Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer

https://doi.org/10.1016/j.semcdb.2019.05.012Get rights and content
Under a Creative Commons license
open access

Abstract

Metabolic reprogramming in cancer targets glutamine metabolism as a key mechanism to provide energy, biosynthetic precursors and redox requirements to allow the massive proliferation of tumor cells. Glutamine is also a signaling molecule involved in essential pathways regulated by oncogenes and tumor suppressor factors. Glutaminase isoenzymes are critical proteins to control glutaminolysis, a key metabolic pathway for cell proliferation and survival that directs neoplasms’ fate. Adaptive glutamine metabolism can be altered by different metabolic therapies, including the use of specific allosteric inhibitors of glutaminase that can evoke synergistic effects for the therapy of cancer patients. We also review other clinical applications of in vivo assessment of glutaminolysis by metabolomic approaches, including diagnosis and monitoring of cancer.

Abreviations

AcCoA
acetyl coenzyme A
AKG
α-ketoglutarate
ERK
extracellular signal-regulated kinases
FH
fumarate hydratase
GA
glutaminase
GAB
long glutaminase 2 isoform
GABA
gamma-aminobutyric acid
GAC
short glutaminase isoform
GBM
glioblastoma
GCS
gamma-glutamylcysteine synthetase
GFAT
glutamine:fructose-6-phosphate aminotransferase
GLUD
glutamate dehydrogenase
Glc
glucose
Gln
glutamine
GLS
glutaminase isoenzyme
GLS2
glutaminase 2 isoenzyme
Glu
glutamate
GSH
glutathione
2-HG
2-hydroxyglutarate
HIF
hypoxia-inducible factor
IDH
isocitrate dehydrogenase
KGA
long glutaminase isoform
KRAS
V-Ki-ras2 Kirsten rat sarcoma
LGA
short glutaminase 2 isoform
mTOR
mammalian target of rapamycine
MS
mass spectrometry
NADH
reduced nicotinamide adenine dinucleotide
NADPH
reduced nicotinamide adenine dinucleotide phosphate
NEAAs
non-essential aminoacids
NF-κB
nuclear factor-kappa B
NSCLC
non-small-cell lung cancer
OXPHOS
oxidative phosphorylation
PC
pyruvate carboxylase
PDAC
pancreatic ductal adenocarcinoma
PDH
pyruvate dehydrogenase
PET
positron emission tomography
PI3K
phosphatidylinositide 3-kinase
PKB
protein kinase B
PKM2
pyruvate kinase M2 isoform
PPP
pentose phosphate pathway
ROS
reactive oxygen species
SDH
succinate dehydrogenase
TCA
tricarboxylic acid
TME
tumor microenvironment
TNBC
triple-negative breast cancer

Keywords

Cancer
Combination therapy
Glutaminase inhibitors
Glutamine imaging
Glutaminolysis
Metabolomics

Cited by (0)

1

These authors contributed equally.