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Glycosyltransferase Changes Upon Differentiation of Caco-2 Human Colonie Adenocarcinoma Cells1

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Glycosyltransferase Changes Upon Differentiation of Caco-2 Human Colonie Adenocarcinoma Cells1 [CANCER RESEARCH 51. 3136-3142. June 15. 1991] Glycosyltransferase Changes upon Differentiation of CaCo-2 Human Colonie Adenocarcinoma Cells1 I. Brockhausen,2 P. A. Romero, and A. Herscovics Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 ¡I.B.];and McGill Cancer Centre, McGill University, Montreal, Quebec, Canada H3G l Y6 [P. A. R., A. H.J ABSTRACT primarily associated with /V-linked carbohydrate chains, a sig nificant proportion of glucosamine-labeled glycopeptides were The spontaneous differentiation of CaCo-2 human colonie adenocar- also found in alkali-labile O-linked oligosaccharides (2). The cinuma cells to enterocytes in culture is associated with a decrease in polylactosaminoglycans, particularly those attached to the lysosomal proportion of fucosylated polylactosaminoglycans known to membrane glycoprotein h-lamp-1 (Youakim et al., Cancer Res., 49:6889- carry oncodevelopmental antigens decreases significantly dur 6895, 1989). To elucidate the biosynthetic mechanisms leading to these ing differentiation (2). In particular, the lysosomal membrane alterations we have compared glycosyltransferase activities that are protein h-lamp-1 was shown to be affected by these glycosyla- involved in the synthesis of polylactosaminoglycans and of the ,V-and O- tion changes (3). glycan structures that provide the framework for the attachment of these To elucidate the mechanisms responsible for the decrease in chains. Glycosyltransferase activities in cell homogenates obtained from polylactosaminoglycans with differentiation, we compared the undifferentiated and differentiated CaCo-2 cells were assayed by high glycosyltransferase activities that are involved in the synthesis pressure liquid chromatography separation of enzyme products. The 0- of polylactosaminoglycan chains (Fig. 1) and of the backbone galactosidase activities and extremely high pyrophosphatase activities in structures of O- and TV-linked oligosaccharides in UD3 and D differentiated cells were effectively inhibited by 5 m\i 7-galactonolactone and 10 HIMAMP, respectively. CaCo-2 cells contain most of the enzymes CaCo-2 cells. The synthesis of core structures and of branches of A'-and O-glycans requires distinct sets of glycosyltransferases that are involved in /V-glycan branching jiY-acetylglucosamine (GlcNAc) transferases I to V| with the exception of GlcNAc transferase VI. (4, 5). However, most of the enzymes involved in the elongation The levels of GlcNAc transferase I activities were comparable in un of N- and O-glycans and in the addition of terminal antigens differentiated and differentiated cells, but GlcNAc transferase II to V are the same for both types of glycans. We found increased activities were significantly increased upon differentiation. The enzyme activities for both O- and A'-glycan branching enzymes and activities that are directly involved in the synthesis of linear polylacto decreased activity of the transferase responsible for the syn saminoglycans (Gal|84GlcNAc/33- repeating units), blood group i UDP- thesis of