Please use this identifier to cite or link to this item:
Title: Glycosylation defects, offset by PEPCK-M, drive entosis in breast carcinoma cells
Author: Hyroššová, Petra
Aragó, Marc
Muñoz Pinedo, Cristina
Viñals, Francesc
García-Roves, Pablo M. (Pablo Miguel)
Escolano, Carmen
Méndez Lucas, Andrés
Perales, Jose C.
Keywords: Càncer de mama
Breast cancer
Issue Date: 24-Aug-2022
Publisher: Springer Science and Business Media LLC
Abstract: On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi). In this context, curbing protein glycosylation defects with N-acetyl-glucosamine partially rescued entosis, whereas limiting glycosylation in the presence of glucose with tunicamycin or NGI-1, but not with other unrelated ER-stress inducers such as thapsigargin or amino-acid limitation, stimulated entosis. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is upregulated by glucose deprivation, thereby enhancing cell survival. Therefore, we presumed that PEPCK-M could play a role in this process by offsetting key metabolites into glycosyl moieties using alternative substrates. PEPCK-M inhibition using iPEPCK-2 promoted entosis in the absence of glucose, whereas its overexpression inhibited entosis. PEPCK-M inhibition had a direct role on total protein glycosylation as determined by Concanavalin A binding, and the specific ratio of fully glycosylated LAMP1 or E-cadherin. The content of metabolites, and the fluxes from C-13-glutamine label into glycolytic intermediates up to glucose-6-phosphate, and ribose- and ribulose-5-phosphate, was dependent on PEPCK-M content as measured by GC/MS. All in all, we demonstrate for the first time that protein glycosylation defects precede and initiate the entosis process and implicates PEPCK-M in this survival program to dampen the consequences of glucose deprivation. These results have broad implications to our understanding of tumor metabolism and treatment strategies.
Note: Reproducció del document publicat a:
It is part of: Cell Death & Disease, 2022, vol. 13, num. 8, p. 730
Related resource:
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Files in This Item:
File Description SizeFormat 
724891.pdf2.71 MBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons