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Ganglioside Biosynthesis in Developing Brains and Apoptotic Cancer Cells: X

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Ganglioside Biosynthesis in Developing Brains and Apoptotic Cancer Cells: X Neurochem Res (2012) 37:1245–1255 DOI 10.1007/s11064-012-0762-9 OVERVIEW Ganglioside Biosynthesis in Developing Brains and Apoptotic Cancer Cells: X. Regulation of Glyco-genes Involved in GD3 and Sialyl-Lex/a Syntheses Subhash Basu • Rui Ma • Joseph R. Moskal • Manju Basu Received: 11 November 2011 / Revised: 12 March 2012 / Accepted: 22 March 2012 / Published online: 10 April 2012 Ó Springer Science+Business Media, LLC 2012 Abstract Gangliosides, the acidic glycosphingolipids D-PDMP (inhibitor of glucosylceramide biosynthesis), (GSLs) containing N-acetylgalactosamine and sialic acid Betulinic Acid (a triterpinoid isolated from bark of certain are ubiquitous in the central nervous system. At least six trees and used for cancer treatment in China), Tamoxifen a DSL-glycosyltransferase activities (GLTs Gangliosides, drug in use in the west for treatment of early stages of the the acidic glycosphingolipids (GSLs) containing N-acety- disease in breast cancer patients), and cis-platin (an lgalactosamine and sialic acid (or NAc-Neuraminic acid) inhibitor of DNA biosynthesis used for testicular cancer are ubiquitous in the central nervous system. At least six patients) were used for induction of apoptosis in the above- GSL-glycosyltransferase activities (GLTs) of Basu-Rose- mentioned cell lines. Within 2–6 h, transcriptional modu- man pathway catalyzing the biosynthesis of these gan- lation of a number of glyco-genes was observed by DNA- gliosides have been characterized in developing chicken micro-array (containing over 300 glyco genes attached to brains. Most of these glyco-genes are expressed in the early the glass cover slips) studies. Under long incubation time stages (7–17 days) of brain development and lowered in (24–48 h) almost all of the glyco-genes were downregu- the adult stage, but the cause of reduction of enzymatic lated. The cause of these glyco-gene regulations during activities of these GLTs in the adult stages is not known. In apoptotic induction in metastatic carcinoma cells is order to study glyco-gene regulation we used four clonal unknown and needs future investigations for further metastatic cancer cells of colon and breast cancer tissue explanations. These apoptotic agents could be employed as origin (Colo-205, SKBR-3, MDA-468, and MCF-3). The a new generation of anti-cancer drugs after properly glyco-genes for synthesis of SA-LeX and SA-LeA (which delivered to the patients. contain N-acetylglucosamine, sialic acid and fucose) in these cells were modulated differently at different phases Keywords Apoptosis Á Breast cancer cells Á (between 2 and 48 h) of apoptotic inductions. L-PPMP, Ganglioside biosynthesis Á GD3 Á SA-Lex Á Glyco-gene regulation Special Issue: In Honor of Bob Leeden. Introduction S. Basu (&) Á M. Basu Department of Chemistry and Biochemistry and Cancer Drug Delivery Research Foundation, University of Notre Dame, In the field of Glycosphingolipids (GSLs), the term POBox-752, Notre Dame, IN 46556, USA ‘‘Ganglioside’’ is meant for the GSLs containing sialic e-mail: [email protected] acids (NeuAc or NeuGc). These compounds were isolated