Altered glycosylation of proteins produced by malignant cells, and application for the diagnosis and immunotherapy of tumours

Kobata, Akira; Amano, Junko

doi:10.1111/j.1440-1711.2005.01351.x

Cited by 222 publications

(183 citation statements)

References 59 publications

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“…18,19 Analyses of the Ost3p and its yeast paralogue Ost6p (human MagT1/IAP) demonstrated their function in regulating glycosylation efficiency 36 and recently also uncovered their oxidoreductase activity as well as a possible role in magnesium transport. 37 Aberrant glycosylation of proteins can be observed in essentially all in vitro cancer models and human cancers, and many glycosylated epitopes constitute tumor-associated antigens, 38,39 sustaining a long-standing debate regarding whether and how protein glycosylation is involved in tumorigenesis. Recently, global DNA methylation changes in ovarian cancer cells were linked to significant alterations of protein glycosylation.…”

Section: Discussionmentioning

confidence: 99%

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Pils

Horak

Vaňhara

et al. 2012

Cancer

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BACKGROUND. Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer. METHODS. Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction-based methods. RESULTS. The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression-free and overall survival. CONCLUSIONS. TUSC3 hypermethylation predicted progression-free and overall survival in ovarian cancer. The current observations suggested a role for N-glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease. Cancer 2013;119:946-54. V C 2012 American Cancer Society.KEYWORDS: TUSC3, methylation, ovarian cancer, glycosylation, progression-free survival, overall survival, biomarker.. INTRODUCTIONEpithelial ovarian cancer is the most lethal gynecologic malignancy and the fourth most frequent cause of cancer-related death among women in industrialized countries. 1 Because >75% of women are diagnosed with advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stages III and IV), an early diagnosis presents 1 of the challenges of this disease. Patients with advanced ovarian cancer undergo intensive multimodal therapy consisting of cytoreductive surgery and (neo)adjuvant platinum-based and taxane-based chemotherapy. Regardless of the progress made in surgical and medical therapies over recent decades, the outcome for women with advanced ovarian cancer remains grim. Innovative, hypothesis-driven approaches to biomarker development remain essential even in the era of high-throughput sequencing and various omics. Studies of promoter methylation patterns in tumor suppressor genes have yielded several promising methylated biomarker candidates. [2][3][4] In contrast to a gene or protein expression analysis, methylation can easily be detected using polymerase chain reaction (PCR)-based methods in both tumor material and body fluids. [5][6][7] TUSC3 (tumor suppressor candidate 3), originally named N33, was identified as a potential tumor suppressor gene in prostate cancer 8,9 and is located on chromosome band 8p22. Known homozygous deletions of this region in pancreatic cell lines 10,11 and prostate cancer cell lines 12,13 contain no other cancer-related genes except TUSC3, although mutations of the T...

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Section: Discussionmentioning

confidence: 99%

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Pils

Horak

Vaňhara

et al. 2012

Cancer

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“…In addition, alterations of the sugar chain of glycoproteins are associated with various diseases such as cancer (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

“…It is the most prevalent co-translational modification that occurs in the lumen of the ER. N-linked glycosylation plays an important role in maintaining protein stability, modulating protein-protein interactions, and protein membrane targeting (19)(20)(21).In addition, alterations of the sugar chain of glycoproteins are associated with various diseases such as cancer (22)(23)(24).In human GGCX, there are 9 potential N-linked glycosylation sequons. A study of the membrane topology of GGCX (25) demonstrated that all of the potential glycosylation sites are located in the ER lumen where the glycosylation enzymes occur.…”

mentioning

confidence: 99%

Identification of the N-Linked Glycosylation Sites of Vitamin K-Dependent Carboxylase and Effect of Glycosylation on Carboxylase Function

