INTERMEDIARY%20METABOLISM%20IN%20CANCER%20%20MOLECULAR%20ONCOLOGY%202015

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INTERMEDIARY METABOLISM IN CANCERMOLECULAR
ONCOLOGY2015

• Michael Lea

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Intermediary Metabolism - Lecture Outline

• Glycolysis and respiration in cancer cells
• Convergence and deletions
• Correlation of biochemical parameters with tumor
  growth
• Polyamines

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GLYCOLYSIS AND RESPIRATION IN CANCER CELLS

• The first metabolic pathways to be studied in
  cancer cells were those of glycolysis and cell
  respiration. Otto Warburg studied these
  parameters using tissue slices incubated in a
  bicarbonate buffer in flasks attached to a
  manometer. By incubating in media gassed with
  either 95 oxygen/5 CO2 or 95 nitrogen/5 CO2
  it was possible to measure glycolysis under
  aerobic or anaerobic conditions. The production
  of lactic or pyruvic acids causes the release of
  CO2 from the bicarbonate buffer. Quotients were
  measured for aerobic glycolysis (QL O2),
  anaerobic glycolysis (QL N2) and respiratory
  activity (QO2).
• The data indicated that, in general, glycolysis
  was greater in malignant than in non-malignant
  tissues. This was more marked under aerobic than
  anaerobic conditions. This difference suggested
  that the Pasteur effect was greater in normal
  tissues. It should be noted that there is an
  overlap of values in Warburgs data.

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For debate see Science, 124 267-272, 1956
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CONVERGENCE AND DELETIONS

• Warburg concluded that cancer originated from an
  irreversible injury of respiration
• Greenstein noted that many tumors showed a
  convergence in their metabolic patterns
• In 1947 the Millers suggested that carcinogenesis
  results from a permanent alteration or loss of
  proteins essential for the control of growth.
• Studies by Weber on the Morris series of
  chemically induced hepatomas in rats led to the
  Molecular Correlation Concept in which some
  biochemical parameters are viewed as correlating
  with tumor growth. (Reference G. Weber, New
  England J. Med. 296 486 and 541, 1977)

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UPREGULATION OF GLYCOLYSIS LEADS TO
MICROENVIRONMENTAL ACIDOSIS

• Clinical use of 18fluorodeoxyglucose
  positron-emission tomography (FdG PET) has
  demonstrated that increased glucose uptake is
  observed in most human cancer.
• Increased FdG uptake occurs because of
  upregulation of glucose transporters, notably
  GLUT1 and GLUT3, and results in increased
  glycolysis.
• Increased glycolysis results in
  microenvironmental acidosis and requires further
  adaptation through somatic evolution to
  phenotypes resistant to acid-induced toxicity.
• Reference R.A. Gatenby and R.J. Gillies. Why do
  cancers have high aerobic glycolysis? Nature
  Reviews Cancer 4 891-899, 2004.

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INHIBITING GLYCOLYSIS

• A lack of tumor-specific inhibitors of glycolysis
  has historically prevented glycolysis being used
  as a chemotherapeutic target.
• Glycolysis can be activated by an increase in the
  concentration of fructose 2,6-bisphosphate which
  activates the rate-limiting enzyme
  phosphofructokinase 1.
• Fructose 2,6-bisphosphate is produced by the
  bifunctional enzyme phosphofructokinase 2/
  fructose 2,6-bisphosphatase (PFKFB).
• The inducible PFKFB3 isozyme is constitutively
  expressed by many tumor cells.
• A small molecule inhibitor of PFKFB3 has been
  reported to inhibit the growth of tumors in mice.
• Reference Clem et al., Mol. Cancer Ther. 7
  110-120, 2008

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Levine and Puzio-Kuter Science
330 1340-1344. 2010
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TIGAR TP53 induced glycolysis and apoptosis
regulator
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ERK1/2-dependent phosphorylation and nuclear
translocation of PKM2 promotes the Warburg effect

• Pyruvate kinase M2 (PKM2) is upregulated in
  multiple cancer types and contributes to the
  Warburg effect by unclear mechanisms.
  EGFR-activated ERK2 binds directly to PKM2 Ile
  4291Leu 431 through the ERK2 docking groove and
  phosphorylates PKM2 at Ser 37, but does not
  phosphorylate PKM1. Phosphorylated PKM2 Ser 37
  recruits PIN1 for cis-trans isomerization of
  PKM2, which promotes PKM2 binding to importin a5
  and translocating to the nucleus. Nuclear PKM2
  acts as a coactivator of beta-catenin to induce
  c-Myc expression, resulting in the upregulation
  of GLUT1, LDHA and, in a positive feedback loop,
  PTB-dependent PKM2 expression. Replacement of
  wild-type PKM2 with a nuclear translocation-defici
  ent mutant (S37A) blocks the EGFR-promoted
  Warburg effect and brain tumour development in
  mice. In addition, levels of PKM2 Ser 37
  phosphorylation correlate with EGFR and ERK1/2
  activity in human glioblastoma specimens. These
  findings suggest the importance of nuclear
  functions of PKM2 in the Warburg effect and
  tumorigenesis.
• Reference Yang, W et al., Nature Cell Biol. 14
  1295 (2012)

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IDH mutations and cancer

•   Mutations in isocitrate dehydrogenase 1 and 2
  result in the formation of 2-hydroxyglutarate
  (2HG) instead of alpha-ketoglutarate. 2HG is a
  competitive inhibitor of alpha-ketoglutarate-depen
  dent dioxygenases. Dioxygenases have an important
  role in demethylation reactions for histones and
  DNA causing hypermethylation in glioma and AML.
• Reference Yen KE and Schenkein DP
  Cancer-associated isocitrate dehydrogenase
  mutations. The Oncologist 17 5-5, 2012

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Fumarate hydratase

•   Low activities of fumarate hydratase (fumarase)
  drives a metabolic shift to aerobic glycolysis in
  some kidney tumors and thereby enhances the
  Warburg effect in which aerobic glycolysis tends
  to be increased in cancer cells

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POLYAMINES

• Polyamines are organic cations formed by the
  enzymatic decarboxylation of ornithine to yield
  putrescine and by further additions from
  decarboxylated S-adenosyl methionine to form
  spermidine and spermine.
• Ornithine decarboxylase and polyamine content are
  increased in many carcinomas including skin and
  colon cancer.
• DFMO (difluoromethylornithine) is an inhibitor of
  ornithine decarboxylase and has some antitumor
  action.
• Polyamines work at least in part by regulating
  specific gene expression
• Reference E.W. Gerner and F.L. Meyskens.
  Polyamines and cancer old molecules, new
  understanding. Nature reviews Cancer 4 781-792,
  2004.

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INTERMEDIARY METABOLISM - SUGGESTED READING

• R.W. Ruddon and R.W. Kufe, In Holland-Frei Cancer
  Medicine - 8th Ed, Part II, Section 1, 9.
  Biochemistry of Cancer (2010)
• A.J. Levine and A.M. Puzio-Kuter. The control of
  the metabolic switch in cancers by oncogenes and
  tumor suppressor genes. Science 330 1340-1344,
  2010.