are nuclear receptors for retinoids involved in the ...

In: Retinoic Acid Editors: L. Cheng and Y. Ito

Chapter 2

ISBN 978-1-62100-597-1 © 2012 Nova Science Publishers, Inc.

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ARE NUCLEAR RECEPTORS FOR RETINOIDS INVOLVED IN THE CONTROL OF THE EXPRESSION AND ACTIVITY OF P-GLYCOPROTEIN? Zdena Sulová,1 Julius Brtko,2 Dana Macejová,2 and Albert Breier1* 1

Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia 2 Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic

ABSTRACT Nuclear retinoid and retinoid X receptors play key roles in several processes, including cell differentiation and homeostasis, and are involved in the etiology and pathogenesis of several diseases, such as cancer. These nuclear receptors are ligandactivated DNA-binding proteins involved in the molecular mechanisms responsible for the transcriptional control of target genes. Nuclear retinoid receptor isoform dysfunction is involved in carcinogenesis. Ligands of these receptors, natural and synthetic retinoids, are believed to induce cell differentiation and apoptosis in poorly differentiated cancer cells, which is the main reason for the application of retinoids in chemotherapy of several neoplastic diseases. It is suggested that a link may exist between the regulatory pathways of nuclear receptors for retinoids and multidrug resistance (MDR) of cancer cells, which is mediated by P-glycoprotein expression. MDR of neoplastic tissues represents a real obstacle in the effective chemotherapy of cancer. Several mechanisms of MDR have been identified, of which the overexpression and efflux activity of P-glycoprotein (P-gp), a plasma membrane ATPase and an ABCB1 member of the ABC transporter family, is the most commonly observed reason for chemotherapy failure in neoplastic diseases. The overexpression of P-gp in neoplastic cells may result in more than a 100-fold higher resistance of these cells to several drugs. Relatively little is known about the regulation of P-gp expression; therefore, serious *

Corresponding author (AB) fax: +421 2 54773666, E-mail: [email protected], [email protected].

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Zdena Sulová, Julius Brtko, Dana Macejová, et al. efforts have been made to identify all aspects involved in the regulation of P-gp expression. Nuclear retinoic acid receptors are involved in regulating the expression of a large number of different proteins. Several authors have described that all-trans retinoic acid, the ligand of retinoic acid receptors (RARs), may induce alterations in P-gp expression and/or activity in drug-resistant malignant cell lines. There are also other nuclear receptors for 9-cis retinoic acid, such as retinoid X receptors (RXRs) that are known to act as dimerization partners of several nuclear receptors, such as RARs, thyroid hormone receptors (TRs), the vitamin D receptor (VDR), pregnane X receptors (PXRs) and the constitutive androstane receptor (CAR). The expression of P-gp was described to be influenced by the PXR, CAR, VDR and TR. We have shown in a previous paper that alltrans retinoic acid in combination with verapamil is able to down regulate P-gp expression and activity in a P-gp-positive cell variant of L1210 cells, indicating that nuclear retinoid receptors may be involved in the control of P-gp expression. The current paper attempts to summarize the knowledge about the interplay between the functions of nuclear receptors for retinoids and MDR mediated by P-gp.

1. INTRODUCTION Nuclear retinoid/rexinoid receptors are considered to be major targets for novel drug discovery and may have key roles in development and homeostasis and in many diseases such as obesity, diabetes and cancer. Both retinoid and rexinoid nuclear receptors are considered to be ligand-activated, DNA-binding, trans-acting, transcription-modulating proteins that are involved in a general molecular mechanism responsible for transcriptional responses in target genes (Brtko and Thalhamer 2003; Brtko and Dvorak 2011). The ligands of these receptors include naturally occurring and synthetic vitamin A metabolites and analogs that are known to inhibit tumor development via the suppression of cell transformation and inhibition of carcinogenesis in various organs (Lotan 1996). Retinoids, including all-trans retinoic acid, a natural metabolite of vitamin A, induce important effects on cell development, proliferation and differentiation, and their effects are mediated by the retinoid and rexinoid nuclear receptors (Bruserud et al., 2000). Cell differentiation and subsequent apoptosis in several types of malignant cells with immature phenotypes are known to be induced by all-trans retinoic acid (Kalemkerian and Ramnath 1996). Clinically, all-trans retinoic acid has been approved for the treatment of patients with acute promyelocytic leukemia. Synthetic retinoids may induce apoptosis without differentiation in a variety of malignant epithelial cells in vitro (Kalemkerian and Ramnath 1996). Another use for retinoids in cancer therapy may be derived from several lines of evidence that indicate that receptors for retinoids/rexinoids could also be involved in the development and regulation of multidrug resistance (MDR), particularly the MDR subtype mediated by the membrane transporter P-glycoprotein (P-gp) (Grandjean Forestier et al., 2009). All-trans retinoic acid was assumed to modulate P-gp expression and/or drug-efflux activity and consequently alter the reduced drug sensitivity of P-gppositive cells (Sulova et al., 2008). Resistance against the all-trans retinoic acid treatment for acute promyelocytic leukemia can occur and may induce a failure of chemotherapy (Gallagher 2002). A weak improvement of P-gp expression could accompany the development of all-trans retinoic acid resistance in several cell models (Takeshita et al., 2000).

