Hopefully devoted to Q: targeting glutamine addiction in cancer

Abstract

Altered cell metabolism enables tumours to sustain their increased energetic and biosynthetic needs. Although tumour metabolism has long been considered a promising discipline in the development of cancer therapeutics, the majority of work has focused on changes in glucose metabolism. However, the complexity of cellular metabolism means that very rarely is an individual metabolite required for a single purpose, and thus understanding the overall metabolic requirements of tumours is vital. Over the past 30 years, increasing evidence has shown that many tumours require glutamine as well as glucose for their proliferation and survival. In this minireview, we explore the complexity of glutamine metabolism in tumour cells, discussing how the overall context of the tumour dictates the requirement for glutamine and how this can affect the design of effective therapeutic strategies.

Figure 1

Glutamine is required for multiple pathways in cells. Glutamine is converted to glutamate by glutaminase. Glutamate is then converted to αKG, which can be performed by GLUD to produce ammonia, which can regulate autophagy. Alternatively, this conversion can be performed through an aminotransferase reaction to produce an amino acid as well as αKG. This αKG can be used for both the forward and reverse fluxes of the TCA cycle, and can be used to regulate TET proteins, which alter DNA methylation. Bidirectional transport of glutamine and essential amino acids controls mTOR activation and autophagy regulation. Glutamine is used in the production of glutathione, which helps maintain the redox balance. Glutamine is also required for hexosamine biosynthesis and nucleotide biosynthesis.

Figure 2

2D in vitro cell culture lacks many of the features of the tumour microenvironment. The majority of in vitro cell culture systems involve growing a single cell type in a 2D monolayer, in nutrient-rich medium, and at fixed oxygen and carbon dioxide levels. In the tumour, cells grow in 3D, making cell:cell contacts and interact with a number of different cell types. The surrounding immune and stromal cells also affect the nutrient availability in the tumour microenvironment, as does proximity to blood vessels. Similarly, proximity to blood vessels also dictates the amount of oxygen that a cell receives.