Otto Heinrich Warburg (Friburgo in Brisgovia, 8 ottobre 1883 –

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Otto Heinrich Warburg (Friburgo in Brisgovia, 8 ottobre 1883 –
Otto Heinrich Warburg (Friburgo in Brisgovia, 8 ottobre 1883 –
Berlino, 1 agosto 1970)
Warburg O, Posener K, Negelein E. Uber den Stoffwechsel
der Tumoren [On metabolism of tumors]. Biochem Z
1924; 152:319–344.
Warburg O. The metabolism of
London; 1930.
tumours. Constable:
Warburg O. On the origin of cancer cells. Science 1956;
123:309–314.
Warburg O. On respiratory impairment in cancer cells.
Science 1956; 124: 269–270.
90 years after Otto Warburg’s discovery we
still ask ourselves “why do cancers have
high aerobic glycolysis?”
This question, however, can be understood
in two different ways:
1. What is the cause of increased aerobic
glycolysis in tumor cells?
or
2. What is the advantage of increased
aerobic glycolysis for tumor cells?
Otto Warburg
Nobel Prize in Physiology or Medicine 1931.
Every year, between 20 and 25 Nobel Laureates spend a week in
the Lake Constance area to meet the next generation of leading
scientists.
The Prime Cause and Prevention of Cancer
Lecture at the meeting of the Nobel-Laureates on
June 30, 1966
at Lindau, Lake Constance, Germany
by
Otto Warburg
Director, Max Planck-Institute for Cell Physiology, Berlin-Dahlem
Cell metabolism
Quiescent versus proliferating cells
Proliferating versus cancer cells
The example illustrates that the biosynthesis of
many cellular building blocks requires nutrients in
excess of those needed for ATP production alone
BIOMASS
Glicolisi: Fase Esoergonica
 Decima reazione: seconda
fosforilazione a livello del substrato
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PEP
Il
prodotto
finale
della 10° reazione è
dunque il piruvato in
forma chetonica.
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Interconversione
spontanea
chetopiruvato
enolpiruvato
forma chetonica)
(forma enolica)
Pyruvate kinase isoforms
• Liver (L)
PKL gene
• Red blood cell (R)
• M1, expressed in most adult tissues
PKM gene
• M2,
expressed predominantly in
embryonic tissue and tumors
The
specific
activity
of
PKM2 that is
fully activated
by
FBP is
approximately
half that of
PKM1.
In the absence of FBP, PKM2 had less than one quarter of
the activity of PKM1.
Science. 2010 September 17; 329(5998): 1492–1499.
Evidence for an alternative glycolytic pathway
in rapidly proliferating cells
Matthew G. Vander Heiden1,2,3,*, Jason W. Locasale2,3, Kenneth D. Swanson2,
Hadar Sharfi2, Greg J. Heffron4, Daniel Amador-Noguez5, Heather R. Christofk2,
Gerhard Wagner4, Joshua D. Rabinowitz5, John M. Asara2, and Lewis C.
Cantley2,3,†
1Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
2Beth Israel Deaconess Medical Center, Division of Signal Transduction and Department
of
Medicine, Harvard Medical School, Boston, MA 02115
3Department of Systems Biology, Harvard Medical School, Boston, MA 02115
4Department of Biological Chemistry and Molecular Pharmacology; Harvard Medical
School,
Boston, MA 02115
5Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton
University, Princeton, NJ 08544
Cancer Cell. 2012 November 13; 22(5): 585–600.
Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis
to promote tumor growth
Taro Hitosugi et al.
3-PG
2-PG
BIOSINTESI DELLE PIRIMIDINE
Ciclo di Krebs: enzimi
O
acetilCoA
S
C
H3C
CoA
CoA
H2 O
COOH
C O
HO
citrato
-
NADH+H +
H
C
NAD+
COOH
8
COOH 2
2
2°deidrogenazione
isomerizzazione
H
C
HOOC
C
idratazione
3
CH
4
H
FADH
NAD
NADH+H
COOH
CH2
GTP
GDP+Pi
CH2
COOH
succinato
5
C S CoA
+
O
CH2
CH2
 chetoglutarato
CoA SH
CH2
COOH
succinil-CoA
succinato
deidrogenasi
COOH
4
O
CH2
CoA SH
+
6
CO
72
+
C
fosforilazione a livello
del substrato
FAD
succinil-CoA
sintetasi
COOH
5
2
5
8
2°decarbossilazione
ossidativa
CO2
deidrogenasi
3
4
1°deidrogenazione
COOH
NAD +
NADH+H
6
CH
6
OH
isocitrato CH2
COOH
1°decarbossilazione
ossidativa
isocitrato
deidrogenasi
-chetoglutarato
COOH
7
COOH
fumarato
3
CH2
1
COOH
malato
7
C
2
condensazione
OH
CH2
H2 O
aconitasi
CH2
1
ossaloacetato
COOH
COOH
1
COOH
CH2
8
citrato sintasi
SH
fumarasi
malato
deidrogenasi
glutaminolysis
l’enzima malico catalizza la reazione che
concorre a fornire equivalenti riducenti per la
•
sintesi
degli acidi grassi
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Fase delle decarbossilazioni ossidative
(reazioni 3, 4):
AA 07/08
Reazione n°3: 1a decarbossilazione ossidativa.