Are Nuclear Receptors for Retinoids Involved in the Control of the Expression …

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This review focuses on the state-of-the-art information about the involvement of nuclear receptors for retinoids and rexinoids in cancer development and therapy, with particular attention to P-gp-mediated MDR and the possible modulation of P-gp transcriptional control.

2. NUCLEAR RETINOID/REXINOID RECEPTORS Retinoids and rexinoids, the cognate ligands for nuclear retinoid and rexinoid receptors, are polyisoprenoid compounds that contain a cyclohexenyl ring. Currently, the groups of retinoids and rexinoids comprise over 4000 natural and synthetic molecules structurally and/or functionally related to vitamin A (retinol), a compound that is not synthesized by humans or any animal species and is only obtained through the diet in the form of retinol, carotene (a precursor of vitamin A) or retinyl ester (Bushue and Wan 2011). An assortment of retinoic acid-induced pathways are linked with the existence of at least three subtypes of nuclear receptors for all-trans retinoic acid, RARand and three subtypes of nuclear receptors for 9-cis retinoic acid, RXRandwhich have distinct amino- and carboxyterminal domains. Today, two major isoforms of RAR (and2and RAR (and2) and four major isoforms of RAR(1,and4)have extended this group of RARs. Similarly, two major isoforms of RXR(and2, RXR(and2, and RXR(and2have been identified to-date (Chambon 1996; Sun and Lotan 2002). The retinoids that are selective ligands that specifically bind to RXRs are called rexinoids. Proteins of the nuclear receptor superfamily are single polypeptide chains with several principal domains. The amino terminal A/B-domain of the nuclear receptor molecule is known to contain a constitutive activation function that is independent of the ligand (AF-1). The next domain is a central C-domain, a cysteine-rich DNA-binding area that consists of two highly conserved zinc fingers. The DNA-binding domain of the nuclear receptor contains two sets of four cysteine residues that are involved in zinc ion coordination, forming loops known as zinc fingers. The D-domain is a highly flexible structure, and it was confirmed that it plays a role as a hinge in the nuclear receptor molecule. The carboxy-terminal E-domain has several functions: it is responsible for ligand binding and dimerization, and it contains an inducible transactivation function, which is dependent on the ligand known as activation function 2 (AF-2) (Chambon 1996). Upon all-trans retinoic acid binding, nuclear all-trans retinoic acid receptors act as alltrans retinoic acid-inducible transcription factors by directly interacting as heterodimers with nuclear 9-cis retinoic acid receptors. The role of the RXR/RAR heterodimer is to interact with specific DNA response elements, retinoic acid response elements (RAREs), of target genes, and its effect on ligand-induced transcription is mediated through the recruitment of a number of coregulators and corepressor and coactivator molecules (Mangelsdorf et al., 1995; Aranda and Pascual 2001). RXR/RAR heterodimers bind RAREs, which are characterized by direct repeats of two nucleotide AGGTCA hexamers separated predominantly by two nucleotides (DR+2) or five nucleotides (DR+5). In the absence of all-trans retinoic acid, the RAR/RXR heterodimer recruits nuclear receptor corepressor proteins, such as nuclear receptor corepressor (N-CoR) or silencing mediator of retinoid and thyroid hormone receptor (SMRT), and associated enzymes, such as histone deacetylases or DNA-methyl transferases, leading to an inactive, condensed chromatin structure that prevents the transcription process. Ligand

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Zdena Sulová, Julius Brtko, Dana Macejová, et al.

