MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype.

Vincent Tambay,Valérie-Ann Raymond,Marc Bilodeau

doi:10.3390/cancers13174484

Abstract

Simple SummaryIn the last decade, metabolic reprogramming has emerged as a driving characteristic of cancer cells. The MYC oncogene, a transcription factor, has become of growing interest as a fundamental driver of differential cancer cell metabolism. Furthermore, the non-essential amino acid glutamine is deemed to be an important nutrient for cancer cells. In fact, glutamine can integrate into a wide variety of metabolic pathways, from energy metabolism to nucleotide synthesis. This review offers a comprehensive and specific overview of recent discoveries in the regulation of MYC oncogene activation on glutamine metabolism in cancer cells.Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.

Highlights

Through over a decade of research, glutamine has become a focal point in characterizing the cellular metabolism driven by c-Myc
As a transcription factor, c-Myc drives the expression of key genes involved in glutamine metabolism, which is essential for the survival and proliferation of these cells
C-Myc acts as a major regulator of the intracellular role and metabolism of glutamine, from its synthesis to its degradation, and in other non-metabolic functions such as mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling

Summary

MYC Oncogene Activation and Glutamine Addiction

Glutamine is the most abundant amino acid in blood circulation and can integrate a wide variety of metabolic pathways inside the cell [18] (Figure 2). Notwithstanding, the positive correlations observed between the mRNA expression of these five genes and c-Myc suggest that the latter acts at least transcriptionally This has been demonstrated by Sun et al, who showed the direct binding of c-Myc to E-box sequences near the transcription start site of the PSAT1 promoter in Hep3B and P493-6 cells [64]. Oxygen consumption rates were substantially increased in c-Myc-overexpressing osteogenic sarcoma cells compared to MYC-inactive osteocytes [24] Such findings suggest that mitochondrial activity and oxidative phosphorylation is dependent on glutamine in the context of c-Myc-reprogrammed metabolism. C-Myc promotes glutamine flux toward nucleotide biosynthesis by upregulating the expression of glutamine-utilizing biosynthetic genes PPAT, PFAS, and CAD in the IMP and UMP synthesis pathways

13. Interactions between Intracellular Pathways

Findings

14. Conclusions