Ikingly, addition of NacetylDglucosamine, a particular substrate for the hexosamine biosynthesis pathway (HBP), to glucosedepleted cells fully prevents transformed cell death, stressing the crucial role of glucose in HBP fuelling to make sure UPR attenuation and increased cell survival. Interestingly, these benefits have been totally recognized within a human model of breast cancer, MDAMB231 cells. In conclusion, we show that glucose deprivation, major to dangerous accumulation of unfolded proteins in consequence of a reduction of protein glycosylation, induces a UPRdependent cell death mechanism. These findings may possibly open the way for new therapeutic techniques to specifically kill glycolytic cancer cells. Cell Death and Disease (2013) 4, e732; doi:10.1038/cddis.2013.257; published on the internet 18 JulySubject Category: Cancer MetabolismRemodeling of power metabolism is actually a recognized hallmark of cellular transformation that supports the sustained proliferation of cancer cells beneath circumstances that restrict normal cell development.1,2 Therefore, cancer cells rely mainly on glycolysis for ATP production as compared with parental typical cells that use mainly oxidative phosphorylation (OXPHOS).3,4 The shift of power metabolism to aerobic glycolysis is driven each by environmental development conditions and by oncogenic mutations of protoncogenes and tumorsuppressor genes.five,6 Impaired mitochondrial function is a further crucial feature of transformed cell metabolic reprogramming.2,three,7 In situations of limited glucoseavailability, very proliferating glucoseaddicted cancer cells lose their enhanced growth capacity and, ultimately, die.8 Diverse processes are related with and may contribute for the death of transformed cells in glucose deprivation, like ATP level lower, radical oxygen species (ROS) accumulation and typically mitochondrial dysfunction.91 After triggered, these processes may perhaps induce cell death by activating a mitochondrial apoptotic route, through regulation of Bcl2 homology 3only proteins, by activating a caspase8dependent apoptotic method or by inducing necrosis.6-Bromo-7-methoxyquinazolin-4(1H)-one custom synthesis 124 Because the glucosedependent mechanism of cancer cell death may well present a valuable target by way of which apoptosis may well be induced in tumors while1 SYSBIO, Centre of Systems Biology, Piazza della Scienza two, Milano 20126, Italy; 2Department of Biotechnology and Biosciences, University of MilanoBicocca, Piazza ` della Scienza 2, Milano 20126, Italy; 3LATOHSR G.Pd 122 web Giglio, contrada Pietrapollastra Pisciotto, Cefalu 90015, Italy; 4Institute of Bioimaging and Molecular Physiology, National Research Council, through F lli Cervi 93, Segrate 20090, Italy and 5Department of Biomedical Sciences for Well being, University of Milan, by means of F lli Cervi 93, Segrate 20090, Italy Corresponding author: F Chiaradonna, SYSBIO, Centre of Systems Biology, Piazza della Scienza two, 20126 Milano (MI), Italy or Division of Biotechnology and Biosciences, University of MilanoBicocca, Piazza della Scienza 2, Milano 20126, Italy.PMID:33657961 Tel: 39 02 64483526; Fax: 39 02 64483552; E mail: [email protected] 6 Present address: Department of Experimental Oncology, European Institute of Oncology (IEO), By way of Adamello 16, 20139 Milan, Italy. Key phrases: cancer cell metabolism; glucose depletion; unfolded protein response; hexosamine biosynthesis pathway; cancer cell death Abbreviations: CHOP, C/EBP homology protein; CHX, cycloheximide; eIF2a, eukaryotic initiation aspect 2a; ER, endoplasmic reticulum; GlcNAc, NacetylDglucosamine; Grp78, gl.