Glycobiology Advance Access originally published online on July 27, 2006
Glycobiology 2006 16(11):1045-1051; doi:10.1093/glycob/cwl027
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Down-regulation of ß1,4-galactosyltransferase V is a critical part of etoposide-induced apoptotic process and could be mediated by decreasing Sp1 levels in human glioma cells
Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, Gene Research Center, Shanghai Medical College of Fudan University (formerly Shanghai Medical University), Shanghai 200032, China
1 To whom correspondence should be addressed; e-mail: jxgu{at}shmu.edu.cn
Received on March 16, 2006; revised on July 21, 2006; accepted on July 23, 2006
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Abstract |
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ß1,4-Galactosyltransferase V (ß1,4GalT V; EC 2.4.1.38 [EC] ) is considered to be very important in glioma for expressing transformation-related highly branched N-glycans. Recently, we have characterized ß1,4GalT V as a positive growth regulator in several glioma cell lines. However, the role of ß1,4GalT V in glioma therapy has not been clearly reported. In this study, interfering with the expression of ß1,4GalT V by its antisense cDNA in SHG44 human glioma cells markedly promoted apoptosis induced by etoposide and the activation of caspases as well as processing of Bid and expression of Bax and Bak. Conversely, the ectopic expression of ß1,4GalT V attenuated the apoptotic effect of etoposide on SHG44 cells. In addition, both the ß1,4GalT V transcription and the binding of total or membrane glycoprotein with Ricinus communis agglutinin-I (RCA-I) were partially reduced in etoposide-treated SHG44 cells, correlated well with a decreased level of Sp1 that has been identified as an activator of ß1,4GalT V transcription. Collectively, our results suggest that the down-regulation of ß1,4GalT V expression plays an important role in etoposide-induced apoptosis and could be mediated by a decreasing level of Sp1 in SHG44 cells, indicating that inhibitors of ß1,4GalT V may enhance the therapeutic efficiency of etoposide for malignant glioma.
Key words: apoptosis / etoposide / glioma / Sp1 / ß1,4-galactosyltransferase V
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Introduction |
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Malignant gliomas, the most common subtype of primary brain tumors, are considered one of the deadliest of human cancers (Maher et al., 2001
). The poor outcome for patients with malignant glioma is mainly attributed to two characteristics of the tumor: one is invasiveness, which makes total resection less feasible, and the other is drug resistance, resulting in unsuccessful chemotherapy (Weller et al., 1998; DeAngelis, 2001). Because most anticancer agents exert effects via activation of apoptotic pathways common to many cellular stresses, any gene alteration disrupting the intrinsic pathways to execute physiological cell death during tumor development can also make malignant cells resistant to chemotherapy (Bogler and Weller, 2002; Johnstone et al., 2002). Such anti-apoptotic alterations are routinely observed in malignant gliomas, including both the functional loss of tumor suppressors and the deregulated hyperfunction of oncogenic proteins (Johnstone et al., 2002; Steinbach and Weller, 2004).
In this report, we have focused on ß1,4-galactosyltransferase V (ß1,4GalT V) as a potential regulator of apoptosis in glioma cells. Among seven members of ß1,4GalT family that transfer uridine-5-diphosphate-galactose to their respective substrates (Guo et al., 2001; Sato et al., 2001), the ß1,4GalT V preferentially galactosylates the GlcNAcß1
6Man arm of the highly branched N-glycans (Sato et al., 1998), which are characteristic of glioma (Yamamoto et al., 2000). A series of results acquired with great efforts of both our laboratory and others have testified that ß1,4GalT V is essential for glioma to express this transformation-related oligosaccharide (Arango and Pierce, 1988; Shirane et al., 1999; Sato et al., 2000; Xu et al., 2001), indicating a role of ß1,4GalT V in glioma malignancy. More recently, we have reported that ß1,4GalT V performs as a positive growth regulator in several glioma cell lines through Ras/mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling pathways (Jiang et al., 2006). Given the intimate relations between the pathways of cellular proliferation and apoptosis (Harrington et al., 1994), these findings shed light on the role of ß1,4GalT V in the apoptotic response of glioma to chemotherapeutic drugs.
