Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells

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.

Sugar-free approaches to cancer cell killing

“…For instance, tumors with deregulated myc expression may be less sensitive to inhibition of glycolysis than tumors with overactivation of the Akt pathway. Instead, myc-overexpressing tumors could be more susceptible to inhibition of mitochondrial/ glutamine metabolism (Yuneva et al, 2007;Fan et al, 2010).…”

Glutamine at focus: versatile roles in cancer

“…The first to appreciate that glutamine withdrawal induces Myc-dependent apoptosis were Yuneva et al They demonstrated that apoptosis precedes TCA cycle intermediary depletion and might be reverted when cells were incubate in the presence of pyruvate and OAA [15]. Mechanistically, Myc regulates glutamine uptake and glutaminolysis due in part by increasing the transcriptional expression of glutamine transporters, GLS1, and lactate dehydrogenase (LDH).…”

“…The metabolic state is primarily based on nutrients available to the tumors which have rewired their metabolic pathways, thereby contributing to this metabolic autonomy [5][6][7][8]. The discoveries of oncogenes and tumor suppressors that regulate nutrient uptake and its utilization have provided insights that nutrients per se play a pivotal role in cell growth and proliferation through a wide array of cell signaling pathways [9][10][11][12][13][14][15].…”

L’effet Warburg

“…Ce dernier peut, soit être excrété, soit rentrer dans le cycle de Krebs où il est transformé en -cétoglutarate. Les cellules exprimant l'oncogène Myc deviennent dépendantes de la glutamine et entrent en apoptose quand ce composé est retiré du milieu de culture [20].…”