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      Biosynthetic Machinery Involved in Aberrant Glycosylation: Promising Targets for Developing of Drugs Against Cancer

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          Abstract

          Cancer cells depend on altered metabolism and nutrient uptake to generate and keep the malignant phenotype. The hexosamine biosynthetic pathway is a branch of glucose metabolism that produces UDP-GlcNAc and its derivatives, UDP-GalNAc and CMP-Neu5Ac and donor substrates used in the production of glycoproteins and glycolipids. Growing evidence demonstrates that alteration of the pool of activated substrates might lead to different glycosylation and cell signaling. It is already well established that aberrant glycosylation can modulate tumor growth and malignant transformation in different cancer types. Therefore, biosynthetic machinery involved in the assembly of aberrant glycans are becoming prominent targets for anti-tumor drugs. This review describes three classes of glycosylation, O-GlcNAcylation, N-linked, and mucin type O-linked glycosylation, involved in tumor progression, their biosynthesis and highlights the available inhibitors as potential anti-tumor drugs.

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Mucins in cancer: protection and control of the cell surface.

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              Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.

              O-GlcNAcylation is the addition of β-D-N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins. O-linked N-acetylglucosamine (O-GlcNAc) was not discovered until the early 1980s and still remains difficult to detect and quantify. Nonetheless, O-GlcNAc is highly abundant and cycles on proteins with a timescale similar to protein phosphorylation. O-GlcNAc occurs in organisms ranging from some bacteria to protozoans and metazoans, including plants and nematodes up the evolutionary tree to man. O-GlcNAcylation is mostly on nuclear proteins, but it occurs in all intracellular compartments, including mitochondria. Recent glycomic analyses have shown that O-GlcNAcylation has surprisingly extensive cross talk with phosphorylation, where it serves as a nutrient/stress sensor to modulate signaling, transcription, and cytoskeletal functions. Abnormal amounts of O-GlcNAcylation underlie the etiology of insulin resistance and glucose toxicity in diabetes, and this type of modification plays a direct role in neurodegenerative disease. Many oncogenic proteins and tumor suppressor proteins are also regulated by O-GlcNAcylation. Current data justify extensive efforts toward a better understanding of this invisible, yet abundant, modification. As tools for the study of O-GlcNAc become more facile and available, exponential growth in this area of research will eventually take place.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/244407
                URI : http://frontiersin.org/people/u/73863
                URI : http://frontiersin.org/people/u/244442
                URI : http://frontiersin.org/people/u/244449
                URI : http://frontiersin.org/people/u/234696
                URI : http://frontiersin.org/people/u/73869
                URI : http://frontiersin.org/people/u/54877
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                25 June 2015
                2015
                : 5
                : 138
                Affiliations
                [1] 1Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brasil
                [2] 2Department of Biochemistry, Cardiovascular Proteomics Center, Boston University School of Medicine , Boston, MA, USA
                Author notes

                Edited by: Ala-Eddin Al Moustafa, McGill and Concordia Universities, Canada; Syrian Research Cancer Center of the Syrian Society Against Cancer, Syria

                Reviewed by: Daniel Christian Hoessli, International Center for Chemical and Biological Sciences, Switzerland; Olivier Micheau, Institut national de la santé et de la recherche médicale, France

                *Correspondence: Adriane Regina Todeschini, Instituto de Biofísica Carlos Chagas Filho,Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373 - Cidade Universitária, Rio de Janeiro, 21941902, Rio de Janeiro, Brazil, adrianet@ 123456biof.ufrj.br

                Specialty section: This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2015.00138
                4479729
                26161361
                b3181768-2b60-4eb4-afe7-9297c5c0aed7
                Copyright © 2015 Vasconcelos-dos-Santos, Oliveira, Lucena, Mantuano, Whelan, Dias and Todeschini.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 May 2015
                : 02 June 2015
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 335, Pages: 23, Words: 21983
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                glycans,glycosyltransferases,inhibitors,cancer,hexosamine biosynthetic pathway,o-linked glycan,n-linked glycan,glycoconjugate

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