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 language | English (US) |
|---|---|
| Pages (from-to) | 3647-3658 |
| Number of pages | 12 |
| Journal | FEBS Journal |
| Volume | 282 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 1 2015 |
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Keywords
- apoptosis
- cancer metabolism
- ER stress
- glucose
- rhabdomyosarcoma
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
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 journal › Article
}
TY - JOUR
T1 - ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells
AU - Leõn-Annicchiarico, Clara Lucía
AU - Ramírez-Peinado, Silvia
AU - Domínguez-Villanueva, Dídac
AU - Gonsberg, Anika
AU - Lampidis, Theodore
AU - Muñoz-Pinedo, Cristina
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - apoptosis
KW - cancer metabolism
KW - ER stress
KW - glucose
KW - rhabdomyosarcoma
UR - http://www.scopus.com/inward/record.url?scp=84942042112&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84942042112&partnerID=8YFLogxK
U2 - 10.1111/febs.13369
DO - 10.1111/febs.13369
M3 - Article
C2 - 26172539
AN - SCOPUS:84942042112
VL - 282
SP - 3647
EP - 3658
JO - FEBS Journal
JF - FEBS Journal
SN - 1742-464X
IS - 18
ER -