R. Ma and purified from brain tissues [1–5] and peripheral ner- Global Assay Development, Siemens Healthcare Diagnostic vous systems [6–10]. Since discovery of GM2-ganglioside Div., Elkhart, IN 46515, USA from human Tay-Sachs brain by Klenk and his associates in 1939 [1] and GM3 from horse erythrocytes by Yama- J. R. Moskal The Falk Center for Molecular Therapeutics, Northwestern kawa and his co-workers in 1951 [11]. Structures of over University, Evanston, IL 60201, USA 180 gangliosides are documented in literature [12]. Kuhn 123 1246 Neurochem Res (2012) 37:1245–1255 and Wiegandt first established the chemical structures of acidic-GSLs were being established in different laborato- GM1, GD1a, and GD1b in 1963 [3]. Structures of all these ries around world, interest in searching the mechanism of naturally occurring gangliosides revealed they could be their synthesis in the normal tissues and cancer cells began classified in three families (Fig. 1) according to the third at almost the same time. The biosynthetic pathway-a for sugar present in the oligosaccharide chains next to cera- synthesis of GD1a ganglioside from ceramide was pro- mide: (1) Ganglio- (GalNAc-Gal-Glc-ceramide), (2) Lacto- posed by Basu and Roseman in 1975 [26–32] (Fig. 3) and (GlcNAc-Gal-Glc-ceramide), and (3) Globo- (Gal-Gal- was first established in embryonic chicken brains. All of Glc-ceramide). However, the simplest gangliosides G7 those glycosyltransferases were isolated, characterized, and (NeuAc2, 3Gal-Ceramide), GM3 (NeuAca2, 3Galb1, cloned in different laboratories. These days it is proved that 4Glc-ceramide), and GD3 (NeuAca2, 8-NeuAca2, 3Galb1, a different gene product catalyzes each enzymatic activity, 4Glc-ceramide) are free of hexosamines (Fig. 2). Sialic and isozymes are widely distributed in different animal acid-containing gangliosides were first characterized in systems. Expression of these genes in normal and diseased brain tissues; later on distribution of these acidic Glyco- stages could be studied by analysis of mRNAs, but very sphingolipids (GSLs) containing both NeuAc and NeuGc little is known about the regulation of these gene expres- has been characterized in blood and other tissues of higher sions during varied biological conditions. Recognition of eukaryotes except in marine animals. In recent years GM3, the exact regulation of these Glyco-genes would give us GD3, LD1, SA-Lex, and SA-Lea have been characterized in tools for disease control and cure in humans. many cancer cells [13–16] including breast and colon In this article an attempt is made to compare gene reg- carcinomas. In case of various neurological inherited dis- ulation of glycosyltransferases in developing brains eases, deposition of specific gangliosides in the tissues is with apoptotic cancer cells. All the enzymes of GD3 and recognized. GM2 is known to be the main ganglioside deposited in Tay-Sachs-diseased (TSD) brain, but how Abbreviated Names Structures excess deposition of this ganglioside hinders the normal Hexosamine Free α function in TSD brain [17, 18] remains unknown. Recently, G7 NeuAc 2-3Gal-Cer NeuAcα2-3Galβ1-4Glc-Cer Dwek and his associates indicated [19] using mouse GM3 GD3 NeuAca2-8NeuAca2-3Galb1-4Glc-Cer models of GM1 and GM2 gangliosidosis that inflammation may play an important role in the pathogenesis of the GalNAcβ1-4Gal-Glc-Cer