The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)–AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.
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The authors apologize to colleagues whose work they were unable to discuss due to space constraints. Research in the Manning lab related to the subject of this review was supported by grants to B.D.M. from the NIH (R35-CA197459 and P01-CA120964), DOD (W81XWH-18-1-0370 and W81XWH-18-1-0659) and a Rothberg Courage Award from the Tuberous Sclerosis Alliance.
B.D.M. is a shareholder and scientific advisory board member of Navitor Pharmaceuticals and LAM Therapeutics. G.H. declares no competing interests.
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- Redox homeostasis
Maintaining proper levels of cellular NAD(P)H and NAD(P)+ for metabolic reduction and oxidation reactions, respectively.
- Metabolic flexibility
The ability of a cell to adapt its metabolism in response to changing environmental conditions, such as nutrient and energy availability.
- Anaplerotic metabolism
Metabolic reactions that replenish tricarboxylic acid (TCA) cycle intermediates used for biosynthetic processes.
The two-step removal of the amide and amine nitrogens from glutamine to produce the TCA cycle intermediate α-ketoglutarate; these reactions can serve as one form of anaplerosis.
- Anabolic processes
Metabolic processes and pathways that utilize nutrients and ATP to generate macromolecules such as proteins, lipids and nucleotides.
- Quantitative flux analysis
Measurement of the rate of consumption and production of metabolites in specific metabolic pathways, often achieved through the tracing of stable isotope-labelled nutrients and quantification via mass spectrometry.
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Hoxhaj, G., Manning, B.D. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 20, 74–88 (2020). https://doi.org/10.1038/s41568-019-0216-7
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