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      Inhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis

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          Abstract

          Cancer aberrant N- and O-linked protein glycosylation, frequently resulting from an augmented flux through the Hexosamine Biosynthetic Pathway (HBP), play different roles in tumor progression. However, the low specificity and toxicity of the existing HBP inhibitors prevented their use for cancer treatment. Here we report the preclinical evaluation of FR054, a novel inhibitor of the HBP enzyme PGM3, with a remarkable anti-breast cancer effect. In fact, FR054 induces in different breast cancer cells a dramatic decrease in cell proliferation and survival. In particular, in a model of Triple Negative Breast Cancer (TNBC) cells, MDA-MB-231, we show that these effects are correlated to FR054-dependent reduction of both N- and O-glycosylation level that cause also a strong reduction of cancer cell adhesion and migration. Moreover we show that impaired survival of cancer cells upon FR054 treatment is associated with the activation of the Unfolded Protein Response (UPR) and accumulation of intracellular ROS. Finally, we show that FR054 suppresses cancer growth in MDA-MB-231 xenograft mice, supporting the advantage of targeting HBP for therapeutic purpose and encouraging further investigation about the use of this small molecule as a promising compound for breast cancer therapy.

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          Most cited references34

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          Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls.

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            Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation.

            The number of N-glycans (n) is a distinct feature of each glycoprotein sequence and cooperates with the physical properties of the Golgi N-glycan-branching pathway to regulate surface glycoprotein levels. The Golgi pathway is ultrasensitive to hexosamine flux for the production of tri- and tetra-antennary N-glycans, which bind to galectins and form a molecular lattice that opposes glycoprotein endocytosis. Glycoproteins with few N-glycans (e.g., TbetaR, CTLA-4, and GLUT4) exhibit enhanced cell-surface expression with switch-like responses to increasing hexosamine concentration, whereas glycoproteins with high numbers of N-glycans (e.g., EGFR, IGFR, FGFR, and PDGFR) exhibit hyperbolic responses. Computational and experimental data reveal that these features allow nutrient flux stimulated by growth-promoting high-n receptors to drive arrest/differentiation programs by increasing surface levels of low-n glycoproteins. We have identified a mechanism for metabolic regulation of cellular transition between growth and arrest in mammals arising from apparent coevolution of N-glycan number and branching.
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              Cell surface protein glycosylation in cancer.

              Glycosylation of proteins is one of the most important PTMs, with more than half of all human proteins estimated to be glycosylated. It is widely known that aberrant glycosylation has been implicated in many different diseases due to changes associated with biological function and protein folding. In cancer, there is increasing evidence pertaining to the role of glycosylation in tumour formation and metastasis. Alterations in cell surface glycosylation, particularly terminal motifs, can promote invasive behaviour of tumour cells that ultimately lead to the progression of cancer. While a majority of studies have investigated protein glycosylation changes in cancer cell lines and tumour tissue for individual cancers, the review presented here represents a comprehensive, in-depth overview of literature on the structural changes of glycosylation and their associated synthetic enzymes in five different cancer types originating from the breast, colon, liver, skin and ovary. More importantly, this review focuses on key similarities and differences between these cancers that reflect the importance of structural changes of cell surface N- and O-glycans, such as sialylation, fucosylation, degree of branching and the expression of specific glycosyltransferases for each cancer. It is envisioned that the understanding of these biologically relevant glycan alterations on cellular proteins will facilitate the discovery of novel glycan-based biomarkers which could potentially serve as diagnostic and prognostic indicators of cancer. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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                Author and article information

                Contributors
                +39 02 64483526 , ferdinando.chiaradonna@unimib.it
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                7 March 2018
                7 March 2018
                March 2018
                : 9
                : 3
                : 377
                Affiliations
                [1 ]ISNI 0000 0001 2174 1754, GRID grid.7563.7, Department of Biotechnology and Biosciences, , University of Milano-Bicocca, ; Milan, 20126 Italy
                [2 ]ISNI 0000 0001 1940 4177, GRID grid.5326.2, Institute of Molecular Bioimaging and Physiology (IBFM), , CNR, ; Segrate, 20090 Italy
                [3 ]ISNI 0000000106678902, GRID grid.4527.4, Environmental Health Sciences Department, , Istituto di Ricerche Farmacologiche Mario Negri, ; Milan, 20156 Italy
                [4 ]ISNI 0000 0001 2174 1754, GRID grid.7563.7, School of Medicine and Surgery, , University of Milan-Bicocca, ; Monza, 20900 Italy
                Author information
                http://orcid.org/0000-0001-8529-2732
                Article
                405
                10.1038/s41419-018-0405-4
                5841296
                29515119
                1e7ba12c-4307-4602-b7de-9f1f9079790a
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 December 2017
                : 12 February 2018
                : 14 February 2018
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                © The Author(s) 2018

                Cell biology
                Cell biology

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