Tie¹,

Zheng²,

Pope³

et al. 2006

Biochemistry

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The vitamin K-dependent carboxylase is an integral membrane protein which is required for the post-translational modification of a variety of vitamin K-dependent proteins. Previous studies have suggested carboxylase is a glycoprotein with N-linked glycosylation sites. In the present study, we identified the N-glycosylation sites of carboxylase by mass spectrometric peptide mapping analyses combined with site-directed mutagenesis. Our mass spectrometric results show that the N-linked glycosylation in carboxylase occurs at positions N459, N550, N605, and N627. Eliminating these glycosylation sites by changing asparagine to glutamine caused the mutant carboxylase to migrate faster in SDS-PAGE gel analyses, adding further evidence that these sites are glycosylated. In addition, the mutation studies identified N525, a site not recoverable by mass spectroscopy analysis, as a glycosylation site. Furthermore, the potential glycosylation site at N570 is glycosylated only if all the five natural glycosylation sites are simultaneously mutated. Removal of the oligosaccharides by glycosidase from wild-type carboxylase or by eliminating the functional glycosylation sites by site-directed mutagenesis did not affect either the carboxylation or epoxidation activity when the small pentapeptide FLEEL was used as substrate, suggesting that N-linked glycosylation is not required for the enzymatic function of carboxylase. In contrast, when site N570 and the five natural glycosylation sites were mutated simultaneously, the resulting carboxylase protein was degraded. Our results suggest that N-linked glycosylation is not essential for carboxylase enzymatic activity but it is important for protein folding and stability.The vitamin K-dependent carboxylase, also known as gamma-glutamyl carboxylase (GGCX) 1 , is an integral membrane protein of the endoplasmic reticulum. It catalyzes the post-translational modification of specific glutamic acid residues of vitamin K-dependent proteins to γ-carboxyglutamic acid residues. This post-translational modification is critical for the biological functions of the vitamin K-dependent proteins involved in blood coagulation, bone metabolism, signal transduction, and cell proliferation (1-3). In addition to its vitamin K-dependent substrate, the carboxylation reaction, which occurs in the lumen of the ER (4, 5), requires the co-substrates carbon dioxide, oxygen, and vitamin K hydroquinone. During the process of carboxylation, the γ-proton of the glutamic acid is abstracted, followed by the addition of carbon dioxide (6-9). Concomitant with carboxylation, vitamin K hydroquinone is oxidized to vitamin K epoxide which must be converted back to vitamin K by the enzyme vitamin K epoxide reductase, thus completing the vitamin K cycle (1, 10). The formation of vitamin K epoxide during the carboxylation reaction has been called an epoxidation reaction (9,11,12 It has been reported that GGCX binds to lectin suggesting that it is a glycoprotein (14, 15). Moreover, Endoglycosidase H treatment of GGCX purifi...

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“…1,2 Glycosylation of proteins has been shown to change during malignant transformation; oligosaccharide expression is highly relevant to many diseases and the alteration of PTMs in proteins is one of the common features of cancer. 3,4 Among those, the most significant changes in carbohydrates have been described in terms of increased N-acetylglucosamine -1-6 branching in oligosaccharides, 5 inappropriate expression of polylactosamine extension, 6 or sialylation of the MUC1 mucin molecule resulting in the presence of truncated O-linked oligosaccharides chains accompanying breast cancer. 7,8 Aggressive cancers have also been reported to induce elevated levels of mono-and trisialylated oligosaccharides, found only in trace levels in nonaggressive cancers.…”

Section: Introductionmentioning

confidence: 99%

N-Glycomic Changes in Human Breast Carcinoma MCF-7 and T-Lymphoblastoid Cells After Treatment with Herceptin and Herceptin/Lipoplex

et al. 2010

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The humanized monoclonal antibody IgG1 in combination with chemotherapy has been demonstrated to enhance survival benefit in cancer treatment. Despite positive outcomes, some cancer cells develop multidrug resistance. Numerous mechanisms in cancers can be involved in the process of treatment therapy and most of them are not still well understood. To address how the carbohydrate moieties of cells are affected during treatment, the glycan profiles from the two most common cancer cell lines s human breast MCF-7 carcinoma and T-lymphoblastoid CEM cells s were studied here and compared with profiles after treatment with Herceptin alone or in combination with Lipofectamine mixed with plasmid DNA to form Lipoplex. N-Glycans were released from total cells by digestion with PNGaseF and analyzed by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). In summary, both original cell lines showed a dominant occurrence of high-mannose glycans. After treatment, these structures were suppressed and biantennary core-fucosylated glycans originating from IgG1 were the major carbohydrate products identified in cells. The high incidence of additional fucosylated or nonfucosylated galactosylated oligosaccharides, which were not detected in original cells or Herceptin, varied with conditions and time of exposure of cells to the antibody. The results presented in this study provide strong evidence for a role of glycosylation during antibody treatment.

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Altered glycosylation of proteins produced by malignant cells, and application for the diagnosis and immunotherapy of tumours

Cited by 222 publications

References 59 publications

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Methylation status of TUSC3 is a prognostic factor in ovarian cancer

Identification of the N-Linked Glycosylation Sites of Vitamin K-Dependent Carboxylase and Effect of Glycosylation on Carboxylase Function

N-Glycomic Changes in Human Breast Carcinoma MCF-7 and T-Lymphoblastoid Cells After Treatment with Herceptin and Herceptin/Lipoplex

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