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Energy metabolism and redox

Energy metabolism and redox. - the cancer cell scenario. Maria Shoshan, Cancer Center Karolinska. metabolism. redox. life & death. Fuels are consumed - oxidized -. - in order to build something new. This requires reductive events. metabolism. redox. life & death. Cancer cells:

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Energy metabolism and redox

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

  2. metabolism redox life & death Fuels are consumed - oxidized - - in order to build something new. This requires reductive events Maria Shoshan

  3. metabolism redox life & death Cancer cells: - increased macromolecule synthesis • increased • ox stress • decreased • apoptosis Maria Shoshan

  4. Hanahan and Weinberg, 2000 ”The Hallmarks of Cancer” Altered energy metabolism Immune system Maria Shoshan

  5. Tumor cells have: • High glycolytic rate • aerobic glycolysis High uptake of glucose High expression of GLUT1-3 Maria Shoshan

  6. Normal cells: 95% of ATP from mitochondria - electron transport chain, ox-phos… Tumor cells: 40-60% of ATP is via glycolysis Maria Shoshan

  7. Glucose Purine synthesis Glu-6-P glut; ser NADPH ATP; Amino acids Fatty acids Pyruvate acetyl-CoA Krebs cycle, ATP via mitoch. Advantages for the tumor cell: Maria Shoshan

  8. Anti-apoptotic via AKT/HXK glut; ser lactate Advantages for the tumor cell: Glucose Glu-6-P ATP; Amino acids Fatty acids Pyruvate acetyl-CoA Krebs cycle, ATP via mitoch. Maria Shoshan

  9. What comes first - transformation, decreased ox-phos or metabolic adaptations? Maria Shoshan

  10. Oncogenic signaling Metabolic alterations Redox events Maria Shoshan

  11. Glycolytic effects Oncogenic signaling Mitochondrial 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) Maria Shoshan

  12. Oncogenic signaling Metabolism HIF HIF + O2 OHdegradation Fe2+ Fe3+ RNS (iNOS + ROS) Glycolysis & PDK1 + ascorbate 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 PHD FIH-1 - another regulatory hydroxylase Maria Shoshan

  13. HIF1 repression of differentiation stimulation of angiogenesis IGF, MMP-2 extracellular acidification Tumor progression High levels of HIF1a correlate with poor prognosis Maria Shoshan

  14. Metabolism Growth; anti-apoptosis AKT- PTEN phosphatase PI3K P Nox: NADPH oxidases Nox O2* - PTEN inhibition PTPase inhibition Loss of PTEN leads to increased AKT activity PTEN is a tumor suppressor. PTEN mutations are common in human cancer. PTEN is inhibited by oxidization (two Cys). In a growth-factor stimulated cell (or with onco-Ras) : PI3K Maria Shoshan

  15. PTEN(ox) PTEN(red) TrxR/Trx NADPH NADP+ PTEN is reduced (activated) by NADPH-TrxR/Trx Helps keep AKT- mediated glycolytic metabolism in check Resp./ETC Accumulation of NADH (Krebs cycle) NADH PTEN reactivation, by competing with NADPH PTEN can also be inhibited by Trx-1 binding. PTEN is inactivated upon impaired respiration Pelicano et al., 2006 Maria Shoshan

  16. 17 ov ca ascitic samples were tested in vitro for 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 • mtDNA mutations • - sustained hypoxia, HIF1a • sustained PTEN inactivation / AKT activation • impaired respiration correlates with increased • glycolytic dependence, tumor progression and chemoresistance Maria Shoshan

  17. ROS in cancer cells: ROS from growth factor/GFR signaling - Nox family upregulation in cancer - ROS stimulation of growth and motility NAD(P)H oxidases (Nox) • inhibit PTPs • Rac1 • also target TFs • AP-1, NFkB Maria Shoshan

  18. ROS-sensitive mitoch enzymes Fe/S (aconitase & other Krebs cycle enz., COX) Thiols ROS in cancer cells: Mitochondrial ROS: Higher metabolic rate; Impaired respiration/ETC; Decreased antioxidant defense Fewer mitochondria RNS, peroxynitrite; iNOS (mtNOS?) ROS induction by chemotherapy Maria Shoshan

  19. Pervaiz & Clement, 2007 Opposite effects of superoxide and peroxide? e.g., caspase inhibition PTEN inhibition e.g., via modif. of cardiolipin, cyto c release, caspase activation Maria Shoshan

  20. Pouysségur et al., Nature review 2006 Higher intracellular pH in cancer cells - and lower extracellular pH NHE-1: Na+/H + exchanger-1 MCT1-4: monocarboxylate transp. CA IX: carbonic anhydrase AE: Cl-/HCO3- transporter Possible therapeutic targets! Cancer cells may use lactate to fuel Krebs/ox-phos Maria Shoshan

  21. AKT HIF1a p53 AKT HIF1a GFR/NOX Ras Oncogenic signaling Metabolic alterations Redox events ROS, RNS pH Hypoxia Mitoch. functions Maria Shoshan

  22. pyruvate Krebs cycle CO2 NADH, FADH2 e- H2O and ROS O2 Maria Shoshan

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