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Sigma-I and Sigma-2 Receptors Are Expressed in a Wide Variety of Human and Rodent Tumor Cell Lines

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Sigma-I and Sigma-2 Receptors Are Expressed in a Wide Variety of Human and Rodent Tumor Cell Lines [CANCERRESEARCH55, 408-413, January 15, 19951 Sigma-i and Sigma-2 Receptors Are Expressed in a Wide Variety of Human and Rodent Tumor Cell Lines Bertold J. Vilner, Christy S. John, and Wayne D. Bowen' Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institute of Diabetes Digestive and Kidney Diseases, National institutes of Health, Bethesda, Maryland 20892 [B. J. V.. W. D. B.], and Radiopharmaceutical Chemistry Section, Department of Radiology, The George Washington University Medical Center, Washington, DC 20037 (C. S .1.1 ABSTRACT Sigma receptors occur in at least two classes which are distinguish able both pharmacologically and by molecular properties (1, 8—10). Thirteen tumor-derived cell lines of human and nonhuman origin and The prototypic sigma ligands, haloperidol, DTG,2 and (+)-3-PPP do from various tissues were examined for the presence and density of not strongly differentiate the sites. However, sigma-i sites are readily sigma-i and sigma-2 receptors. Sigma-i receptors of a crude membrane fraction were labeled using [3H](+)-pentazocine, and sigma-2 receptors distinguished from sigma-2 sites on the basis of their affinity for were labeled with [3H11,3-di-o-tolylguanidine ([3HJDTG); in the presence benzomorphan-type opiates such as pentazocine and SKF 10,047. or absence ofdextrallorphan. [3H](+)-Pentazocine-bindingsites were het Sigma-i receptors exhibit high affinity for (+)-benzomorphans and erogeneous. In rodent cell lines (e.g., C6 glioma, N1E-115 neuroblastoma, lower affinity for the corresponding (—)-enantiomer.Sigma-2 recep and NG1OS—15neuroblastoma x glioma hybrid), human T47D breast tors show the opposite enantioselectivity, having very low affinity for ductal careinoma, human NCI-H727 lung carcinold, and hwnan A375 (+)-benzomorphans. (—)-Benzomorphans do not readily differentiate melanoma, [3H](+)-pentazocine bound to high- and low-affinity sites with the two sites. Other differentiating features of these two sites are as Kdl 0.67-7.0 UM,B@1 = 25.5-108 fmol/mg protein, K@2= 127-600 follows: (a) the apparent molecular weight of sigma-i receptors is fiM, and B@12 = 942-5431 fmol/mg protein. However, [311](+)-pentazo 25,000,comparedto 18,000—21,500forsigma-2,(b) sigma-i recep cine bound to a single site in other cell lines. In human U-13SMG glib tors appear to be sensitive to guanine nucleotides, while sigma-2 blastoma, SK-N-SH neuroblastoma, and LNCaP.FGC prostate, Kd 28-61 asi andB@ = 975-1196fmol/mgprotein,whereasin ThP-1 receptors are not, and (c) sigma-i receptors are allosterically modu leukemia Kd 146 ass and B_11,, = 1411 fmol/mg protein The sigma-i-like lated by ropizine and phenytoin, while sigma-2 sites are not. Sigma-i nature of[3H](+)-pentazocine-biading sites was confirmed by competition receptors are selectively labeled using the (+)-benzomorphan, studies which revealed high affinity for haloperidol and enantloselectlvlty [3H](+)-pentazocine (1 1). No selective probe yet exists for sigma-2 for (+)-pentazocine over (—)-pentazocine.Interestingly,human MCF-7 sites, but they can be labeled using [3H]DTG in the presence of breast adenocarcinoma showed little or no specific binding of I@Hl(+) dextrallorphan to mask labeling of sigma-i sites (1 1, 12, 13, 14). pentazocine, suggesting the absence of sigma-i receptors in this cell line. Cell lines expressing neurotransmitter and hormone receptors All cell lines examined expressed a high density of slgma-2 receptors with have been quite useful in elucidating receptor function at the Kd values for [3H]DTG ranging from 20 to 101 nsi and B@ values of 491 biochemical and cellular levels. Sigma receptors have previously to 7324 fmol/mg protein. Competition studies indiCated possible hetero been demonstrated in tumor-derived cell lines from rodents. Some geneity of sigma-2 receptors. While sites labeled by [311]DTGin all cell lines tested exhibited affinity for haloperidol and prefrrence for (—)- of theseincludePC12pheochromocytomacells(8),NCB-20cells pentazocine over the (+)-enantiomer, human cell lines generally showed (15, 16), and C6 glioma (13). In fact, PC12 cells, C6 glioma, and 4-to7-foldloweraffinityforhaloperidolandapproximately10-foldlower several other rodent-derived cell lines were instrumental in our affinity for (—)-pentazocinecompared with the rodent cell lines. The high initial demonstration of the existence of sigma-2 receptors (8, 13). density of sigma-i and sigma 2-binding sites in these cell lines suggests Here we examine the existence of sigma receptor subtypes in important cellular functions in cancer, as well as potential diagnostic additional cell lines of nonhuman origin, as well as in human tumor utility for tumor-imaging agents which target sigma sites. These cell lines cell lines derived from various tissues and organs. may be