the O-glycan core 1 (Gal/33GalNAc-R) upon differ GlcNAc:Gal/9-R 03-GlcNAc transferase and UDP-Gal:GlcNAc 04-Gal entiation. Unexpectedly, the enzymes directly involved in transferase, were found at similar levels in undifferentiated and differ polylactosaminoglycan biosynthesis, Le, UDP-Gal:GlcNAc entiated CaCo-2 cells. Since GlcNAc transferase III activity is known /34-Gal transferase (/34-Gal-T) and blood group i UDP- to inhibit further branching and galactosylation, these results suggest that its increased activity in differentiated CaCo-2 cells may be partly GlcNAc:Gal,94GlcNAc-R 03-GlcNAc transferase (i 03-Gn-T), responsible for the decreased synthesis of fucosylated polylactosamino remain essentially unchanged with differentiation of CaCo-2 glycans. Differentiated cells showed a 2-fold increase in O-glycan core cells; blood group I UDP-GlcNAc: GlcNAc/33Gal/3-R (GlcNAc 2 UDP-GlcNAc:Gal#JGalNAca-R |GlcNAc to A'-acetylgalactosamine to Gal) ß6-GlcNActransferase, responsible for branching, was (GalNAc)l /?6-GlcNAc transferase activity. In contrast, O-glycan core 1 undetectable. UDP-Gal:GalNAca-R 03-Gal transferase activity was found decreased. Several enzymes that are found in homogenates from normal human colonie tissue are absent or barely detectable in CaCo-2 cells. MATERIALS AND METHODS These include blood group I UDP-GlcNAc:GlcNAc03Gal/3-R (Glc Materials. AG 1-X8 (100-200 mesh, Cl~ form) was purchased from NAc to Gal) 06-GlcNAc transferase, O-glycan core 3 UDP-Glc- Bio-Rad. Bovine serum albumin, Gal/3l-4GlcN Ac, AMP, Triton X- NAc:GalNAca-R /83GlcNAc transferase and O-glycan core 4 UDP- 100, 7-galactonolactone, Galß3GalNAca-Bn, GlcNAc/33 Gal/3-methyl, GlcNAc:GlcNAc/33GalNAc-R (GlcNAc to GalNAc) 06-GlcNAc and GalNAca-Bn were purchased from Sigma. Acetonitrile (190 UV transferase. cutoff) was from Fisher Scientific Co. or Caledon Laboratories. UDP- A'-[l-'4C]acetylglucosamine was synthesized as described previously (6) and diluted with UDP-GlcNAc from Sigma. UDP-[t/-14C]galactose was INTRODUCTION purchased from Amersham and diluted with UDP-Gal from Sigma. CaCo-2 human colonie adenocarcinoma cells differentiate Substrates and Standards. GlcNAc/31-3 GalNAc«-Bn, GlcNAc/31-6 spontaneously into cells with the properties of enterocytes upon (Gal/il-3) GalNAca-Bn, GlcNAc01-6(GlcNAc/31-3)GalNAca-Bn, and GlcNAc/31-6(GlcNAc/31-3Gal£il-3)GalNAc«-Bn were synthesized prolonged culturing (1). This differentiation is accompanied by by Dr. K. L. Matta, Buffalo, NY. GlcNAc/32Man«6 (GlcNAc/32 the acquisition of a brush border and of hydrolytic enzymes Man«3)Man/J-(CH2)8COOCH, |2,2mco) was donated by Dr. O. Hinds- typical of absorptive intestinal cells. CaCo-2 cells were previ gaul, Edmonton, Alberta, Canada. GlcNAc06 (GlcNAc/32) Mana- ously shown to contain polylactosaminoglycans, which could methyl was provided by Dr. R. Shah, Toronto, Ontario, Canada. Man«6 be labeled with fucose and glucosamine. Although these are 3The abbreviations used are: UD, undifferentiated CaCo-2 cells; Bn, benzyl; Received 12/10/90; accepted 4/4/91. D. differentiated CaCo-2 cells; Gal, G, D-galactose; GalNAc, GA, A/-acetyl-D- The costs of publication of this article were defrayed in part by the payment galactosamine: GlcNAc, Gn, A/-acetyl-D-glucosamine; HPLC, high pressure liquid of page charges. This article must therefore be