Nutrient acquisition strategies of mammalian cells

Abstract

Mammalian cells are surrounded by diverse nutrients, such as glucose, amino acids, various macromolecules and micronutrients, which they can import through transmembrane transporters and endolysosomal pathways. By using different nutrient sources, cells gain metabolic flexibility to survive periods of starvation. Quiescent cells take up sufficient nutrients to sustain homeostasis. However, proliferating cells depend on growth-factor-induced increases in nutrient uptake to support biomass formation. Here, we review cellular nutrient acquisition strategies and their regulation by growth factors and cell-intrinsic nutrient sensors. We also discuss how oncogenes and tumour suppressors promote nutrient uptake and thereby support the survival and growth of cancer cells.

Figure 1. The Nutritional Requirements for Mammalian Cell Growth

a, Contributions of major nutrients present in mammalian circulation towards the synthesis of cellular macromolecules. Nucleic acids (DNA and RNA) are synthesized intracellularly from glucose and glutamine. Other non-essential amino acids can also contribute to nucleotide production (not shown). Saccharides are derived from glucose, with nitrogen groups being donated by glutamine. Amino acids for protein synthesis can be imported in their free form or derived from catabolism of extracellular proteins. Non-essential amino acids can also be synthesized from glucose and glutamine. Extracellular lipids are delivered by lipoproteins and serum albumins. Most lipids are not essential for mammalian cells and can also be generated from glucose and glutamine carbons. Cells further require exogenous supply of a variety of essential micronutrients such as inorganic ions and vitamins. b, Fractional contribution of proteins, lipids, saccharides, nucleic acids (DNA and RNA), inorganic ions and metabolites to dry mass of a representative mammalian cell. The proportion of essential and non-essential amino acids contained within proteins are indicated.

Figure 2. Coordination of Cell Growth and Nutrient Uptake

Eukaryotic cells import low molecular weight nutrients such as glucose and amino acids through plasma membrane transporters and can also ingest bulk extracellular macromolecules through the non-selective endocytic pathway of macropinocytosis. a, Unicellular eukaryotes take up nutrients as they become available in the environment. In addition to supplying bioenergetic and biosynthetic pathways, nutrients function as direct signals for unicellular organisms to commit to growth and proliferation. b, The cells of metazoan organisms have lost the ability to regulate nutrient acquisition cell-autonomously; rather, they are instructed by growth factor signalling pathways to engage in nutrient uptake, thereby ensuring that nutrient supply matches the metabolic demands of cell growth. c, Components of growth factor signalling pathways are frequently mutated in cancer. These oncogenes cause cellular transformation in part by granting a cell autonomy over nutrient uptake and by increasing availability of precursors for macromolecular synthesis.

Figure 3. Metabolic Control by the mTORC1 Signalling Pathway

Full activation of mTORC1 kinase requires concerted inputs from growth factor signalling and intracellular amino acids. Once active, mTORC1 enhances cell growth by promoting protein translation as well as biosynthesis of lipids and nucleotides. mTORC1 also increases cell surface amino acid transporter levels, but suppresses lysosomal catabolism of proteins derived from endocytosis or autophagy, thereby rendering cells dependent on availability of free amino acids.

Figure 4. Growth Factor Signalling Regulates the Repertoire of Nutrient Uptake Pathways in Mammalian Cells

a, Growth factor activation of PI3-kinase/Akt signalling induces trafficking of the glucose transporter GLUT1 from intracellular vesicles to the plasma membrane. GLUT1 is transcriptionally upregulated through Ras and Akt. Growth factor signalling can also increase membrane concentrations of GLUT3. b, PI3-kinase/Akt and the transcription factor Myc increase expression of various amino acid transporters including the glutamine transporters ASCT2 and SNAT5 and the neutral amino acid transporter LAT1. c, PI3-kinase upregulates receptor-mediated endocytosis of Tfn and LDL, which enhances cellular acquisition of iron and cholesterol. d, Ras and PI3-kinase initiate macropinocytosis for bulk ingestion of extracellular macromolecules and cellular debris. Macropinocytosis mediates uptake of albumin, which can release bound lipids in endosomes and is recycled through the neonatal Fc receptor (FcRn). If the cellular amino acid sensor, mTORC1, becomes inactive, lysosomal catabolism of ingested albumin increases to liberate its amino acid content. e, Cells can engulf neighbouring cells through entosis, and digest them in the lysosome to recover their amino acid content. Entosis could also supply other nutrients, although this remains to be addressed experimentally. f, Under favourable conditions, mTORC1 suppresses catabolism of cellular contents through autophagy. When mTORC1 becomes inactive upon nutrient deprivation or growth factor withdrawal, cells engulf cytosolic constituents and organelles in autophagosomes for delivery and subsequent catabolism in the lysosome. Autophagy allows recycling of amino acids, lipids, nucleic acids and saccharides from intracellular nutrient stores.

Figure 5. Metabolic Cooperation between Cancer Cells and Non-Transformed Cells

Non-transformed cells in the tumor microenvironment can secrete a variety of metabolites that supply energy-producing and biosynthetic pathways of cancer cells. Nutrients released by normal cells can support survival and growth of cancer cells when the existing vascular supply becomes limiting. Cancer cells can also enter symbioses with non-transformed cells engaging in metabolic activities that are not active in cancer cells. For example, fatty acids released by adipocytes can serve as bioenergetic fuel for cancer cells. The generation of amino acids from autophagic degradation of intracellular proteins or the deposition of proteins as extracellular matrix can also provide nutrients. Astrocytes are capable of de novo glutamine synthesis and supply glutamine to glioblastoma cells. Bone marrow stromal cells import cystine and release it as cysteine, which is taken up by chronic myeloid leukaemia cells that do not express cystine transporters. Tumours can also induce catabolism of lipid stores in fat and structural proteins in muscle, resulting in elevated levels of fatty acids and amino acids in circulation, which might improve nutrient supply for cancer cells.