Download - Energy metabolism and redox - the cancer cell scenario Maria Shoshan, Cancer Center Karolinska
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life & death
metabolism
redox
Fuels areconsumed- oxidized -
- in order to build something new. This requires reductive events
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life & death
metabolism
redox
Cancer cells:- increasedmacromoleculesynthesis
- increasedox stress
- decreasedapoptosis
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Hanahan and Weinberg, 2000”The Hallmarks of Cancer”
Altered energymetabolism
Immune system
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High glycolytic rate- aerobic glycolysis
High uptake of glucose
High expression of GLUT1-3
Tumor cells have:
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Normal cells:95% of ATP from mitochondria
- electron transport chain, ox-phos…
Tumor cells:40-60% ofATP is via glycolysis
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Advantages for the tumor cell:
Glucose
Glu-6-P
ATP;Amino acids
Fatty acidsPyruvate acetyl-CoA
Purine synthesis
Krebs cycle,ATP via mitoch.
NADPHglut;ser
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Advantages for the tumor cell:
Glucose
Glu-6-P
ATP;Amino acids
Fatty acidsPyruvate acetyl-CoA
Krebs cycle,ATP via mitoch.
glut;ser
Anti-apoptoticvia AKT/HXK
lactate
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What comes first -
transformation,
decreased ox-phos
or
metabolic adaptations?
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Oncogenicsignaling
Mitochondrial effects
Glycolytic effects
Mutations in SDH and FH (complex II, Krebs cycle)
Loss of p53 leading to loss of SCO2 (complex IV)
Loss of p53 leading to increased PGM (glycolysis)Loss of PTEN leading to sustained AKT activity (glycolysis)
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Increased HIF1 (glycolysis)
- by hypoxia, via ablation of PHD and mito-ROS- by anomalous inhibition of PHD (succinate, fumarate, oxaloacetate, pyruvate; H2O2)- by loss of p53, or loss of PTEN
Metabolism Oncogenic signaling
PHD
Glycolysis& PDK1
HIF + O2 HIF OH degradation
Fe2+
Fe3+
+ ascorbate
RNS (iNOS + ROS)
FIH-1 - another regulatory hydroxylase
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HIF1 repression of differentiation
stimulation of angiogenesis
IGF, MMP-2
extracellular acidification
Tumor progression
High levels of HIF1a correlate with poor prognosis
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Loss of PTEN leads to increased AKT activity
PTENphosphatase
PI3K AKT- PMetabolismGrowth; anti-apoptosis
PTEN is a tumor suppressor. PTEN mutations are common in human cancer.
PTEN is inhibited by oxidization (two Cys).
PI3KO2
* -PTEN inhibitionPTPase inhibition
In a growth-factor stimulated cell (or with onco-Ras) :
Nox
Nox: NADPH oxidases
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PTEN is inactivated upon impaired respiration
Resp./ETC Accumulation of NADH (Krebs cycle)
NADH PTEN reactivation, by competing with NADPH
Pelicano et al., 2006
PTEN is reduced (activated) by NADPH-TrxR/Trx
PTEN(ox) PTEN(red) Helps keep AKT-mediated glycolytic metabolism in check
NADPH NADP+
TrxR/Trx
PTEN can also be inhibited by Trx-1 binding.
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17 ov ca ascitic samples were tested in vitrofor antiproliferative effects of cisplatin ± DG,a glycolysis inhibitor. In 10 samples, DG reduced individual IC50:s by >50%; these were classified as HP (high-potentiated).Low levels of ß-ATPase protein correlated with sensitivity to potentiation.
Hernlund et al., MCT 2009
Impaired respiration supports oncogenic signaling
- impaired respiration correlates with increasedglycolytic dependence, tumor progression and chemoresistance
- mtDNA mutations- sustained hypoxia, HIF1a- sustained PTEN inactivation / AKT activation
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ROS from growth factor/GFR signaling
NAD(P)H oxidases (Nox)
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
- Nox family upregulation in cancer- ROS stimulation of growthand motility
- inhibit PTPs- Rac1
- also target TFs AP-1, NFkB
ROS in cancer cells:
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ROS in cancer cells:
Mitochondrial ROS:
Higher metabolic rate;Impaired respiration/ETC;Decreased antioxidant defenseFewer mitochondria
ROS-sensitive mitoch enzymes
Fe/S (aconitase & other Krebs cycle enz., COX)Thiols
RNS, peroxynitrite; iNOS (mtNOS?)
ROS induction by chemotherapy
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Pervaiz & Clement, 2007
e.g., caspase inhibitionPTEN inhibition
e.g., via modif. of cardiolipin,cyto c release, caspase activation
Opposite effects of superoxide and peroxide?
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Pouysségur et al., Nature review 2006
Higher intracellular pH in cancer cells- and lower extracellular pH
NHE-1: Na+/H + exchanger-1MCT1-4: monocarboxylate transp.CA IX: carbonic anhydraseAE: Cl-/HCO3- transporter
Possible therapeutic targets!
Cancer cells may use lactateto fuel Krebs/ox-phos
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Oncogenic signaling
Redox events
Metabolic alterations
AKTHIF1aGFR/NOXRas
AKTHIF1ap53
HypoxiaMitoch. functions
ROS, RNSpH