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La reazione, catalizzata dall’enzima isocitrato deidrogenasi, prevede
l’ossidazione dell’isocitrato
con formazione
di un intermedio,
l’ossalsuccinato, dal quale si distacca una molecola di CO2. Si ha dunque
formazione di NAD ridotto e liberazione di una molecola di anidride
carbonica. L’ossalsuccinato viene decarbossilato mentre si trova legato
all’enzima e non compare mai in forma libera
glutamine
glucose
Acetyl-CoA
from other sources
(fatty acids, amino
acids)
% of total
NADH/FADH2
production
60
30
10
Whatever its function, the occurrence of the
Warburg effect reflects the activation of
oncogenic
signaling
pathways
whose
physiological function is to promote glucose
uptake and anabolic metabolism.
Metabolic Reprogramming: A Cancer
Hallmark Even Warburg Did Not Anticipate
Patrick S. Ward1,2 and Craig B. Thompson1,*
1 Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer
Center, New York, NY
10065
2 Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the
University of
Pennsylvania, Philadelphia, PA 19104
Cancer Cell. 2012 March 20; 21(3): 297–308.
Via della serina
GLICOLISI
glucosio
glutamina
GLS-2
PHGDH
PSAT
piruvato
Lattato o Acetil-CoA
PSPH
PHGDH: fosfoglicerato deidrogenasi
PSAT: fosfoserina aminotransferasi
PSPH: fosfoserina fosfoidrolasi
GLS-2: glutaminase-2
Nat Genet. 2011 Jul 31;43(9):869-74.
Phosphoglycerate dehydrogenase diverts
glycolytic flux and contributes to oncogenesis.
Locasale JW, et al.
Department of Systems Biology, Harvard Medical
School, Boston, Massachusetts, USA
Suppression of PHGDH in MDA-MB-468 cells caused a large
reduction in the levels of a-keto-glutarate. In fact, of the
major metabolites measured, aKG was the one with the most
significant and largest change upon PHGDH suppression,
whereas serine levels were not significantly changed.
glutamine
Science. 2012 May 25;336(6084):1040-4.
Metabolite profiling identifies a key role for
glycine in rapid cancer cell proliferation.
Jain M, Nilsson R, Sharma S, Madhusudhan N,
Kitami T, Souza AL, Kafri R, Kirschner MW, Clish
CB, Mootha VK.
Broad Institute, Cambridge, MA 02142, USA.
We measured the consumption and release (CORE) profiles
of 219 metabolites from media across the NCI-60 cancer
cell lines, and integrated these data with a preexisting atlas
of gene expression. This analysis identified glycine
consumption and expression of the mitochondrial glycine
biosynthetic pathway as strongly correlated with rates of
proliferation across cancer cells.
Antagonizing glycine uptake and its mitochondrial
biosynthesis preferentially impaired rapidly proliferating
cells.
Moreover, higher expression of this pathway was associated
with greater mortality in breast cancer patients. Increased
reliance on glycine may represent a metabolic vulnerability
for selectively targeting rapid cancer cell
proliferation.
Original Article
Recurring Mutations Found by Sequencing an
Acute Myeloid Leukemia Genome
Elaine R. Mardis, Ph.D., Li Ding, Ph.D., David J. Dooling, Ph.D., David E.
Larson, Ph.D., Michael D. McLellan, B.S., Ken Chen, Ph.D., Daniel C.
Koboldt, M.S., Robert S. Fulton, M.S., Kim D. Delehaunty, B.A., Sean D.
McGrath, M.S., Lucinda A. Fulton, M.S., Devin P. Locke, Ph.D., Vincent J.
Magrini, Ph.D., Rachel M. Abbott, B.S., Tammi L. Vickery, B.S., Jerry S.
Reed, M.S., Jody S. Robinson, M.S., Todd Wylie, B.S., Scott M. Smith, Lynn
Carmichael, B.S., James M. Eldred, Christopher C. Harris, B.S., Jason
Walker, B.A., B.S., Joshua B. Peck, M.B.A., Feiyu Du, M.S., Adam F. Dukes,
B.A., Gabriel E. Sanderson, B.S., Anthony M. Brummett, Eric Clark, Joshua
F. McMichael, B.S., Rick J. Meyer, M.S., Jonathan K. Schindler, B.S., B.A.,
Craig S. Pohl, M.S., John W. Wallis, Ph.D., Xiaoqi Shi, M.S., Ling Lin, M.S.,
Heather Schmidt, B.S., Yuzhu Tang, M.D., Carrie Haipek, M.S., Madeline E.
Wiechert, M.S., Jolynda V. Ivy, M.B.A., Joelle Kalicki, B.S., Glendoria Elliott,
Rhonda E. Ries, M.A., Jacqueline E. Payton, M.D., Ph.D., Peter Westervelt,
M.D., Ph.D., Michael H. Tomasson, M.D., Mark A. Watson, M.D., Ph.D., Jack
Baty, B.A., Sharon Heath, William D. Shannon, Ph.D., Rakesh Nagarajan,
M.D., Ph.D., Daniel C. Link, M.D., Matthew J. Walter, M.D., Timothy A.
Graubert, M.D., John F. DiPersio, M.D., Ph.D., Richard K. Wilson, Ph.D., and
Timothy J. Ley, M.D.
Vol 361(11):1058-1066, September 10, 2009
Study Overview
• A comparison of the genomic sequence of a
tumor sample from a patient with acute
myeloid leukemia (AML) and that of a normal
skin sample from the same patient revealed an
estimated 750 somatic mutations, of which 12
were in the coding sequences of genes and 52
were in conserved regions or regions with
regulatory potential
• Four mutations were found to be recurrent in
AML, including mutations in NRAS, NPM1,
IDH1, and a conserved region on chromosome
10
AML patients with the IDH1 R132 mutation harbored high serum levels of 2-HG.
Maxmen Journal of Experimental Medicine
2010:0:jem.2072iti5-jem.2072iti5
© 2010 Maxmen
In cytogenetically normal AML, mutated IDH1 is
found in 10.9% of patients, while mutated IDH2 is
found in 12.1%. Mutations in IDH1 are almost
exclusively found at amino acid arginine 132 and
IDH2 mutations are found more frequently at
position R140 and less frequently at position R172.
TET
Cancer Cell. 2011 Jan 18;19(1):17-30.
Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of
α-ketoglutarate-dependent dioxygenases.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu
LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL,
Zhao SM, Xiong Y.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Shanghai
Medical School, Fudan University, Shanghai 20032, China.
IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia,
leading to simultaneous loss and gain of activities in the production of
α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we
demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent
dioxygenases, including histone demethylases and the TET family of
5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in
the active site of histone demethylases. Ectopic expression of tumor-derived IDH1
and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma,
IDH1 mutations are associated with increased histone methylation and decreased
5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations
reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide
histone and DNA methylation alterations.
A novel inhibitor of mutant IDH1 inhibits human AML cell growth
As inhibition of several signalling pathways did not selectively inhibit
IDH1mut cells, we performed a computational drug screen using the
ZINC library and the published crystal structure of mutant IDH1. By
computational screening we identified a potential inhibitor of mutant
IDH1
termed
2-[2-[3-(4-fluorophenyl)pyrrolidin-1-yl]ethyl]-1,4dimethylpiperazine (here termed HMS-101). Computational modeling
showed that HMS-101 binds to the isocitrate-binding pocket of mutant
IDH1.
The IC50 for HMS-101 was significantly lower in mouse bone
marrow cells transduced with IDH1mut compared to IDH1wt (1 μM
vs. 12 μM, respectively, P<.001). Treatment of HoxA9+IDH1mut
cells with HMS-101 at 10 μM significantly reduced intracellular R2HG levels in vitro. HMS-101 induced apoptosis in IDH1mut cells
as evidenced by Annexin V staining and cell cycle analysis by BrDU