hereby marked advertisement in chromatography; Man, M, D-mannose; meo, (CH2)gCOOCH3; MES, 2-(A/-mor- accordance with 18 U.S.C. Section 1734 solely to indicate this fact. pholino)ethanesulfonate; nmr, nuclear magnetic resonance; T, transferase; ' This research was supported by a grant from the Canadian Cystic Fibrosis 10.2+FI, M«6(GnfJ2M«3)M/i4-Gníí4(F«6)Gn;|2,2+F|, Gn/32 M«6(Gn/32 Foundation to Harry Schachter (Hospital for Sick Children, Toronto), and by M«3) M/i4-Gn/i4(F«6) Gn; |2.24|. Gnf¡2M«6 (Gnß4[Gnß2]Mai) Mß4- grants from the Cancer Research Society and the Canadian Foundation for lleitis GníMGn; |26,24|, Gnfíó(Gnß2)Ma6 (Gnß4[Gnß2]Mai) Mß4-Gnß4Gn; and Colitis to A. H. and the Medical Research Council of Canada to I. B. |bis26.24|, Gnrfó (Gn/i2) M«6(Gnß4[Gnß2]M«3)[Gn/34] M/í4-GníJ4Gn; 2To whom requests for reprints should be addressed, at the Research Institute. |2,2mco|. Gnß2M«6(Gnp¡2M«3)M/3-mco: |bis2,2mco|, Gn/J2 M«6(Gn/J2 The Hospital for Sick Children. 555 University Avenue. Toronto, Ontario M5G M«3)[Gnfí4]Mff-mco; |2,24mco|, Gnf)2 Mnó (Gn/34 [Gnfi2) M«3)Mo-mco; 1X8, Canada. |bis2,24mco|, Gnß2M«6(Gnß4[Gnß2]M«3)[Gnf)4] M/J-mco. 3136 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1991 American Association for Cancer Research. GLYCOSYLTRANSFERASES IN CaCo-2 CELLS Gß4Gn I antigen Nuclear Magnetic Resonance. Samples were prepared by exchanging 106 G(54Gn03 G|M Gnß-H twice with 99.8% D,O (Aldrich) and twice with 99.96% D2O (Merck, Sharpe and Dohme). Samples were dissolved in 99.96% D;O with Sa-Gal-T acetone as the internal standard. Proton nmr spectra were recorded at the Toronto Carbohydrate Research Centre with a Bruker 500-MHz Gn spectrometer. The acetone signal was set at 2.225 ppm. 106 Gnß3Gß4Gnß-R Gn(33G(54Gnß3Gß4-Gnß-R High Pressure Liquid Chromatograph). HPLC separations were car ried out with an LKB or a Waters system as described (12, 13). k i S3-Gn-T Acetonitrile/water mixtures were used as the mobile phase for all columns at a flow rate of 1 ml/min. To separate enzyme products with ß4-Gal-T meo, hexyl, benzyl, and methyl groups, a reverse phase Cm column was Gnß3G(}4Gn(Jfl •*•Gß4Gnß3G(i4Gn0-R used. Free reducing sugars or methylglycosides were separated on a propylamine (NH;) column (Waters carbohydrate analysis column). i antigen Elution of compounds was monitored by measuring the absorbance at 195 nm and counting the radioactivity of collected fractions (12). Gß4Gnß-R Assays for GlcNAc Transfcrases (Table 1). The standard assay mix ture for GlcNAc transferases contained the following ingredients in a total volume of 40/il: 0.125 M GlcNAc; 0.125 M MES, pH 7; 0.125% Gnßfl Triton X-IOO; 12.5 mM MnCl:; 10 niM AMP; 5 mM -y-galactonolactone Fig. 1. Pathways of polylactosaminoglycan synthesis. The enzymes involved (only for substrates with terminal Gal at the nonreducing end as in the synthesis of the blood group i antigen attached to R (R = jV-linked or O- indicated in Table 1); 0.87 mM UDP-[l-'4C]acetylglucosamine (5486 linked oligosaccharides) are present in CaCo-2 cells. The fíó-GIcNActransferase dpm/nmol); substrate (as indicated in Table 1); and 10 >i\cell homog- activity synthesizing the branch of the blood group I antigen is absent from CaCo- enate (0.057 or 0.068 mg protein/ml for D or UD cells, respectively).
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