New aspects of amino acid metabolism in cancer

Abstract

An abundant supply of amino acids is important for cancers to sustain their proliferative drive. Alongside their direct role as substrates for protein synthesis, they can have roles in energy generation, driving the synthesis of nucleosides and maintenance of cellular redox homoeostasis. As cancer cells exist within a complex and often nutrient-poor microenvironment, they sometimes exist as part of a metabolic community, forming relationships that can be both symbiotic and parasitic. Indeed, this is particularly evident in cancers that are auxotrophic for particular amino acids. This review discusses the stromal/cancer cell relationship, by using examples to illustrate a number of different ways in which cancer cells can rely on and contribute to their microenvironmentboth as a stable network and in response to therapy. In addition, it examines situations when amino acid synthesis is driven through metabolic coupling to other reactions, and synthesis is in excess of the cancer cell's proliferative demand. Finally, it highlights the understudied area of non-proteinogenic amino acids in cancer metabolism and their potential role.

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

“…Since glutamine plays an important role as a source of nitrogen in amino acids and nucleic acids, it is known that many cancer cells have a high dependence on glutamine [ 66 , 67 , 68 , 69 , 70 ]. Glutamine uptake and metabolism in cancer cells is regulated by PI3K, Kras, and c-myc [ 26 , 43 , 66 , 67 , 71 , 72 , 73 , 74 , 75 ]. Tryptophan is an important amino acid for the activation of immune cells, but cancer cells overexpress the tryptophan-metabolizing enzyme IDO, which suppresses immune cell function by depleting tryptophan in the tumor microenvironment [ 66 ].…”

Metabolism and cancer: the future is now

“…In this special issue, Nanda et al 8 provide a comprehensive description of the genetic and environmental cues that drive cancer metabolism, with a specific focus on the cell-intrinsic and cell-extrinsic factors that contribute to metabolic heterogeneity. Importantly, as highlighted by Vettore and colleagues, 9 cancer cells and other components of the tumour microenvironment, including fibroblasts and immune cells, form a metabolic community and exchange metabolites regulating each other's functions. Intriguingly, metabolites within the tumour microenvironment can affect cancer cell behaviour beyond providing energy substrates.…”

Malignancy Grade-Dependent Mapping of Metabolic Landscapes in Human Urothelial Bladder Cancer: Identification of Novel, Diagnostic, and Druggable Biomarkers

“…Alanine was also increased in the TCCSUP (high-grade) cell line compared to the RT4 (low grade) one [28]. An abundance of amino acids is important for the proliferative cancer cells, not only as substrates of protein synthesis, but also for energy generation, cellular redox homeostasis, and nucleotide biosynthesis [41]. Pyruvate consumption and alterations in glycolytic profile have also been related to UBC aggressiveness, as anaerobic conditions in high(er) grade UBC favor the conversion of pyruvate to lactate, or alanine [28].…”