occupancy (all-trans retinoic acid for RARs and 9-cis retinoic acid for RXRs) in RXR/RAR heterodimers was found to synergistically enhance transcriptional activity (Minucci et al., 1997; Crowe 2002). Nuclear RARs were found to bind both all-trans retinoic acid and 9-cis retinoic acid with similar affinities, while RXRs bind only 9-cis retinoic acid (Germain et al., 2006a). All-trans retinoic acid binding to the nuclear receptor molecule results in the dissociation of corepressor proteins, which enables the association of coactivator proteins (e.g., steroid receptor coactivator-1 (SRC-1), histone acetyltransferases or histone arginine methyltransferases), resulting in the activation of gene transcription (Freedman 1999; Privalsky 2001). Increasing the phosphorylation state of the cellular environment can enhance the retinoic acid-mediated transcriptional activation of target genes. The mechanisms for this enhanced transcriptional activation are not yet clear but may involve the phosphorylation of RARs, RXRs, and/or coactivators (Perissi and Rosenfeld 2005). Also, the poly(ADP-ribose) polymerase 1 (PARP-1), which is known to interact with RARα, has been shown to be indispensable to the RAR-mediated transcription from the RARβ2 promoter (Pavri et al., 2005). Thus, the retinoid receptors are considered to be ligand-activated, DNA-binding, transacting, transcription-modulating nuclear proteins that are involved in a general molecular mechanism responsible for the transcriptional responses of target genes (Germain et al., 2006c; Brtko 2007a; Brtko and Dvorak 2011). The retinoic acid receptors are known to mediate both the organismal and cellular effects of retinoids, a generic term that includes both the compounds of natural dietary vitamin A (retinol) metabolites and its analogs as well as active synthetic analogs (Chambon 2005). Retinoids and their cognate nuclear receptor types and subtypes are involved in the complex arrangements of physiological and developmental responses in many tissues of higher vertebrates, including embryonic development, vision, reproduction, bone formation, hematopoiesis, metabolism, growth and the differentiation of a variety of cell types, apoptosis and processes of carcinogenesis (De Luca 1991; Lotan 1995; Brtko and Dvorak 2011). Despite the fact that RAR agonists can autonomously activate transcription through such heterodimers, RXRs are unable to respond to RXR-selective agonists (rexinoids) in the absence of an RAR ligand. The molecular basis of this phenomenon, referred to as RXR subordination or silencing, has been dissected. Agonist binding to the RXR in the absence of an RAR ligand is unable to induce the dissociation of the corepressor from the RXR-RAR heterodimer, preventing coactivator recruitment (Germain et al., 2002). In knockout experimental approaches, RAR-null mutant males have been found to be sterile due to the degeneration of the seminiferous epithelium, which causes the inhibition of spermatogenesis (Germain et al. 2006a); reviewed in (Brtko and Dvorak 2011). Also, RARnull mice were found to display abnormalities in the vitreous body in eyes and impaired abilities in locomotion and motor coordination, and the ablation of RAR causes both skeletal and epithelial defects (Chapellier et al., 2002). Moreover, the loss of RXRwas found to be lethal during fetal life due to hypoplasia of the myocardium, which appears to be the principal cause of animal death. Moreover, fetuses lacking RXRhave ocular malformation. Also, it has been shown that RXR is involved in the mediation of a teratogenic effect due to the administration of exogenous retinoids (Germain et al., 2006b). The ablation of RXRled to approximately 50 % lethality in utero. Males lacking RXR are sterile and exhibit testicular defects and abnormal spermatid maturation, leading to defects in spermatozoa. Moreover, an RXRmutation causes abnormal lipid metabolism in Sertoli cells, suggesting functional


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interactions of RXRwith other nuclear receptors that control lipid metabolism. RXR-null mutants are fertile, but they have higher serum levels of both L-thyroxine and thyroidstimulating hormone (TSH) and an increased metabolic rate when compared to wild-type animals (Germain et al. 2006b); reviewed in (Brtko and Dvorak 2011). In all species of mammals, retinoids increase the expression of CYP26A1 and CYP26B1 through RAR(Germain et al. 2006c) As recently reviewed by (Brtko and Dvorak 2011), there are numerous indications for mutual interactions between AhR and RXRs or RARs both in vivo and in vitro. The levels of AhR mRNA and 2,3,7,8-tetracholorodibenzo-p-dioxins (TCDD)-inducible CYP1A1 mRNA were decreased by all-trans retinoic acid in the human keratinocyte cell line HaCaT, probably by an indirect mechanism. Several synthetic retinoids were found to activate AhR by a mechanism involving the binding of these compounds to AhR and transforming the receptor into the transcriptionally active form. Retinoids, via their cognate nuclear retinoid receptors, share the SMRT co-regulator with AhR, giving a link for transcriptional cross-talk between AhR and RARs (Gambone et al., 2002). In general, RARs and RXRs, members of the nuclear hormone receptor superfamily, play an important role in higher organisms as transcription factors that are induced by biologically active ligand(s) and work in concert with co-activators and co-repressors to regulate gene expression.

3. NUCLEAR RETINOID AND REXINOID RECEPTORS IN SELECTED MALIGNANCIES Dysfunction of nuclear receptor signaling leads to proliferative, reproductive and metabolic diseases. Moreover, at least two retinoid response elements and possible interactions between RARs and RXRs were found to greatly increase the number of retinoic acid-dependent responses, leading to a molecular explanation for the multiple actions of both retinoids and rexinoids. The RAR/RXR content of certain tumors seems to be important for the potential therapeutic employment of retinoids (van der Leede et al., 1996; Katsetos et al., 1998). It has been shown that the phosphorylation of RXR delays nuclear export and RXR degradation and inhibits RAR-dependent transcription in hepatocellular carcinoma cells (Matsushima-Nishiwaki et al., 2001). The direct implication of RARs in human disease is in acute promyelocytic leukemia (Lin et al., 1999; Brtko and Thalhamer 2003). Acute promyelocytic leukemia has been found to be associated with the reciprocal translocation of the RAR gene on chromosome 17, which translocates and fuses to other genes, including the promyelocytic leukemia gene (PML) (Lin et al. 1999; Melnick and Licht 1999). It has been shown that PML-RAR is capable of forming homodimers, thus competing with RAR for binding to the retinoic acid responsive element of target genes (Melnick and Licht 1999). The all-trans retinoic acidinduced differentiation of cells is due to the degradation of PML-RAR and the induction of the dissociation of co-repressors from PML-RAR (Lin et al. 1999). The loss of RAR inducibility and growth inhibition by all-trans retinoic acid has frequently been reported in prostate (Lou et al., 2005), breast (Liu et al., 1996), colon (Nicke et al., 1999), and lung cancers (Zhang et al., 1994). In different types of cancer, RAR2 expression was found to be low or even lost (Jing et al., 1996; Wu et al., 1998). A variety of

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different mechanisms by which RAR2 transcription is reduced in tumor cells include the hypermethylation of the RAR2 promoter (reviewed in (Cai and Gudas 2009), loss of histone H3 acetylation (Suh et al., 2002), and involvement of additional transcription factors responsible for the differential regulation of RAR2 expression in tumor cells versus normal cells (Wu et al., 1997). Prostate cancer is the second-most common diagnosed cancer in males and the sixth leading cause of cancer deaths (Jemal et al., 2011). Several studies have shown that various analogues of vitamin A inhibit the proliferation of normal human prostate epithelial cells and some lines of human prostate cancer cells in vitro or in animal models (Peehl et al., 1993; Blutt et al., 1997; Campbell et al., 1998; Zheng et al., 2004). All-trans retinoic acid and 13-cis retinoic acid have been exploited predominantly in combination with other therapeutic agents, such as paclitaxel and IFN, for the treatment of human prostate cancer (DiPaola et al., 1999; Thalasila et al., 2003; Zheng et al. 2004). It has been shown that all-trans retinoic acid decreases the number of human prostate cancer LNCaP cells via the RAR receptor (Sadikoglou et al., 2009). Gyftopoulos et al., (2000) detected a significantly elevated expression of RAR in moderately and poorly differentiated AR+ prostate carcinomas, whereas RXR expression was more frequently observed in patients with AR-negative prostate carcinomas (Kolar et al., 2002). Lou et al. (2005) have shown that prostate cancer LNCaP cells express much lower levels of RARs than do normal cells. Recently, Cai and Gudas (2009) showed lower levels of RAR2 mRNA in the PC-3 human prostate cancer cell line when compared to those in cultured normal human prostate epithelial cells (PrEC), which is in agreement with earlier reports showing the decreased expression of RARs in tumor progression (Hansen et al., 2000). Furthermore, it has been shown that the induction of RARexpression by all-trans retinoic acid is mediated by RAR and not RAR and that all-trans retinoic acid did not regulate the expression of RAR and RAR genes in prostate cells (Lou et al. 2005). These findings are in agreement with various studies performed in cervical cells (Geisen et al., 1997) and MCF7 breast cancer cells (Liu et al. 1996; Shang et al., 1999). Enhanced expression levels of RAR in prostatic stromal cells may result from the more active RAR, which therefore mediates the action of all-trans retinoic acid in reducing 24-hydroxylase expression in stromal cells (Lou et al. 2005). In general, the hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. It has been shown that RAR functions as a tumor suppressor gene in human PCa cells and xenograft models (Jeronimo et al., 2004; Vanaja et al., 2006). The RAR promoter was found to be frequently hypermethylated (in up to 97.5% of PCa) and silenced in the early stages of PCa progression (Jeronimo et al. 2004; Singal et al., 2004; Vanaja et al. 2006). He et al., (2009) reported that overexpression of the proto-oncogene Myc increased methylation in several CpG sites of the RAR promoter. Many chemopreventive chemicals of natural origin and/or an FDAapproved methylase inhibitor lead to the reactivation of RAR (Yang et al., 2002; Fang et al., 2003; Fang et al., 2005). Resistance to the anti-carcinogenic effects of 1,25(OH)2D3 has been reported in various tumor cell models, including skin, breast cancer, acute myeloid leukemia, and prostate cancer cell lines (reviewed in Zhang et al., (2010). Zhang et al. (2010) also suggested an important role of RXR in the prolonged, constitutive Ras–MAPK activation that impairs vitamin D signaling in prostate epithelial cells; this effect may be due to the phosphorylation of the


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RXR AF-1 domain and impaired recruitment of the transcriptional co-factor SRC-1. According to Narayanan et al., (2004), the predominant RXR isoform within a cell deﬁnes whether the activation of MAPK signaling enhances or inhibits 1,25(OH)2D3-mediated gene transcription. Like Solomon et al., (1999), they have shown that RXR was the target of MAPK-mediated inhibition. Youn et al., (2011) demonstrated that the transcriptional activity of RAR could be enhanced by the association of the coregulator MED25 with CREB-binding protein (CBP, CREB = cAMP-responsive element binding protein) through the PTOV domain, which is also present in prostate tumor over-expressed protein 1 (PTOV1). MED25 and PTOV1 reciprocally regulate RAR transcriptional activity through competitive binding to CBP and the opposite regulation of CBP recruitment to the gene promoter responsive to RAR. Nuclear retinoid and rexinoid receptors are expressed differently in normal and malignant epithelial cells and are critical for normal development (Zanardi et al., 2006). Recently, Macejova et al., (2005a) showed marked differences between nonlactating and postlactating mammary glands in the rat. RAR, RXR, N-CoR, and SMRT levels were significantly increased in postlactating mammary glands when compared to those of nonlactating mammary tissue. Postlactating mammary glands were found to express all RAR and RXR subtypes studied when compared to nonlactating mammary tissues, which exclusively express the RAR and RXR subtypes. The enhanced expression of a number of nuclear hormone receptors and their coregulators in the mammary tissue of postlactating rats in comparison with nonlactating animals have thus identified a potential role for retinoid signaling pathways after the lactation period (Macejova et al. 2005a). Growth inhibition of breast cancer cells by all-trans retinoic acid has been associated with a marked enhancement of RAR expression, which may act as a tumor suppressor and appears to be down-regulated in breast cancer tissue and cell lines and conversely up-regulated in normal mammary epithelial cells (Zhang et al., 1996). The data on the expression of all the subtypes of RARs and RXRs in a number of hormone-dependent and hormone-independent breast cancer cells have shown a similar expression pattern for RAR, RAR, RXR and RXR. However, all-trans retinoic acid was found to be a strong inductor of RAR gene expression in several hormone-dependent breast cancer cell lines. Zhang et al. (1996) suggested that the lack of RAR may contribute to retinoid resistance in certain cancer cells and may account for the ineffective treatment with retinoids in patients with advanced breast cancer. The malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation, known as the malignant Triton tumor, belongs to a class of rare and very aggressive tumors (Stasik and Tawfik 2006). Kostler et al., (2003) have reported that after experimental treatment with retinoid isotretinoin and interferon- for one year, patients with a malignant Triton tumor did not have any evidence of disease for more than three years. In the case of a 12-year-old patient with a malignant Triton tumor in Slovakia, malignant tissues excised from the neck or abdomen expressed all subtypes of RARs or RXRs. These data allowed the introduction of a novel diagnostic approach in clinical oncology based on the analysis of the expression of retinoid and rexinoid receptors in relation to the potential to exploit retinoic acid and its derivatives in malignant Triton tumor therapy (Brtko et al., 2009). Thyroid non-Hodgkin's lymphoma (TNHL) is a relatively rare tumor, representing 2–8% of thyroid malignancies and approximately 1–2% of extranodal lymphomas. It occurs most frequently in elderly women and has been linked to Hashimoto's thyroiditis (Harrington et al.,