GalNAc-containing α2-3 gangliosides. GD3 ganglioside has been found in excess in GM2 NeuAc Galβ1-3GalNAcβ1-4Gal-Glc-Cer human meningiomas [20], gliomas [21], and melanomas α2-3 [22]. However, the relationship of these gangliosides to the GM1 NeuAc Galβ1-3GalNAcβ1-4Gal-Glc-Cer exact physiological disorders is not yet known. Both GD1a α2-3 α2-3 x a NeuAc NeuAc SA-Le and SA-Le are present on the cell surfaces of β β GlcNAc-containing Gal 1-4GlcNAc 1-3Gal-Glc-Cer α α1-3 breast and colon cancers [23–25]. A direct role of these X 2-3 SA-Le NeuAc Fuc acidic GSLs to cancer metastasis has not been established. During the last five decades while the structures of these Fig. 2 Structure of gangliosides with and without NAc-hexosamines Fig. 1 Broad classification of (Glycose)n—O—Sphingosine glycosphingolipids (GSLs) | CERAMIDE n=1 to 10 glycoses NH R=C to C | Fatty acid 13 15 CO—R ACIDIC - GSLs NEUTRAL- GSLs Glucuronyl- Sialyl- Mono- Di- Oligo-glycosyl- Gal-cer Glc-cer Gal-Glc-cer ceramide Mono- Di- Polysialo- Blood Groups Globosides Gangliosides- …. (….GlclNAc-Gal-Glc-cer) (….Gal-Gal-Glc-cer) (GalNAc-Gal-Glc-cer) (NeuAc or, NeuGc) Series—[Ganglio-Gg] —[Lacto-Lc] —[Globo-Gb] 123 Neurochem Res (2012) 37:1245–1255 1247 Fig. 3 Basu-Roseman Ceramide D-/L-PDMP ganglioside pathway and cancer GlcT D-/L-PPMP Galα1- 3Galβ1- 4GlcNAcβ1-3Lc2 GSL pathways Inhibitors Glc-Cer GalT-2 nLc5 GlcNAcT- 1 Galβ1-4Glc-Cer SAT-1 Galβ1-4Glc-Cer GlcNAcβ1-3Lc2 α GalT-5 2-3 Lc2 Lc3 SA GM3 GalT-4 SAT- 2 Galβ1-4Glc-Cer GalNAcT-1 β β SA GD3 Gal 1- 4GlcNAc 1-3Lc2 α β 2-8 nLc4 GalNAc 1-4Gal-Glc-Cer SA GalNAcT-1 SAT-3 SA GM2 GlcNAcT-2 Galβ1- 4GlcNAcβ1-3Lc2 GalT-3 β GalNAc 1-4Gal-Glc-Cer α2-3 LM1 SA GlcNAcβ1-3nLc4 β SA GD2 FucT-3 Gal 1- 3GalNAc-Gal-Glc-Cer GalT-3 inLc5 SA SAT-4 SA GM1 Galβ1- 4GlcNAcβ1-3Lc2 GlcNAcT-3 Galβ1-3GalNAc-Gal-Glc-Cer α1-3 SA Fuc Gal-GalNAc-Gal-Glc-Cer GD1b GlcNAcβ1-3 i α SA 2-3 SA-LeX nLc4 SA SA GD1a GlcNAcβ1-6 SA GT1b I Carcino-Embryonic Ii Basu-Roseman Pathway Pathway-b Antigen Ii Core GSLs (or Pathway-a) (Cancer Cells) Lymphoma Cells Embryonic Brain Sialyl-LeX/A biosynthesis are expressed in both the sys- the GlcNAc-containing nLcOse4-ceramide (the intermedi- tems (embryonic brains and breast cancer cells). The age- ate of gangliosides SA-Lex) was established in rabbit bone dependent expression studies of those glycolipid glyco- marrow [50, 51], human neuroblastoma (IMR-32) cells syltransferases raised the question whether those enzymes [52], cultured TSD cells [53], mouse T- and B-lymphomas could be modulated also under induced apoptotic condi- [54, 55], bovine spleen [56, 57], embryonic chicken brains tions of cancer cells. Of course, the expression of glyco- [58–60], and carcinoma cells of colon origin [61–63]. sphingolipids on the surfaces of both apoptotic and Complete biosynthesis of SA-Lex from nLcOse4-ceramide nonapoptotic cells has not yet been revealed exhaustively. to SA-Lex (Fig. 3) has been achieved in colo-205 and However, our finding on the activity and DNA-microarrays embryonic chicken brains [60, 61]. Biosynthesis in studies suggested these could be different at different time vitro of Ii-core glycosphingolipids (GlcNAcbeta1,6(Glc- points (2 and 24 h) and with different concentrations of NAcbeta1,3)Galbeta1,4Glc-R) was achieved in mouse the apoptotic agents (L-PPMP; 2–16 lmol).
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