Abstract
In the past decade, there has been a resurgence of interest in elucidating how metabolism is altered in cancer cells and how such dependencies can be targeted for therapeutic gain. At the core of this research is the concept that metabolic pathways are reprogrammed in cancer cells to divert nutrients toward anabolic processes to facilitate enhanced growth and proliferation. Importantly, physiological cellular signaling mechanisms normally tightly regulate the ability of cells to gain access to and utilize nutrients, posing a fundamental barrier to transformation. This barrier is often overcome by aberrations in cellular signaling that drive tumor pathogenesis by enabling cancer cells to make critical cellular decisions in a cell-autonomous manner. One of the most frequently altered pathways in human cancer is the PI3K-Akt-mTOR signaling pathway. Here, we describe mechanisms by which this signaling network is responsible for controlling cellular metabolism. Through both the post-translational regulation and the induction of transcriptional programs, the PI3K-Akt-mTOR pathway coordinates the uptake and utilization of multiple nutrients, including glucose, glutamine, nucleotides, and lipids, in a manner best suited for supporting the enhanced growth and proliferation of cancer cells. These regulatory mechanisms illustrate how metabolic changes in cancer are closely intertwined with oncogenic signaling pathways that drive tumor initiation and progression.
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Abbreviations
- PI3K:
-
Phosphoinositide 3-kinase
- mTOR:
-
Mammalian target of rapamycin
- RTKs:
-
Receptor tyrosine kinases
- GPCRs:
-
G-protein-coupled receptors
- PIP3 :
-
Phosphatidylinositol-3,4,5-trisphosphate
- PIP2 :
-
Phosphatidylinositol-4,5-bisphosphate
- PTEN:
-
Phosphatase and tensin homolog
- PH:
-
Pleckstrin homology
- PDK1:
-
Phosphoinositide-dependent protein kinase 1
- mTORC1/2:
-
Mammalian target of rapamycin complex 1/2
- HK:
-
Hexokinase
- PFK1/2:
-
Phosphofructokinase 1/2
- TSC1/2:
-
Tuberous sclerosis 1/2
- GAP:
-
GTPase-activating protein
- S6K1/2:
-
S6 kinase 1/2
- 4E-BP1/2:
-
eIF4E (eukaryotic initiation factor 4E)-binding protein 1/2
- FoxO:
-
Forkhead box O
- GSK-3β:
-
Glycogen synthase kinase-3β
- HIF:
-
Hypoxia-inducible factor
- SREBP:
-
Sterol regulatory element-binding protein
- SRE:
-
Sterol regulatory elements
- TXNIP:
-
Thioredoxin-interacting protein
- AMPK:
-
AMP-dependent protein kinase
- 18FDG:
-
18-fluoro-deoxyglucose
- PET:
-
Positron emission tomography
- G6P:
-
Glucose 6-phosphate
- VDAC:
-
Voltage-dependent anion channel
- OMM:
-
Outer mitochondrial membrane
- PDK1:
-
Pyruvate dehydrogenase kinase 1
- PDH:
-
Pyruvate dehydrogenase
- TCA:
-
Tricarboxylic acid
- NADH:
-
Nicotinamide adenine dinucleotide
- LDHA:
-
Lactate dehydrogenase A
- GPI:
-
Glucose phosphate isomerase
- GAPDH:
-
Glyceraldehyde-3-phosphate dehydrogenase
- TPI:
-
Triosephosphate isomerase
- PGK1:
-
Phosphoglycerate kinase 1
- ENO1:
-
Enolase
- GCK:
-
Glucokinase
- ALDOB:
-
Aldolase B
- PK1:
-
Pyruvate kinase 1
- PPP:
-
Pentose phosphate pathway
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- Ru5P:
-
Ribulose 5-phosphate
- R5P:
-
Ribose 5-phosphate
- F6P:
-
Fructose 6-phosphate
- Ga3P:
-
Glyceraldehyde 3-phosphate
- G6PD:
-
Glucose 6-phosphate dehydrogenase
- TKT:
-
Transketolase
- PGD:
-
6-phosphogluconate dehydrogenase
- RPE:
-
Ribulose 5-phosphate epimerase
- RPIA:
-
Ribulose 5-phosphate isomerase
- TALDO1:
-
Transaldolase 1
- CAD:
-
Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase
- PRPP:
-
Phosphoribosyl pyrophosphate
- ACL:
-
ATP citrate lyase
- αKG:
-
α-ketoglutarate
- GLS:
-
Glutaminase
- GLUL:
-
Glutamine synthetase
- GDH:
-
Glutamate dehydrogenase
- ASNS:
-
Asparagine synthetase
- GFPT1:
-
Glutamine–fructose 6-phosphate transaminase 1
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Lien, E.C., Lyssiotis, C.A., Cantley, L.C. (2016). Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer. In: Cramer, T., A. Schmitt, C. (eds) Metabolism in Cancer. Recent Results in Cancer Research, vol 207. Springer, Cham. https://doi.org/10.1007/978-3-319-42118-6_3
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