ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells

Clara Lucía Leõn-Annicchiarico, Silvia Ramírez-Peinado, Dídac Domínguez-Villanueva, Anika Gonsberg, Theodore Lampidis, Cristina Muñoz-Pinedo

Research output: Contribution to journalArticle

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Abstract

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 ATF4 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 ATF4. 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. Glucose deprivation and 2-deoxyglucose are frequently considered identical stimuli. Here we show that in the same cell lines, these stimuli induce necrosis (glucose withdrawal) or apoptosis (2-deoxyglucose). Intriguingly, both treatments induce the Unfolded Protein Response transcription factor ATF4, which mediates cell death in both instances.

Original languageEnglish (US)
Pages (from-to)3647-3658
Number of pages12
JournalFEBS Journal
Volume282
Issue number18
DOIs
StatePublished - Sep 1 2015

Fingerprint

Deoxyglucose
Necrosis
Apoptosis
Glucose
Cell death
Cell Death
Activating Transcription Factor 4
Endoplasmic Reticulum Stress
Rhabdomyosarcoma
Starvation
Metabolism
Cells
Glycosylation
Unfolded Protein Response
Tunicamycin
Cell Line
Hexoses
Mannose
Caspases
Antioxidants

Keywords

  • apoptosis
  • cancer metabolism
  • ER stress
  • glucose
  • rhabdomyosarcoma

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Leõn-Annicchiarico, C. L., Ramírez-Peinado, S., Domínguez-Villanueva, D., Gonsberg, A., Lampidis, T., & Muñoz-Pinedo, C. (2015). ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells. FEBS Journal, 282(18), 3647-3658. https://doi.org/10.1111/febs.13369

ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells. / Leõn-Annicchiarico, Clara Lucía; Ramírez-Peinado, Silvia; Domínguez-Villanueva, Dídac; Gonsberg, Anika; Lampidis, Theodore; Muñoz-Pinedo, Cristina.

In: FEBS Journal, Vol. 282, No. 18, 01.09.2015, p. 3647-3658.

Research output: Contribution to journalArticle

Leõn-Annicchiarico, CL, Ramírez-Peinado, S, Domínguez-Villanueva, D, Gonsberg, A, Lampidis, T & Muñoz-Pinedo, C 2015, 'ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells', FEBS Journal, vol. 282, no. 18, pp. 3647-3658. https://doi.org/10.1111/febs.13369
Leõn-Annicchiarico CL, Ramírez-Peinado S, Domínguez-Villanueva D, Gonsberg A, Lampidis T, Muñoz-Pinedo C. ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells. FEBS Journal. 2015 Sep 1;282(18):3647-3658. https://doi.org/10.1111/febs.13369
Leõn-Annicchiarico, Clara Lucía ; Ramírez-Peinado, Silvia ; Domínguez-Villanueva, Dídac ; Gonsberg, Anika ; Lampidis, Theodore ; Muñoz-Pinedo, Cristina. / ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells. In: FEBS Journal. 2015 ; Vol. 282, No. 18. pp. 3647-3658.
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