useful as model systems In which to study the functions of sigma sites in normal tissues, as well as their possible role in tumor blologj@. MATERIALS AND METHODS INTRODUCTION Cell CUltUre. Cells were plated at a density of 2 X 10―cellsf7S-cm2 plastic flask (Coming Co., Corning, NY) and cultured using standard procedures at Because of their high affinity for most typical neuroleptic drugs, 37°Cina humidified atmosphere of 5% CO@I95%air. Human glioblastoma sigma receptors have received much attention as potential alternative U-138 MG, melanoma A375 (amelanotic), neuroblastoma SK-N-SH, and targets for the development of antipsychotic drugs. However, their breast adenocarcinoma MCF-7 were cultured in DMEM supplemented with high affinity for other classes of compounds, including some anticon 10% FBS. Human breast ductal carcinoma T47D, lung carcinoma NCI-H727, vulsants, antitussives, and neuroprotective agents, have suggested leukemia ThP-1, and metastatic prostate adenocarcinoma LNCaP.FGC were other possible roles of sigma sites (1—7).Details of the functional roles cultured in RPMI with 10% FBS. Rat glioma C6 and mouse neuroblastoma of sigma receptors have remained elusive, although they have been NB41A3 were grown in RPMI 1640 medium supplemented with 10% FBS. implicated in motor function, neurotransmitter synthesis and release, NG1O8—15mouseneuroblastoma X rat glioma hybrid cells were grown in digestive function, regulation of smooth muscle contraction, and DMEM supplemented with 10% FBS, 1% nonessential amino acids, 1% L-glutamine, and 100 units penicillin and 100 @agstreptomycin/mi medium. neurodegeneration. Mouse neuroblastomas N1E-115 and S-20Y were grown in DMEM supple mented with 10% FBS. Media were changed 3 times a week. Received 7/19/94; accepted 11/7/94. Membrane Preparation. Cells were allowed to grow to confluency. After The costs of publication of this article were defrayed in part by the payment of page decantation of the medium, the cells were washed in situ with HBSS. The cells charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. were then detached by scraping with a cell scraper (Costar Corporation, I To whomrequestsforreprintsshouldbeaddressed,atUnit onReceptorBiochemistry Cambridge, MA) in HBSS. Suspended cells were centrifuged for 5—7mm at and Pharmacology, NlDDKThiboratory of Medicinal Chemistry, Bldg. 8, Rm. B1-23, 8 1000 rpm in a cold table-top centrifuge. The cell pellet was resuspended in Center Dr. MSC 0815, Bethesda, MD 20892—0815. ice-cold 10 mMTris-HC1,pH 7.4, containing 0.32 Msucrose to a concentration 2 The abbreviations used are: DTG, 1,3-di-o-tolylguanidine; (+)-3-PPP, (+)-3-(3- hydroxyphenyl)-N-(1-propyl)piperidine;FBS, fetal bovine serum; SKF 10,047, N-allyl of 1 X iO7-i0'@cells/mIand homogenized by 10—12hand-drivenstrokes in a normetazocine. Potter-Elvehjem homogenizer (Teflon pestle). The homogenate was then cen 408 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1995 American Association for Cancer Research. SIGMA RECEPTOR SUBTYPES IN TUMOR CELL UNES trifuged at 31,000 x g for 15 mm at 4°Cand the supematant discarded. The RESULTS final pellet was resuspended in ice-cold 10 mMTris-HC1,pH 7.4, to a protein concentration of 15—20mg/mI,and aliquots were stored at —80°Cuntiluse. Tables 1 and 2 show the results of Scatchard analysis of [3H](+)- Protein concentration was determined by the method of Lowry et al (17) using pentazocine binding to sigma-i sites and [3HJDTG binding (in the BSA as standard. presence or absence of dextrallorphan) to sigma-2 sites in several Radioligand Binding. Sigma-i receptors were labeled using [3H](+)- tumor cell lines of human and rodent origin. All cell lines examined pentazocine (51.7 Ci/mmol) (11). The indicated concentration of radioligand were found to express a high density of sigma-2 receptors labeled by was incubated in a final volume of0.25 ml of 50 mM Tris-HC1, pH 8.0, for 120 [3H]DTG. In each case, plots were linear, suggesting labeling of a mm at 25 or 37°Cusing200 @gofmembraneprotein. Nonspecific binding was determined in the presence of 10 p.M (+)-pentazocine (a similar level of single population of sites. The Kd values for [3H]DTG were generally nonspecific binding was observed using 10 @.aMhaloperidol).Assays were similar across cell lines (20—46nM)and were close to those obtained terminated by addition of 5 ml of ice-cold 10 [email protected],pH 7.4, and for sigma-2 sites in PCi2 cells, rat liver, and rat kidney (8, 14), filtration through glass fiber ifiters using a Brandel (Gaithersburg, MD) cell although the Kd value in C6 glioma, NB41A3 neuroblastoma, harvester. Filters were then washed twice with 5 ml of ice-cold buffer. Filters NG1O8—15hybrid,andhumanU-138MG glioblastomaweresome were soaked in 0.5% polyethyleneimine for at least 30 mm at 25°Cpriorto use. what higher (62—101nM) than in the other cell lines. Bmas values The filters were counted in CytoScint (ICN, Costa Mesa, CA) after an over ranged from 491 fmol/mg protein in ThP-1 leukemia to 7324 fmol/mg night extraction of counts.
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