Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction

Abstract

Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinositol 3-kinase (PI3K) and its downstream effector AKT have confirmed that these oncogenes play a direct role in stimulating glucose uptake and metabolism, rendering the transformed cell addicted to glucose for the maintenance of survival. In contrast, less is known about the regulation of glutamine uptake and metabolism. Here, we report that the transcriptional regulatory properties of the oncogene Myc coordinate the expression of genes necessary for cells to engage in glutamine catabolism that exceeds the cellular requirement for protein and nucleotide biosynthesis. A consequence of this Myc-dependent glutaminolysis is the reprogramming of mitochondrial metabolism to depend on glutamine catabolism to sustain cellular viability and TCA cycle anapleurosis. The ability of Myc-expressing cells to engage in glutaminolysis does not depend on concomitant activation of PI3K or AKT. The stimulation of mitochondrial glutamine metabolism resulted in reduced glucose carbon entering the TCA cycle and a decreased contribution of glucose to the mitochondrial-dependent synthesis of phospholipids. These data suggest that oncogenic levels of Myc induce a transcriptional program that promotes glutaminolysis and triggers cellular addiction to glutamine as a bioenergetic substrate.cancer ͉ mitochondria

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…Adherent cell lines 293T (purchased from ATCC) and SFXL (SF188 cells with stable expression of Bcl-XL; generated as previously described 51 ) were maintained at low passage number in high glucose DMEM with 10% FBS, glucose 25 mM, glutamine 4 mM, penicillin 100 units/ml, and streptomycin 100 μg/ml and split every 2–3 days before reaching confluence. Cell lines were authenticated by Short Tandem Repeat (STR) profiling.…”

Glutamine at focus: versatile roles in cancer

“…Subsequent experiments showed that Myc-transformed cells, when challenged with an inhibitor of glutamate-dependent transaminases [known as aminooxyacetate (AOA)], activated the intrinsic apoptotic pathway as the mechanism of cell death. Interestingly, when Myc-transformed cells were supplemented with cell-permeable α-KG, these cells increased sensitivity to resist apoptosis [14]. Other studies have shown that Myc regulates glutamine metabolism in human cancer cells by transcriptionally repressing microRNAs: known as miR23a/b.…”

“…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].…”

The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming

“…Overexpression of Myc promotes the expression of the glutamine transporters ASCT2 and SN2, and the mitochondrial enzyme glutaminase, which converts glutamine to glutamate (Wise et al, 2008;Gao et al, 2009). These events cause cells transformed with Myc to be dependent on glutamine for survival (Yuneva et al, 2007).…”