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

  • Evan C. Lien
  • Costas A. Lyssiotis
  • Lewis C. Cantley
Part of the Recent Results in Cancer Research book series (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.

Keywords

PI3K Akt mTOR Cancer Signaling Metabolism 

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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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Evan C. Lien
    • 1
  • Costas A. Lyssiotis
    • 2
    • 3
  • Lewis C. Cantley
    • 4
  1. 1.Department of Pathology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUSA
  3. 3.Department of Internal Medicine, Division of GastroenterologyUniversity of MichiganAnn ArborUSA
  4. 4.Department of Medicine, the Cancer CenterWeill Cornell Medical CollegeNew YorkUSA

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