THE HALLMARKS OF CANCER
METABOLISM IN CANCER
- Many key oncogenic signalling pathways converge to adapt tumour
cell metabolism in order to support their growth and survival
- Some of these metabolic alterations are absolutely required for
malignant transformation
- Intrinsic and extrinsic molecular mechanisms converge to alter core
cellular metabolism: 1. rapid ATP generation to maintain energy
status; 2. increased biosynthesis of macromolecules; 3.
maintenance of appropriate cellular redox status
THE WARBURG EFFECT (Otto Warburg 1920)
Shift from oxidative phosphorylation to glycolysis, even under
normal oxygen concentrations, in order to generate ATP (essential for
maintaining normal cellular processes and for sustaining rapid
proliferation).
GLYCOLYSIS
1.
Hexokinase (HK2) phosphorylates
glucose to glucose 6-phosphate that is
converted to fructose 6-phosphate by
phosphoglucose isomerase (PGI)
2.
Phosphofructokinase (PFKFB3)
phosphorylates fructose 6-phosphate >
fructose 1,6-bisphosphate that is
converted to glyceraldehyde 3
phosphate by fructose biphosphate
aldolase (ALDO)
3.
Glyceraldehyde 3 phosphate
deydrogenase (GAPDH) converts
glyceraldehyde 3 phosphate to 1,3bisphosphoglycerate that is
phosphorylated by Phosphoglycerate
kinase (PGK) > 3-phosphoglycerate
4.
Phosphoglycerate mutase (PGM)
converts 3-phosphoglycerate in 2phosphoglycerate that is converted by
enolase (ENO) to
phosphoenolpyruvate
5.
Pyruvate Kinase (PK) > pyruvate
ATP
ATP
Lactate
deydrogenase
TCA (Kreb cycle) and oxidative phosphorylation
- Pyruvate deydrogenase (PDH) converts
pyruvate in Acetyl-CoA
- Acetyl-CoA enters TCA where is joined to
oxaloacetate by citrate synthase to produce
citrate
- Final step: resynthesis of oxaloacetate new
TCA
Succinate and NADH are further oxidated in
mithochondria (cytochrome c ossidase
complex)
GLUCOSE METABOLISM
PI3K AND GLYCOLYSIS
-
PI3K is one of the most commonly altered signalling
pathways in human cancers (lez. 4)
-
Akt1 stimulates glycolysis:
1. By increasing the expression and membrane
translocation of glucose transporters (GLUT1)
2. By phosphorylating hexokinase (HK2) and
phosphofructokinase (PFKFB3) > increased activity
3. By stimulating mTORC1: stimulates protein and lipid
biosynthesis and cell growth in response to sufficient
nutrient and energy conditions; increases glycolysis
by activating hypoxia-inducible factor 1 (HIF1)
HIF1 AND GLYCOLYSIS
- HIF1 and HIF2 complexes are the major transcription
factors that are responsible for gene expression changes
during the cellular response to low oxygen conditions
- Oncogenic pathways (i.e. PI3K) can activate HIF1 in
normoxic conditions
- HIF1 amplifies the transcription of glucose transporters
(GLUT1) and glycolytic enzymes (es. HK2); activates the
pyruvate dehydrogenase kinases (PDKs) and reduces the
flow of glucose-derived pyruvate into the tricarboxylic acid
(TCA).
- Collaborate with myc in the activation of several glucose
transporters and glycolytic enzymes, as well as lactate
dehydrogenase A (LDHA) and PDK1
SUMMARY: HIF1 MYC
PDK1:inhibits
(phosphorylation)
pyruvate
deydrogenase
(PDH) that generates
Acetyl-CoA from
pyruvate thus
initiating the TCA in
mitochondria
TUMOR SUPPRESSORS AND GLYCOLYSIS
p53:
- Activates the expression of HK2
> G6P
- p53 blocks G6PDH and
pentose phosphate pathway
(PPP)
- Promotes oxidative
phosphorylation by inducing the
expression of factor essential for
oxidative complex in
mitochondria (SCO2)
Mutations of p53 in tumours >
glycolysis
SUMMARY
- PI3K activates AKT, which stimulates
glycolysis directly or through mTORC1.
