissues [6,11]. Published:Received: 2 August 30 June 2021 2021 breast and peripheral blood cells is less frequent [9,10]. PXR expression in neoplastic tissues The structure of the PXR protein is presented in Figure 1. The enlarged, hydrophobic Accepted: 29 July 2021 has also been reported, which differs from the expression levels in normal tissues [6,11]. pocket of PXR enables it to accommodate a larger and more diverse number of ligands Publisher’sPublished: Note: 2 August MDPI2021 stays neu- The structure of the PXR protein is presented in Figure1. The enlarged, hydrophobic tral with regard to jurisdictional thanpocket the rest of of PXR the enablesnuclear itreceptors, to accommodate such as endobiotics, a larger and pharmaceutical more diverse and number herbal of com- ligands claimsPublisher’s in published Note: mapsMDPI and staysinstitu- neutralpounds,than theenvironmental rest of the nuclearfactors and receptors, dietary suchsupplements as endobiotics, and other pharmaceutical xenobiotics [12,13]. and herbal tionalwith affiliations. regard to jurisdictional claims in compounds, environmental factors and dietary supplements and other xenobiotics [12,13]. published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article Figure 1. Structure of PXR protein. PXR consists of a ligand-depended activation function 2 (AF-2) Copyright: © 2021 by the authors. distributed under the terms and Licensee MDPI, Basel, Switzerland.Figureand 1. a highlyStructure conserved of PXR protein. DNA-binding PXR consists domain of (DBD) a ligand-depended in the N-terminal activation with two function zinc-fingers 2 (AF-2) while conditions of the Creative Commons This article is an open access articleandthe a highly DBD isconserved connected DN toA-binding the C-terminal domain ligand (DBD) binding in the domain N-terminal (LBD) with using two a zinc-fingers hinge. while Attribution (CC BY) license distributed under the terms andthe DBD is connected to the C-terminal ligand binding domain (LBD) using a hinge. (http://creativecommons.org/licenses 2. PXR Function conditions of the Creative Commons /by/4.0/). Attribution (CC BY) license (https:// As a master regulator of xenobiotic response PXR adjusts the expression of many phase I creativecommons.org/licenses/by/ and phase II drug metabolizing enzymes (DME), such as cytochrome P450, uridine diphos- 4.0/). phate (UDP)-glucuronosyltransferases, sulfotransferases and carboxylesterases [13,14]. PXR Biomolecules 2021, 11, 1142. https://doi.org/10.3390/biom11081142 www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 1142. https://doi.org/10.3390/biom11081142 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 1142 2 of 14 2. PXR Function Biomolecules 2021, 11, 1142 As a master regulator of xenobiotic response PXR adjusts the expression of many2 of 15 phase I and phase II drug metabolizing enzymes (DME), such as cytochrome P450, uridine diphosphate (UDP)-glucuronosyltransferases, sulfotransferases and carboxylesterases [13,14].also regulates PXR also drug-efflux regulates pumps drug-efflux multi-drug pumps resistance multi-drug gene 1 (MDR1),resistance MDR2, gene ATP-binding 1 (MDR1), MDR2,cassette ATP-binding transporter C cassette 2 (ABCC) transporter and anion-transporting C 2 (ABCC) and polypeptide anion-transp 2 (OATP)orting [14 polypeptide–16]. All the 2aforementioned (OATP) [14–16]. enzymes, All the aforementioned under the control enzy of PXRmes, play under a significant the control role of in PXR the biotransfor-play a sig- nificantmation, metabolismrole in the biotransformation, and clearance of therapeutic metabolism agents, and including clearance chemotherapeutic of therapeutic agents, agents, includingthat may resultchemotherapeutic in drug-drug, agents, drug-herb that and may drug-food result in interactions, drug-drug, toxicity,drug-herb adverse and effectsdrug- foodand reducedinteractions, efficacy toxicity, [13,14 adverse,16,17]. effects The overall and reduced functions efficacy of PXR [13,14,16,17]. protein are presentedThe overall in functionsFigure2. of PXR protein are presented in Figure 2. FigureFigure 2. 2. FunctionsFunctions of of PXR. PXR. Besides Besides being being a a significant significant xenobiotic xenobiotic regulator regulator PXR PXR also also seems seems to to have have an an important important role role in in lipidlipid and and glucose glucose metabolism, metabolism, bile bile acid acid detoxification, detoxification, steroid homeostasis, inflammationinflammation and vitamin metabolism.metabolism. ItIt has has also also been been reported reported PXR’s PXR’s participation participation in in tumor tumor cell cell proliferation proliferation and and growth, growth, apoptosisapoptosis and and metastasis as wellwell
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  • Expression of C-Terminal Modified Serine Palmitoyltransferase-1 Alters Chemosensitivity of Inflammation-Associated Human Cancer Cell Lines

    Expression of C-Terminal Modified Serine Palmitoyltransferase-1 Alters Chemosensitivity of Inflammation-Associated Human Cancer Cell Lines

    Journal of Cancer Therapy, 2014, 5, 902-919 Published Online September 2014 in SciRes. http://www.scirp.org/journal/jct http://dx.doi.org/10.4236/jct.2014.510097 Expression of C-Terminal Modified Serine Palmitoyltransferase-1 Alters Chemosensitivity of Inflammation-Associated Human Cancer Cell Lines Tokunbo Yerokun Department of Biology, Spelman College, Atlanta, Georgia, USA Email: [email protected] Received 21 June 2014; revised 20 July 2014; accepted 15 August 2014 Copyright © 2014 by author and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ Abstract Background: The human serine palmitoyltransferase-1, SPTLC1, subunit is emerging as a stress responsive protein with putative role in modulating cellular stress response behavior. When compared to the parental cell line, recombinant Glioma cells expressing C-terminal modified SPTLC1 are found to show resistance to the cytotoxic effect of polycyclic hydrocarbons, PHs, in- cluding the environmental contaminant 3-methylcholanthrene. This novel functional association of SPTLC1 expression with proliferative capacity is thought to be due, in part, to its ability for crosstalk with protein regulators of different biological processes. Whether the effect of SPTLC1 on sensitivity to PHs extends to therapeutic drugs and the progression of the malignant phenotype is of research interest. Methods: In the current study, sub-cellular localization was by immunos- taining for SPTLC1 in untreated and chemical treated cells and detection with confocal microscopy. The effect expressing C-terminal modified SPTLC1, in cancer cell lines of the inflammation-asso- ciated type, has on chemosensitivity and gene expression was also assessed.