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2005). In the TNHL tissue of a 67-year-old woman from Slovakia, RARβ was found to be the highest expressed isoform of RARs. In contrast to normal thyroid tissue lacking RXRγ expression, TNHL tissue was found to highly express that RXR isoform (Brtko et al., 2010). The rat model of N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas is a well-established animal model for breast cancer (Macejova and Brtko 2001). In mammary tumors induced by MNU in Sprague-Dawley rats, RAR and RXR were found to be expressed in 40% of carcinomas (Mostbock et al., 2003; Macejova et al., 2005b).

4. P-GLYCOPROTEIN-MEDIATED MDR Multidrug resistance in cancer is a special phenotype in which individual cancer cells develop a partial loss of sensitivity to diverse chemotherapeutic agents with different chemical structures and mechanisms of pharmacological actions (Baguley 2010). This phenotype may be intrinsic, i.e., in relation to special properties of tissue from which the cancer cells were originated, or acquired, i.e., as consequence of selection and adaptation processes under chemotherapeutic treatment of cancer (Dizdarevic and Peters 2011). MDR is a real obstacle for effective chemotherapy and is an important molecular cause of poor prognosis in the treatment of neoplastic patients (Baguley 2010). Studies by many investigators have identified variable mechanisms of MDR, which may be categorized in the following four groups (reviewed in Breier et al., 2005): 1. Activation of detoxifying metabolic pathways as a consequence of the activation and/or overexpression of their key enzymes, such as glutathione S-transferase (Morrow and Cowan 1990a), cytochromes P450 (Pfeil et al., 1994), UDPglucuronosyltransferases (Meijerman et al., 2008) and others. 2. Reduced content of enzymes that are dominant targets for drug action, such as DNA topoisomerase isoenzymes (Morrow and Cowan 1990b). 3. Alterations in drug-induced apoptosis due to changes in the expression and regulation of genes involved in the progression of apoptosis (Pommier et al., 2004). 4. Reduced levels of intracellular drug concentrations due to drug extrusion by the efflux activity of members of the family of ABC membrane transporters, such as Pglycoprotein (P-gp, 170-kDa glycoprotein, ABCB1 member of the ABC transporter family) (Breier et al. 2005), MDR associated protein (MRP, 190-kDa glycoprotein, ABCC1 member of the ABC transporter family) (Wijnholds 2002) and breast cancer resistance protein (BCRP, 72-kDa glycoprotein, ABCG2 member of the ABC transporter family) (Doyle and Ross 2003). Massive overexpression of P-gp, which was discovered in 1976 as the first member of the ABC transporter family (Juliano and Ling 1976), leads to the most often observed MDR of cancer cells (Breier et al. 2005). Although P-gp-mediated MDR in cancer tissue is a serious problem in cancer chemotherapy and is therefore extensively studied, it remains unsolved (Zhang and Ma 2010). A large amount of research has aimed to find effective ways to modulate P-gp expression and/or drug efflux activity. Effective inhibition of P-gp drug efflux activity by different substances that may be used in combination with anticancer drugs may


