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Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer

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Metabolism in Cancer

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 207))

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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Authors and Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, EC/CLS-628C, Boston, MA, 02215, USA

    Evan C. Lien

  2. Department of Molecular and Integrative Physiology, University of Michigan, 1150 E. Medical Center Drive, Room 6308, Ann Arbor, MI, 48109, USA

    Costas A. Lyssiotis

  3. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, 1150 E. Medical Center Drive, Room 6308, Ann Arbor, MI, 48109, USA

    Costas A. Lyssiotis

  4. Department of Medicine, the Cancer Center, Weill Cornell Medical College, The Belfer Research Building, 413 East 69th Street, Floor 13 Room BB-1362, New York, NY, 10021, USA

    Lewis C. Cantley

Authors
  1. Evan C. Lien
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  2. Costas A. Lyssiotis
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  3. Lewis C. Cantley
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Correspondence to Lewis C. Cantley .

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Editors and Affiliations

  1. RWTH University Hospital, Molecular Tumor Biology, Pauwelsstrasse 30, 52074 , Aachen, Germany

    Thorsten Cramer

  2. Dept. of Hematology and Oncology, Charité, Berlin, Germany

    Clemens A. Schmitt

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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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  • DOI: https://doi.org/10.1007/978-3-319-42118-6_3

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