Etoposide (VP16), a topoisomerase-II-inhibitor agent, is one of the most common chemotherapy drugs used for the treatment of malignant glioma, but similar to other agents, its usage is limited by drug resistance (Nagane et al., 1999). The present studies are undertaken to examine the role of ß1,4GalT V in the sensitivity of SHG44 glioma cells to etoposide-induced apoptosis. Our results reveal that the down-regulation of ß1,4GalT V transcription in an Sp1-mediated way is an integral and pivotal part of the etoposide-induced apoptotic process in SHG44 cells, suggesting ß1,4GalT V inhibitors in combination with etoposide as a potent modality to treat patients with malignant glioma.
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Results |
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Interference of ß1,4GalT V expression by transfection with ß1,4GalT V antisense cDNA could promote apoptosis induced by etoposide in SHG44 cells
To evaluate the role of in anticancer agent-induced apoptosis, its antisense cDNA construct or control vector was stably transfected into human glioma cell line SHG44, as previously described (Xu et al., 2002
). As shown in Figure 1A, reduction in the ß1,4GalT V expression sensitized SHG44 cells to etoposide-induced apoptosis as indicated by fragmented and condensed nuclei, suggesting a pro-apoptotic effect of decreasing ß1,4GalT V expression on glioma cells. This conclusion was further supported by FACS assay, as the percentage of apoptotic cells in antisense-transfected SHG44 cells was increased compared with that of the controls (data not shown).
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To identify the proteins responsible for the enhanced apoptotic response in antisense-transfected SHG44 cells, we explored whether ß1,4GalT V has influence on the activation of Caspase-9 or Caspase-3, both of which have been proved to mediate etoposide-induced apoptosis in a variety of cell lines (Yin et al., 2000). As described in Figure 1b, suppression of ß1,4GalT V expression markedly increased the cleavage of Caspase-9 and Caspase-3. Consistent with this, the expression of Bax and Bak, two important promoters of Caspase-9 activation (Wei et al., 2001; Degenhardt et al., 2002), was significantly up-regulated in antisense-transfected SHG44 cells. Moreover, reduced ß1,4GalT V expression enhanced Bid cleavage that is mainly executed by active Caspase-8 and then stimulates Caspase-9 processing together with Bax or Bak (Luo et al., 1998). These data suggested that interference with ß1,4GalT V expression might promote etoposide-induced apoptosis by enhancing the activation of Caspase-9 and Caspase-3.
The expression level of ß1,4GalT V mRNA and N-glycans is decreased with etoposide treatment
To test the possibility that the expression of ß1,4GalT V gene could be regulated by etoposide, we measured the contribution of etoposide in the expression level of ß1,4GalT V mRNA by RT–PCR assay. As shown in Figure 2A, endogenous ß1,4GalT V mRNA expression level was partially decreased in etoposide-treated SHG44 cells.
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It has been reported that ß1,4GalT V plays a critical role in the expression of ß1,6-linked GlcNAc-bearing N-glycans, which is a marker of tumor progress in glioma (Sato and Furukawa, 2004). To examine whether etoposide has an effect on the expression of N-glycans in SHG44 cells, we performed lectin blotting analysis using horseradish peroxidase (HRP)-conjugated Ricinus communis agglutinin-I (RCA-I) that interacts with oligosaccharides terminating with the Galß14GlcNAc group or biotinylated Phaseolus vulgaris leucoagglutinin (L-PHA) that interacts with highly branched N-glycans with the Galß14GlcNAcß16(Galß14GlcNAcß12)Man branch (Sato and Furukawa, 2004). As expected, a significant decrease of the binding of total glycoprotein with RCA-I (Figure 2B, left panel) or L-PHA (Figure 2B, right panel) was observed for several protein bands in cells exposed to etoposide compared with that in the controls. Furthermore, the treatment of SHG44 cells with etoposide decreased the binding with RCA-I on the cell surface (Figure 2C). Together, these observations suggested that etoposide might have a negative effect on ß1,4GalT V expression in SHG44 cells, leading to a decreased level of Galß14GlcNAcß16(Galß14GlcNAcß12)Man branch and thus the highly branched N-glycans.
Etoposide down-regulates ß1,4GalT V promoter activity through reducing the level of transcription factor Sp1
To confirm that the down-regulation of ß1,4GalT V expression by etoposide was at the transcriptional level, we constructed the ß1,4GalT V reporter construct pGL3 (–200/+120), which retained relatively strong promoter activity in cancer cells and contained one Sp1-binding site at nucleotide positions –81/–69 (Sato and Furukawa, 2004). As expected, the transient transfection of the construct pGL3 (–200/+120) into SHG44 cells showed a suppressed activity responding to etoposide treatment in a manner similar to that observed in RT–PCR assay (Figure 3A).