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be a suitable way to help resolve this problem at least partially (Li et al., 2007). However, finding an effective way to downregulate P-gp expression in neoplastic tissue is a better possibility to improve the chemotherapy of this type of drug-resistant cancer (Breier et al. 2005). Several drugs, including pentoxifylline (Kupsakova et al., 2004), verapamil (Sulova et al. 2008), oroxylin (Yang et al., 2011) and celecoxib (Huang et al., 2007), were found to block P-gp expression in several cell models. While pentoxifylline, verapamil and celecoxib induced their effects by unknown mechanisms, oroxylin was effective via inhibiting the NF-kappaB signaling pathway. Similarly, metformin downregulated P-gp expression via the depression of the activation of NF-kappaB, which was associated with less active CREB (Kim et al., 2011). However, to find the cause of the downregulation of P-gp expression, effective tools for the modulation of P-gp transcriptional regulation have to be found. Transcriptional control of mdr1, the gene that encodes P-gp, is known to occur by the Pregnan X receptor (PXR) (Kliewer et al., 2002; Cerveny et al., 2007) and constitutive androstane receptor (CAR) activation (Cerveny et al. 2007; Chan et al., 2011). The upregulation of CAR expression could be induced by the activation of the nuclear aryl-hydrocarbon receptor (AhR) by -naphthoflavone (Patel et al., 2007), which may secondarily affect the transcription of CAR-regulated enzymes, including P-gp.

Figure 1. Membrane organization of P-glycoprotein (A) and structure of ABC motif (B). A: TMB – transmembrane domain; NBD – nucleotide binding domain. P-glycoprotein is glycosylated on first extracellular loop. Twelve transmembrane -helixes are believed to form membrane por. B: ABC motif contains two walker motifs common for practically all ABC transporters and often occurred motif C. For more details see (Hyde et al., 1990; Higgins 1992).

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5. MOLECULAR PROPERTIES AND THE REGULATION OF THE EXPRESSION OF P-GLYCOPROTEIN P-gp, an integral glycoprotein in the plasma membrane, is an ATP-hydrolyzing drug efflux pump. It can bind and transport across the plasma membrane an unusually broad, yet well-defined, spectrum of structurally unrelated substances, including antineoplastic agents (vinca alkaloids, taxane, anthracyclines, etc.), immunosuppressive drugs (cyclosporine A, tacrolimus, etc.), opioids (morphine-6-glucuronide, methadone, loperamide, etc.), HIV protease inhibitors (ritonavir, saquinavir, etc.), antibiotics (erythromycin, rifampicin, etc.) and many others (Bauer et al., 2005). We have proposed (Breier et al., 2000) that for recognition at P-gp binding sites, a substrate should possess the following characteristic features: i) a flexible structure giving rise to different structural conformers, ii) a molecular weight lower than 1300 g/mol and iii) a deprotonized character at neutral pH. A relatively high hydrophobicity and molecular size and the existence of at least one tertiary basic nitrogen atom on the drug molecule were found to be important for the interaction with P-gp (Wang et al., 2003). P-gp can also bind P-gp inhibitors, which reverse P-gp-mediated MDR via eliminating its drug efflux activity (Ford et al., 1996). Human P-gp has an apparent molecular mass of 170 kDa (the protein part has an apparent molecular mass of 150 kDa) and contains 1280 amino acids (Loo et al., 2004). The P-gp polypeptide chain consists of two similar halves of 610 amino acids each joined by a linker region consisting of 60 charged residues (Loo and Clarke 1994). Each of the two halves is predicted to form six transmembrane spans and hydrolyze ATP during molecular transport. The minimum functional unit for P-gp in membranes appears to be a monomer. Thus, this structural entity contains i) two transmembrane domains, each composed of six transmembrane helixes, ii) two nucleotide binding domains with consensus to the ABC family and iii) N- and C-termini located in the intracellular space of the cell (Figure 1) (Kvackajova-Kisucka et al., 2001). The identification of P-gp as an ABC transporter comes from its conserved ATP Binding Cassette (ABC) motif common for all ABC transporters. The structural feature of this motif is shown in Figure 1. The twelve -helical spans are believed to form transmembrane pore. The mdr1 gene can be up-regulated in response to diverse stress stimuli induced by several substances, such as vincristine and doxorubicin (Polekova et al., 1992; Bohacova et al., 2006); apicidin, an inhibitor of histone deacetylase (Kim et al., 2008); or by several pathological impulses, such as hypoxia, reoxygenation (Robertson et al., 2009) and intracellular acidification (Lu et al., 2008). Several lines of evidence suggest that regulation occurs at the transcriptional level by the increased activity of the mdr1 promoter region, which contains recognition sites for several transcription factors (Sukhai and Piquette-Miller 2000). As described above, two receptors, PXR and CAR, were identified to be responsible for P-gp transcriptional control (Kliewer et al. 2002; Cerveny et al. 2007; Chan et al. 2011). An additional two nuclear receptors, the vitamin D receptor (VDR) and thyroid hormone receptor (TR), are considered to be modulators of mdr1 gene transcription (Saeki et al., 2011). Substitution of a C by a T at position 7833 in the nuclear receptor-responsive region of mdr1, which is a single nucleotide polymorphism described in the Japanese population (Sai et al., 2003; Sai et al., 2006), decreases the binding affinities of PXR, CAR, VDR and TR to their response elements (Saeki et al. 2011). This substitution also reduces the transcriptional activation of P-gp by these four nuclear receptors. Another single nucleotide polymorphism,


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the substitution of T by a C at position 1211 that was found in Japanese and Caucasian populations, in the mdr1 promoter region (Taniguchi et al., 2003; Takane et al., 2004) results in the formation of a sequence mimic of xenobiotic and hypoxia responsive elements. However, both AhR and hypoxia inducible factor  (HIF ) failed to induce transcriptional activation of mdr1 at this modified site (Saeki et al. 2011).

