ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells
Clara Lucía León-Annicchiarico1, Silvia Ramírez-Peinado1, Dídac Domínguez-Villanueva1
1Cell Death Regulation Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Spain.
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.
Insights
2-deoxyglucose (2-DG) and glucose deprivation induce distinct cell death pathways in rhabdomyosarcoma. 2-DG causes apoptosis, while glucose withdrawal leads to necrosis, both mediated by endoplasmic reticulum stress and ATF4.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Altered cellular metabolism is a key characteristic of cancer, presenting therapeutic targets.
- 2-deoxyglucose (2-DG) is a glucose analog used experimentally to simulate glucose starvation.
- Cancer cells exhibit altered metabolic pathways that can be exploited for treatment.
Purpose of the Study:
- To investigate the distinct cell death mechanisms induced by 2-DG and glucose deprivation in rhabdomyosarcoma.
- To elucidate the role of endoplasmic reticulum stress and ATF4 in mediating these distinct cell death pathways.
Main Methods:
- Rhabdomyosarcoma cell line treated with 2-DG and glucose deprivation.
- Analysis of cell morphology, cell death pathways (apoptosis, necrosis, necroptosis, ferroptosis), and endoplasmic reticulum stress markers.
- Investigation of the transcription factor ATF4's role using various hexoses and antioxidants.
Main Results:
- 2-DG induced apoptotic cell death, whereas glucose deprivation resulted in necrotic cell death.
- Both stimuli activated endoplasmic reticulum stress, with ATF4 mediating the cell death pathways.
- Mannose partially protected against 2-DG-induced apoptosis, and hexoses partially prevented glucose deprivation-induced necrosis, correlating with reduced ATF4 levels.
Conclusions:
- 2-DG and glucose deprivation trigger different cell death modalities in rhabdomyosarcoma.
- Endoplasmic reticulum stress and ATF4 are critical mediators of these distinct cancer cell death pathways.
- Targeting these pathways may offer novel therapeutic strategies for rhabdomyosarcoma.
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