- mTORC1 alters metabolism by enhancing
hypoxia-inducible factor 1 (HIF1) activity
- HIF1 increases the expression of glucose
transporters (GLUT), glycolytic enzymes and
pyruvate dehydrogenase kinase, isozyme 1
(PDK1), which blocks the entry of pyruvate
into the tricarboxylic acid (TCA) cycle.
- MYC cooperates with HIF in activating
several genes that encode glycolytic proteins,
but also increases mitochondrial metabolism.
- loss of p53 or inactivating mutants do not
suppress glycolysis, do not increase
mitochondrial metabolism via SCO2 and do
not support expression of PTEN
- The pyruvate kinase M2 (PKM2) isoform
opposes glycolysis by slowing the pyruvate
kinase reaction and diverting substrates into
alternative biosynthetic (PPP).
MORE THAN GLYCOLYSIS IN CANCER
- ATP generation by aerobic glycolysis is not the sole metabolic
requirement of a cancer cell
- PK (pyruvate kinase): catalyses the rate-limiting ATPgenerating step of glycolysis in which phosphoenolpyruvate is
converted to pyruvate
erythrocytes
liver and kidneys
muscle and brain
embryonic and adult stem cells
PKM2 in many tumour cells
PKM2 IN CANCER
- PKM2 is active as tetramer (high activity)
- PKM2 in tumours is present as dimer (low activity) > slow glycolysis,
thus allowing carbohydrate metabolites to enter other subsidiary
pathways, such as the PPP, which generate macromolecule precursors
to support cell proliferation, and reducing equivalents such as NADPH
Penthose Phosphate Pathway
6-phosphogluconate
dehydrogenase
6-phosphogluconate
ribulose 5 phosphate
NADPH
- Produced as a result of the promotion of the oxidative PPP
by PKM2
- Crucial cofactor that provides reducing power in many
enzymatic reactions for macromolecular biosynthesis
- Crucial antioxidant, quenching the reactive oxygen
species (ROS) produced during rapid cell proliferation
- Reducing power for glutathione (GSH) and thioredoxin
(TRX) systems that scavenge ROS and repair ROS-induced
damage
- Attenuating PPP reduces NADPH production in cancer
cells
Preclinical studies with 6-amino-nicotinamide (6-AN),
which inhibits G6PD have demonstrated anti-tumorigenic
effects in leukaemia, glioblastoma and lung cancer cell
lines
NADPH: Isocitrate dehydrogenases
NADP-dependent
isocitrate
dehydrogenase 1 (IDH1) and IDH2 convert
isocitrate to α-ketoglutarate (Krebs cycle)
thus producing NADPH
- Specific mutations in IDH1 and IDH2 (gain
of functions) are linked to tumorigenesis:
80% of adult grade II and grade III
gliomas and secondary glioblastomas,
30% of acute myeloid leukaemia (AML)
Reactive oxigen species: ROS
NADPH and NADPH oxidase (NOX) induce ROS
production:
- Low levels of ROS increase cell proliferation and
survival through the post-translational modification of
kinases and phosphatases.
- High levels of ROS cause damage to macromolecules,
trigger senescence and cause permeabilization of the
mitochondria, leading to apoptosis
- Cells counteract ROS by producing antioxidant
molecules (GSH and TRX)
- Transformed cells has high ROS production that
counteract by further upregulating antioxidant systems
The paradox of high ROS production in the presence
of high antioxidant levels
Glutamine and myc
- High concentrations of glutamine are
required for cell proliferation
GSl
GCl
- Glutaminase 1 (GLS1) converts
glutamine to glutamate > glutathione
cysteine ligase (GCl) convert glutamate
to GSH (antioxidant)
- Myc: directly increases glutamine
uptake by inducing the expression of
transporters; indirectly increases GLS1,
by inhibiting the expression of
microRNAs that repress its expression
Tumour cells are critically dependent
on glutamine because they have an
up-regulated glutaminolysis
SUMMARY
CONCLUSION
- Mutations in oncogenes and tumor suppressor genes
induce alteration of cell metabolism in order to allow cell
growth and survival
- Intrinsically altered tumour cell metabolism, creates a
unique microenvironment characterized by spatial and
temporal heterogeneity in oxygenation, pH, and the
concentrations of glucose and many other metabolites
- These metabolic adaptations are required for balncing the
3 tumor needs: energy production, macromolecule
biosynthesis and redox balance