6. INTERPLAY BETWEEN P-GP TRANSCRIPTIONAL CONTROL AND NUCLEAR RECEPTORS FOR RETINOIDS All four nuclear receptors active in P-gp transcriptional control (PXR, CAR, VDR and TR) bind to DNA as a heterodimer with RXR (Saeki et al. 2011). This fact indicates that interplay between P-glycoprotein expression and the inducible function of vitamin A metabolites may exist. However, information about the effectiveness of 9-cis-retinoic acid, a ligand of RXR receptors (Brtko and Thalhamer 2003), on P-gp expression is lacking. RAR binds not only 9-cis-retinoic acid but also all-trans retinoic acid (Brtko and Thalhamer 2003). All-trans retinoic acid was described to modulate P-gp expression positively in acute myeloid leukemia cells and monocytic leukemic cells (Tokura et al., 2002; Tabe et al., 2006) and negatively in human colon carcinoma cells (Bartolini et al., 2006). Stable transfection of H9, KG-1, NB4 and K562 leukemia cell lines by the RARgene leads to a slight elevation of mRNA that encodes P-gp only in H9 cells, while the quantity of this transcript remains unchanged in KG-1 and NB4 cells and slightly decreases in K562 cells (Stromskaya et al., 2005). However, these trends were not found to reflect changes in P-gp transport activity, as measured by rhodamine 123 retention assays in FACS. All-trans retinoic acid induced an elevation of P-gp mRNA in all parental and RAR-transfected cells. Differences in RARtransfected cells and wild-type counterpart cells were observed only in H9 cells (Stromskaya et al. 2005). Thus, it could be expected that retinoid nuclear receptors and their ligands would affect P-gp expression differently in different types of cells. In P-gp-positive L1210/VCR cells obtained from P-gp-negative parental counterpart L1210 cells by adaptation with vincristine (Polekova et al. 1992), the overexpression of P-gp is associated with increases in RAR and RAR mRNA Sulova. In contrast, RAR and RXR mRNA was decreased in these drug-resistant cells as compared with sensitive cells. Levels of RXR mRNA were found to be slightly decreased in L1210/VCR cells. Neither L1210 nor L1210/VCR cells contained measurable amounts of RXRmRNA. Any significant changes in the expression of mRNAs encoding these nuclear receptors could not be found when L1210/VCR cells were cultivated in the absence or presence of vincristine as the selection factor (Sulova et al. 2008). The ligand of RAR receptors, all-trans retinoic acid, induced only a weak effect on the viability of L1210 cells and their drug-resistant counterparts. When L1210/VCR cells were treated with all-trans retinoic acid alone, an effect on P-gp expression or efflux activity (measured as calcein retention in FACS) was not observed. However, combined treatment of these cells with both verapamil and all-trans retinoic acid induced the downregulation of P-gp expression and activity (Sulova et al. 2008). This result indicated that all-trans retinoic acid in the absence of verapamil could not enter the intracellular space where it has to interact with RAR and, after dimerization with RXR and binding to RARE, induces specific gene transcription (Brtko and Thalhamer 2003; Brtko and Dvorak 2011). Alltrans retinoic acid will pass through the barrier of the plasma membrane of L1210/VCR cells

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to a reduced extent, and it will not reach effective intracellular levels if P-gp, acting as a transport efflux pump at plasma membrane, is operating against the diffusion of all-trans retinoic acid into the intracellular space of these cells. Verapamil (a generally accepted P-gp inhibitor) will block the transport activity of P-gp and could enable all-trans retinoic acid to enter the intracellular space of L1210/VCR cells and exert its effects, including the downregulation of P-gp expression or drug efflux activity. If this mechanism is valid, alltrans retinoic acid must be a P-gp substrate. However, in several independent experiments, all-trans retinoic acid fails to be transported by P-gp (Takeshita et al. 2000; Sulova et al. 2008). Therefore, verapamil must enable all-trans retinoic acid to modulate P-gp expression by a mechanism distinct from the verapamil-induced blockade of P-gp activity. Verapamil was described as a weak or moderate inhibitor of the cytochrome P450 CYP3A (Neuvonen et al., 2006). Moreover, CYP3A4, 5 and 7 were described as enzymes that could modify alltrans retinoic acid to 4-OH-, 4-oxo-, 18-OH- and 5,6-epoxy-retinoic acid, respectively (Marill et al., 2000; Wang et al., 2008). Thus, verapamil, via the blockade of CYP3A and probably other CYP isoenzyme activities, may prevent all-trans retinoic acid modification, enabling all-trans retinoic acid to interact effectively with RAR and induce its effects on P-gp expression and activity. Cellular resistance to all-trans retinoic acid treatment was described in acute promyelocytic leukemia cells (Takeshita et al. 2000; Gallagher 2002). While all-trans retinoic acid-resistant acute promyelocytic leukemia cells have weakly improved P-gp expression, this glycoprotein plays only a limited role, if any, in the resistance to all-trans retinoic acid (Takeshita et al. 2000). Resistance to all-trans retinoic acid was described to be related to the PXR-induced transcription of cytochromes P450, particularly CYP3A (Wang et al. 2008). Thus, the fact that retinoic acid resistance is associated with an improvement of P-gp expression (Takeshita et al. 2000) may be explained by the dual effect of the activated PXR receptor in the transcription of CYP isoenzymes and P-gp (Chen and Raymond 2006). Functional interplay between P-gp and CYP3A was described in relation to PXR and probably CAR as transcriptional regulator of both proteins (Christians et al., 2005; Mudra et al., 2011; van Waterschoot and Schinkel 2011). All-trans retinoic acid together with verapamil or clotrimazole, another inhibitor of cytochrome P450, was described to induce cell differentiation to mature granulocytes in alltrans retinoic acid-resistant HL-60 cells and fresh all-trans retinoic acid-resistant acute promyelocytic leukemia cells isolated from two patients (Kizaki et al., 1996). Any of these three substances applied alone was not able to induce these effects. This study addressed the ability of verapamil to block P-gp activity, which was assumed to improve the retention of all-trans retinoic acid in the intracellular space of cells. However, the authors misinterpreted this point, and verapamil, similar to clotrimazole, induced its effect due to the inhibition of CYP3A because, as described above, all-trans retinoic acid is not substrate of P-gp. This conclusion is consistent with the finding that verapamil and PSC833, another inhibitor of Pgp and a derivative of cyclosporine A, did not increase the intracellular accumulation of alltrans retinoic acid (Takeshita et al. 2000; Tabe et al. 2006; Sulova et al. 2008).

