Energy metabolism and redox - the cancer cell scenario Maria Shoshan, Cancer Center Karolinska.

Energy metabolism and redox

- the cancer cell scenario

Maria Shoshan,Cancer Center Karolinska

20 april 2023Maria Shoshan 2

life & death

metabolism

redox

Fuels areconsumed- oxidized -

- in order to build something new. This requires reductive events


life & death

metabolism

redox

Cancer cells:- increasedmacromoleculesynthesis

- increasedox stress

- decreasedapoptosis


Hanahan and Weinberg, 2000”The Hallmarks of Cancer”

Altered energymetabolism

Immune system


High glycolytic rate- aerobic glycolysis

High uptake of glucose

High expression of GLUT1-3

Tumor cells have:


Normal cells:95% of ATP from mitochondria

- electron transport chain, ox-phos…

Tumor cells:40-60% ofATP is via glycolysis


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


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


What comes first -

transformation,

decreased ox-phos

or

metabolic adaptations?


Oncogenic signaling

Redox events

Metabolic alterations


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)


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


HIF1 repression of differentiation

stimulation of angiogenesis

IGF, MMP-2

extracellular acidification

Tumor progression

High levels of HIF1a correlate with poor prognosis


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


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.


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


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:


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


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?


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


Oncogenic signaling

Redox events

Metabolic alterations

AKTHIF1aGFR/NOXRas

AKTHIF1ap53

HypoxiaMitoch. functions

ROS, RNSpH


NADH, FADH2

e-

pyruvate Krebs cycle CO2

O2

H2O and ROS

Energy metabolism and redox - the cancer cell scenario Maria Shoshan, Cancer Center Karolinska.

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Transcript of Energy metabolism and redox - the cancer cell scenario Maria Shoshan, Cancer Center Karolinska.