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Onko (Fach) / x12. Troppmair (Lektion)

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• Why would tumor metabolism be altered? However, commonly found oncogenes or tumor suppressor genes do not immediately suggest a role for metabolic perturbations as major contributors to tumor development. Gradually concepts developed, which would (i) result in the identification of pathways linking oncogene/tumor suppressor signaling to metabolic pathways, and (ii) in the demonstration of mutations in metabolic enzymes.
• Which tumor-specific metabolic adaptations are common? (i) cells are not affected by fluctuations in oxygen tension as they may occur during tumor growth, (ii) metabolic end products generated by cancer cells under these conditions (predominantly bicarbonic and lactic acids) favor tumor invasion and suppress antitumor immunity, (iii) by using the pentose phosphate pathway (PPP) cancer cells generate nicotinamide adenine dinucleotide phosphate (NADPH) that ensures the cells’ antioxidant defenses against a hostile microenvironment and NADPH can contribute to fatty acid synthesis. (iv) cancer cells use intermediates of the glycolytic pathway for macromolecular biosynthesis.
• What are the possible underlying causes for these adaptations? (i) HIF-induced upregulation of glucose transporters (GLUT), glycolytic enzymes as well as pyruvate dehydrogenase kinase 1 (PDK1), which blocks entry of pyruvate into the tricarboxylic acid (TCA) cycle. (ii) Beyond the Warburg effect, tumor-specific alterations also affect macromolecular biosynthesis. Pyruvate kinase (PK) normally catalyzes the rate-limiting ATP generating conversion of phosphoenolpyruvate to pyruvate. The M2 isoform, which is frequently expressed by many tumors, however, slaves glycolysis and diverts carbohydrate metabolites into macromolecular biosynthesis, which is required for cell proliferation and the provision of reducing equivalents. Candidate mechanisms for the oncogenic roles of (R)-2-hydroxyglutarate ((R)-2HG), succinate and fumarate. These three oncometabolites are sufficiently similar in structure to 2-oxogluratate (2OG) to inhibit a range of 2OG-dependent dioxygenases, including hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs), histone lysine demethylases (KDMs) and the teneleven translocation (TET) family of 5- methylcytosine (5mC) hydroxylases. In turn, this leads to modulations of HIFmediated hypoxia responses and alterations in gene expression through global epigenetic remodelling that may contribute to malignant transformation. Oxidation of a reactive Cys residue (SH (thiol) to SOH (sulphenic acid)) leads to an alteration in the reduction–oxidation (redox)-sensitive target that can then have myriad effects on protein stability, activity, localization or protein–protein interaction. DVL, Dishevelled; EGFR, epidermal growth factor receptor; NRF2, nuclear factor erythroid 2-related factor 2; NRX, nucleoredoxin; PTP, protein Tyr phosphatase; ROS, reactive oxygen species. Alternativ: Warburg effect → Acidification of the environment (Selection advantage), increased need for lipids → fatty acid biosynthesis (more acetyl-CoA outside the citrate cycle) increased need for proteins
• How may one exploit this knowledge for the design of therapies? targeting metabolic proteins -- enzymes, involved in oxidative glycolysis . . . Example: High dependency on glucose is used to treat cancer cells with 2DG which cannot be metabolized. Normal cells are able to switch their metabolism to oxidative phosphorylation whereas cancer cells suffer from starvation.
• How can we detect alterations in mitochondrial ROS production or morphology? → Through fluorescent dyes that are oxidized by ROS and  detection of fluorescence via FACS, fluorescence microscopy. → MitoTracker red-H2XRos (MTRos) which is a chemically reactive reduced rosamine, which does not emit fluorerscence until it is oxidized by ROS in the mitochondria of living cells. → In order to visualize ROS production, cells were incubated with the cell permeable fluorescent dye 2’, 7’-dichlorofluorescin diacetate (DCF-DA). Acetate groups of DCF-DA were cleaved of by cellular esterases and the nonfluorescent H2DCF-DA was then converted into highly fluorescent 2’, 7’-dichlorofluorescein through oxidation mediated by ROS.

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