7. POSSIBLE MECHANISM OF ALL-TRANS RETINOIC ACID-INDUCED DOWNREGULATION OF P-GP


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All of the above facts indicate that all-trans retinoic acid, when protected against chemical modification with cytochromes P450, may induce the downregulation of P-gp expression. However, the mechanism by which all-trans retinoic acid is able to induce this effect is still unclear. The simplest way to explain the action of all-trans retinoic acid on P-gp expression may be deduced as follows. All nuclear receptors active in P-gp transcriptional control (PXR, CAR, VDR and TR) induce their regulatory effect after heterodimerization with one of the RXR isotypes (Saeki et al. 2011). Nuclear receptors for all-trans retinoic acid form heterodimers predominantly with RXRs (Brtko and Thalhamer 2003; Brtko 2007a, b). Therefore, it could be speculated that the presence of all-trans retinoic acid in the intracellular space of cells gives an advantage to RARs, which have their ligand and bind to RXR receptors preferentially, and crowds out the nuclear receptors that are active in the induction of P-gp transcription from the effective dimerization. This process will finally lead to the lower expression of P-gp. The inter-competition of two nuclear receptors for the same dimerization partner was previously described for HIF and AhR in their dimerization with their common partner ARNT (Gradin et al., 1996; Takacova et al., 2009). This competition was at least partially responsible for the cross-talk between hypoxia- and aryl-hydrocarboninducible pathways. However, more complicated and less direct, unknown mechanisms may be involved in the all-trans retinoic acid-induced control of P-gp transcription and may be connected to the following known activities of all-trans retinoic acid: i) the induction of the expression of p38 protein kinase (Hormi-Carver et al., 2007), ii) the activation of extracellular regulated protein kinase (ERK) by specific phosphorylation (Alique et al., 2007) or iii) the expression of cyclooxygenase-2 (Alique et al. 2007). These changes induced by all-trans retinoic acid may have special meaning in P-gp-positive cells because i) antagonists of p38 and ERK kinase pathways, SB203580 and PD98059, were found to influence the P-gp-mediated drug resistance of L1210/VCR cells (Barancik et al., 2001; Kisucka et al., 2001) and ii) cyclooxygenase-2 was described to be involved in the regulation of P-gp expression (van Vliet et al., 2010; Sui et al., 2011). Apoptosis induced by all-trans retinoic acid is associated with an alteration in intracellular calcium homeostasis (Schmidt-Mende et al., 2006). Overexpression of P-gp in L1210 cells was found to be associated with the alteration in intracellular calcium homeostasis (Sulova et al., 2005; Seres et al., 2008; Sulova et al., 2009) and in the regulation of apoptosis progression (Gibalova et al., 2009).

CONCLUSION Nuclear receptors for retinoids play an important role in several processes of cancer etiology and pathogenesis. Retinoids, the natural and synthetic ligands of these receptors, are known to influence the transcription of a large number of proteins, and therefore, they exert a strong influence on cell regulatory pathways. In poorly differentiated cancer cells, retinoids induce cell differentiation and apoptosis, giving them a possible application in the treatment of several cancers, including acute promyelocytic leukemia. The role of retinoids is highlighted in the treatment of P-gp-positive malignancies, where their suspected P-gp suppressing activity gives them particular therapeutic meaning.

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ACKNOWLEDGMENTS Our laboratories are supported by the grants from the Slovak grant agencies: APVV grant agency No.: APVV-0120-07, APVV-0084-07, APVV-0290-10, VVCE-0064-07 and VEGA grant agency No.: VEGA 2/0008/11, VEGA 2/0123/10, VEGA 2/0155/09. This contribution was edited for proper English language, grammar, punctuation, spelling, and overall style by one or more of the highly qualified native English speaking editors at American Journal Experts.

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