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The general transcription factor Sp1 has been reported as an essential activator in the transcriptional regulation of human ß1,4GalT V gene in cancer cells (Sato and Furukawa, 2004). To investigate whether the inhibitive effect of etoposide on ß1,4GalT V promoter was mediated by Sp1, we introduced site-directed mutagenesis into the Sp1-binding site on the pGL3 (–200/+120) reporter plasmid, as previously described (Sato and Furukawa, 2004). It was found that the mutagenesis of this Sp1-binding site abolished the effects of etoposide on the ß1,4GalT V promoter activity (Figure 3B). In addition, a lower level of Sp1 was observed in extracts prepared from etoposide-treated cells, whereas the level of E2F1, a pro-apoptotic protein, was increased (Figure 3C), suggesting that etoposide may induce apoptosis in glioma cells in part through down-regulating ß1,4GalT V transcription via decreasing Sp1 level. This deduction was further supported in Figure 3d, as the stimulation of ß1,4GalT V promoter activity by transient transfection with Sp1 expression plasmids was largely blunted after etoposide treatment.
Forced expression of ß1,4GalT V could protect SHG44 cells from apoptosis induced by etoposide
To further determine the role of ß1,4GalT V in etoposide-induced apoptosis, we stably transfected SHG44 cells with hemagglutinin (HA)-ß1,4GalT V constructs (Figure 4A) (Jiang et al., 2006). As expected, the ectopic expression of ß1,4GalT V resulted in a remarkable reduction in the number of apoptotic cells in etoposide-contained conditions relative to the control cells (Figure 4B), pointing out that a decreased level of ß1,4GalT V is important for etoposide to induce apoptosis in glioma cells. Similar results were obtained in FACS assay (data not shown).
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Discussion |
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TopAbstractIntroductionResultsDiscussionMaterials and methodsConflict of interest statementAcknowledgmentsReferences |
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Results from previous studies have demonstrated that ß1,4GalT V plays an important role in glioma biology, including growth, invasiveness, and expression of abnormal N-glycans (Shirane et al., 1999
; Xu et al., 2002; Sato and Furukawa, 2004; Jiang et al., 2006). In this study, we explored the relationship between ß1,4GalT V and the sensitivity of glioma cells to etoposide-induced apoptosis. As shown here, morphological and nuclear changes were inhibited, the loss of cell viability was prevented, and the cells in sub-G1 were reduced when ß1,4GalT V expression was suppressed in etoposide-treated SHG44 cells, indicating that ß1,4GalT V might serve as a negative regulator in the apoptotic response of glioma to etoposide.
The activation of caspases plays a critical role in apoptosis (Budihardjo et al., 1999), and two main pathways have been identified to lead to it: one is the extrinsic pathway initiated by death-receptor activation and the other is the intrinsic pathway triggered by various stress signals, including DNA damage and acting through mitochondria (Zimmermann et al., 2001). Crosstalk can occur between these two pathways, resulting in the amplification of mitochondrial release of cytochrome c, which in turn leads to the enhanced activation of Caspase-9 and downstream executioner caspases that are responsible for the cleavage of specific cellular substrates (Zimmermann et al., 2001). To investigate the mechanism by which ß1,4GalT V affected etoposide-induced apoptosis, we examined the potential influence of ß1,4GalT V on the caspase activity. As expected, SHG44 cells transfected with antisense ß1,4GalT V cDNA displayed an enhanced activation of Caspase-9 and Caspase-3, indicating that decreasing ß1,4GalT V expression might sensitize SHG44 cells to etoposide-induced apoptosis via augmenting the transduction of signals leading to the sequential activation of Caspase-9 and Caspase-3. This hypothesis was supported by our observations that the expression of Bax and Bak, two pro-apoptotic Bcl-2-like proteins reported to be essential for mitochondrial dysfunction in response to diverse apoptotic stimuli (Wei et al., 2001), was significantly increased in antisense-transfected SHG44 cells. Furthermore, the cleavage of Bid, another member of the Bcl-2 family, was increased by suppression of ß1,4GalT V expression. Bid is believed to stand at the crossroads of mitochondria and death receptor, as it is cleaved by active Caspase-8 to form truncated Bid (tBid), which in turn stimulates Bax- or Bak-mediated cytochrome c release (Luo et al., 1998; Broaddus et al., 2005). As a DNA topoisomerase-II inhibitor, etoposide causes an accumulation of protein-linked DNA double-strand breaks (Dolega, 1998) and thus induces apoptosis chiefly through mitochondrial pathway with little influence on the activation of Caspase-8 or Bid (Miao et al., 2003; Broaddus et al., 2005). In this background, our observations suggest that interference with ß1,4GalT V expression may complement and reinforce the apoptotic effect of etoposide on glioma via augmenting the signal transduction in both extrinsic and intrinsic pathways, leading to the enhanced activation of caspases.
