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Published on: November 15, 2024
Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells
Mariia Yuneva1, Nicola Zamboni, Peter Oefner
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Abstract:
The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on MYC activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer.
Insights
Glucose deprivation kills normal human cells differently than cancer cells. Glutamine deprivation induces MYC-dependent apoptosis in cancer cells, suggesting glutamine metabolism is a potential therapeutic target.
Area of Science:
- Cellular metabolism
- Cancer biology
- Apoptosis
Background:
- Targeting cancer cell metabolism is a promising therapeutic strategy.
- The proto-oncogene MYC influences cellular responses to nutrient deprivation.
- Glucose and glutamine are key nutrients for cancer cell growth.
Purpose of the Study:
- To investigate the differential effects of glucose and glutamine deprivation on normal human cells and MYC-expressing cancer cells.
- To elucidate the mechanisms underlying nutrient-induced cell death.
- To evaluate the potential of nutrient deprivation as a cancer therapy.
Main Methods:
- Comparative analysis of normal human cells and MYC-transduced cells under glucose and glutamine deprivation.
- Assessment of apoptosis induction and cell viability.
- Measurement of Krebs cycle intermediates and ATP levels.
Main Results:
- Glucose deprivation induced non-apoptotic cell death in normal human cells, independent of MYC.
- Glutamine deprivation triggered MYC-dependent apoptosis in cancer cells.
- This glutamine-induced apoptosis was linked to Krebs cycle disruption but not ATP depletion.
Conclusions:
- Normal human cell responses to nutrient deprivation must be considered in cancer therapy development.
- Glutamine metabolism's link to MYC-dependent apoptosis offers potential new therapeutic avenues for cancer treatment.
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