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ATF 4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2‐deoxyglucose in the same cells
Author(s) -
LeónAnnicchiarico Clara Lucía,
RamírezPeinado Silvia,
DomínguezVillanueva Dídac,
Gonsberg Anika,
Lampidis Theodore J.,
MuñozPinedo Cristina
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13369
Subject(s) - endoplasmic reticulum , apoptosis , programmed cell death , necrosis , unfolded protein response , necroptosis , biology , microbiology and biotechnology , carbohydrate metabolism , tumor necrosis factor alpha , endocrinology , medicine , chemistry , biochemistry
Altered metabolism is a hallmark of cancer that opens new therapeutic possibilities. 2‐deoxyglucose (2‐ DG ) is a non‐metabolizable glucose analog tested in clinical trials and is frequently used in experimental settings to mimic glucose starvation. However, in the present study, conducted in a rhabdomyosarcoma cell line, we find that 2‐ DG induces classical nuclear apoptotic morphology and caspase‐dependent cell death, whereas glucose deprivation drives cells toward necrotic cell death. Necrosis induced by glucose deprivation did not resemble necroptosis or ferroptosis and was not prevented by antioxidants. Both stimuli promote endoplasmic reticulum stress. Moreover, the transcription factor ATF 4 is found to mediate both the apoptosis induced by 2‐ DG and the glycosylation inhibitor tunicamycin, as well as the necrosis provoked by glucose withdrawal. Several hexoses partially prevented glucose deprivation‐induced necrosis in rhabdomyosarcoma, although only mannose prevented apoptosis induced by 2‐ DG . In both cases, a reduction of cell death was associated with decreased levels of ATF 4. Our results confirm previous data indicating the differential effects of these two forms with respect to inhibiting glucose metabolism, and they place endoplasmic reticulum stress as the critical mediator of glucose starvation‐induced cell death.

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