Another important finding of this study is that the expression of ß1,4GalT V gene was partially down-regulated in etoposide-treated SHG44 cells in an Sp1-mediated way, which was suggested by several evidences. (1) The expression level of ß1,4GalT V mRNA was down-regulated with the treatment of etoposide, correlated with a lower level of Sp1. (2) The transient transfection of the ß1,4GalT V reporter construct into SHG44 cells showed a suppressed activity responding to etoposide, which was abolished by the mutagenesis of the Sp1-binding site on the construct. (3) The positive effect of increasing Sp1 expression on ß1,4GalT V promoter activity could be blocked by etoposide treatment. Consistently, the level of highly branched N-glycans with the Galß14GlcNAcß16(Galß14GlcNAcß12)Man branch which has been reported to play a major role in glioma invasivity (Yamamoto et al., 2000) was decreased in etoposide-treated cells, indicating that etoposide may down-regulate ß1,4GalT V transcription as an integral part of its apoptotic action to inhibit the expression of transformation-related highly branched N-glycans. In addition, it has been pointed out that ß1,4GalT V functions as a positive growth regulator in glioma via contributing to the activation of AKT and MAPK pathways (Jiang et al., 2006), both of which are important for facilitating tumor cell proliferation, inhibiting apoptosis, and maintaining the tumor phenotype (Jetzt et al., 2003; Shi et al., 2004; Nakada et al., 2005). Taking all these facts into account, we conclude that etoposide might induce apoptosis in SHG44 cells in part through inhibiting the pro-survival and anti-apoptotic effect of ß1,4GalT V by down-regulating ß1,4GalT V transcription in an Sp1-mediated way.
Furthermore, the forced expression of ß1,4GalT V rendered SHG44 cells considerably resistant to even high-dose etoposide, suggesting that a decreased level of ß1,4GalT V expression is not only an integral part but also an essential condition of etoposide-induced apoptosis in glioma. The detailed mechanism underlying the interaction between ß1,4GalT V and etoposide seems to associate with the complex network of multiple interrelated pathways regulating the proliferation and death of glioma cells and demands further research.
Thus, all data presented here suggest that (1) the down-regulation of ß1,4GalT V expression is an integral and essential part of etoposide-induced apoptosis in glioma and could be mediated by decreasing Sp1 level and (2) interfering with ß1,4GalT V expression could synergistically and additively augment the apoptotic effect of etoposide on SHG44 cells. Our findings may provide some clinical significance in the killing of malignant glioma cells, as combined treatment with ß1,4GalT V inhibitors and DNA-damaging agents will help achieve more effective therapy with less toxicity by using a lower dose of cytotoxic drugs.
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Materials and methods |
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Plasmids
Expression constructs for HA-pcDNA3.0, pGL3 (–200/+120) and M (Sp1) have been previously described (Xu et al., 2002
; Jiang et al., 2006). PEVR2-Sp1 (human) was a generous gift from Prof. Dr. Guntram Suske (Marburg, Germany). PRL-CMV was purchased from Promega Corporation (San Luis Obispo, CA).
Cell culture
Human glioma cell line SHG44 and SHG44 cells stably transfected with pcDNA3.0, HA-ß1,4GalT V, or ß1,4GalT V antisense cDNA were previously described (Xu et al., 2002; Jiang et al., 2006). All these cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% bovine calf serum, 100U/mL of penicillin and 50µg/mL of streptomycin at 37°C in a humidified CO2 incubator (5% CO2, 95% air).
Antibodies and reagents
Bovine calf serum, DMEM, TRIzol reagent and LipofectAMINE reagent were purchased from Invitrogen (Carlsbad, CA). Phenylmethylsulfonyl fluoride, aprotinin, pepstatin, dithiothreitol, Hoechst33258, dimethyl sulfoxide, and etoposide (VP16) were from Sigma Chemical (Saint Louis, MO). Sialidase was from Boehringer Mannheim (Mannheim, Germany). Anti-Sp1 antibody was purchased from Active Motif (Carlsbad, CA). Anti-glyceraldehyde-3-phosphate dehydrogenase (anti-GAPDH) and anti-E2F1 antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-cleaved Caspase-3, anti-cleaved Caspase-9, anti-Bax, anti-Bak, and anti-Bid antibodies were purchased from Cell Signal Technology (Boston, MA). Anti-HA antibody was from Roche Applied Science (Indianapolis, IN). Anti-mouse-HRP secondary antibody and anti-rabbit-HRP secondary antibody were purchased from New England Biolabs (Ipswich, MA). HRP-conjugated RCA-I was from EY Laboratory (San Mateo, CA). Biotinylated L-PHA was purchased from Vector Laboratories (Burlingame, CA). HRP-conjugated Streptavidin was from Southern Biotechnology Associates (Birmingham, AL).
Analysis of nuclear morphology by fluorescence staining
Cells grown on the glass coverslips were treated with different doses of etoposide as indicated for 16h, and then the fluorescence staining was performed as previously described (Li et al., 2005).
Western blot analysis
Total cell lysates from mock- or antisense-transfected SHG44 cells were analyzed by western blot with indicated antibodies as previously described (Li et al., 2005), using an antibody to the GAPDH to ensure equivalent loading.
RT–PCR
Total RNA 1µg extracted from cells treated with different concentrations of etoposide for 4h was analyzed by RT–PCR as our previous report with following primers: ß1,4GalT V forward 5'-TGAGAACAATCGGTGCATCAG-3' and ß1,4GalT V reverse 5'-CTCAATCCGCCAAATAACTC-3' (Xu et al., 2001). The PCR products for ß1,4GalT V were 657bp.
Lectin blotting and RCA-I lectin staining analysis
RCA-I staining analysis was performed basically as previously described (Xu et al., 2002). Briefly, cells coated on the glass coverslips were treated with vehicle or etoposide (200µM) for 12 h and then were fixed with 4% paraformaldehyde/phosphate-buffered saline (PBS) for 30min. To eliminate terminal sialic acid moieties, we treated cells with sialidase (0.03U/mL) for 5h at 37°C. Endogenous peroxidase activity was blocked with 0.3% H2O2/methanol for 30min. To minimize nonspecific binding reactions, we covered specimens for 30 min with 1% bovine serum albumin in Tris-buffered saline (TBS). Following this, cells were incubated at 37°C for 2h in the presence of HRP-conjugated RCA-I (4µg/µL). After rinsing the cells thoroughly in PBS, they were stained by treating the coverslips with 3,3'-diaminobenzidinetetra hydrochloride (DAB) solution for 3min. Finally, the samples were dehydrated, cleared, and mounted.
Total extracts from cells treated with different doses of etoposide for 4h were analyzed by lectin blotting assay with RCA-I or L-PHA (Zhu et al., 2005). The GAPDH western blot served as a loading control.
Dual luciferase assay
Cells seeded in 24-well plates were transfected (Zhu et al., 2005). After 24h, cells were treated with vehicle or etoposide for 4h. Then, cell lysates were prepared, and the luciferase activities were measured using a Dual Luciferase Reagent kit (Promega) and a LB 9507 luminometer (Berthold GmbH, Wildbad, Germany).
Statistics and presentation of data
All experiments were repeated three times. All numerical data were expressed as mean ± SD. Data were analyzed using the two-tailed t-test.
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Conflict of interest statement |
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None declared.
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Acknowledgments |
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TopAbstractIntroductionResultsDiscussionMaterials and methodsConflict of interest statementAcknowledgmentsReferences |
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This work was supported by 863 Program of China (2001AA234031), National Natural Scientific Foundation of China (30330320 and 30300099), National Basic Research Program (2002CB512803), and a grant from the development of science and technology of Shanghai (02DJ14002).
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Abbreviations |
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GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GlcNAc, N-acetylglucosamine; HA, hemagglutinin; HRP, horseradish peroxidase; MAPK, mitogen-activated protein kinase; PHA, Phaseolus vulgaris leucoagglutinin; RCA, Ricinus communis agglutinin; VP16, etoposide; ß1,4GalT V, ß1,4-galactosyltransferase V
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References |
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