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Abstract

Cancer cells ignore oxygen availability, opting for less efficient, anaerobic ways of generating energy. The wisdom behind this choice seems to be in preventing the accumulation of reactive oxygen species, and so oxidative damage.
the loading force, L, or F = µL, where µ is the
coefficient of friction. However, the authors
find that, rather than this friction modulation
averaging to zero, the net friction acting on the
elastomer block goes up and down slightly (by
up to a few per cent) during the sliding experi-
ments (Fig.1b), with the same period as the
ridges. And, surprisingly, the amplitude of this
modulation actually increases when the net
loading force increases.
One of the fundamental advances pro-
vided by Wandersman etal.
2
is their analysis
showing that, if the local friction coefficient
depends even slightly on pressure (which
is equivalent to friction being slightly non-
linear with load), the modulation in friction
can increase with loading force. They find
good agreement between the experiments and
a model in which friction varies non-linearly
with load: F = ALγ, where γ = 0.87 ± 0.04 and
A is a constant. In this model, the roughness
of the surface against which the fingerprint-
like ridges are being slid has the important role
of providing a hetero geneous distribution of
contact pressure locally along the ridges. As
the roughness increases, a wider distribution
of loading pressure occurs, leading to a larger
modulation in friction as a result of the non-
linear nature of friction with load. The spatial
period of the ridges serves to concentrate the
minute variation of friction caused by these
texture-induced pressure modulations all
at one frequency, making it much easier to
discern this variation from the average net
friction.
The sliding of fingerprint-like ridges over
surfaces is not the only area in which Wan-
dersman and colleagues’ analysis should
apply. Because friction forces are rarely strictly
linear with loading forces (as postulated in
Amontons’ law)
5
, we believe that this analysis
could provide a valuable way to use friction
fluctuations to characterize surface rough-
ness on many types of material pairs sliding
CANCER
Sacrifice for survival
Cancer cells ignore oxygen availability, opting for less efficient, anaerobic ways of
generating energy. The wisdom behind this choice seems to be in preventing the
accumulation of reactive oxygen species, and so oxidative damage.
NANA-MARIA GRÜNING & MARKUS RALSER
W
hen oxygen is plentiful, cells con-
vert glucose to energy through the
consecutive processes of glycolysis
and oxidative respiration. However, cancer
cells exhibit what is known as the Warburg
effect: even in the presence of oxygen, they
prefer the much less efficient process of glu-
cose fermentation for energy production1.
This seems counter-intuitive because rapid
cell proliferation, which is required for tumour
growth, has high energetic demands2,3. In a
paper published in Science, Anastasiou and
colleagues
4
provide evidence that cancer cells
undergo this metabolic shift to clear reactive
oxygen species (ROS) and so prevent oxidative
damage. Thus, reconfiguration of the central
carbon metabolism to counteract oxidative
stress seems to be a major prerequisite for
cancer progression.
Textbooks offer two possible explanations
for the decline in respiratory activity during
cancer development. First, with the increase in
nucleotide and macromolecule biosynthesis,
there is a shortage of carbon equivalents for
oxidative respiration. Second, a higher speed
of glycolysis makes anaerobic metabolism
more efficient, with more lactate being gener-
ated from pyruvate, the end product of glyco-
lysis; this allows cancer cells to feed each other
by shuffling lactate2,3.
Neither hypothesis fully explains the meta-
bolic reconfiguration in cancer cells. For one,
against each other. The amplitude and the
load-dependence of the fluctuations reveal
information on the surfaces topographic
characteristics at length scales much smaller
than that of the patterned ridges. As a result,
we think that one exciting area to which the
method developed by Wandersman etal.2
could be extended is the characterization of
surface roughness down to the nanometre
scale or even smaller atomic length scales.
For example, for many years, atomic-scale
modulations of friction have been observed
when the sharp tip of an atomic force micro-
scope (AFM) slides across the periodic
arrangement of atoms on a crystalline surface6.
However, these AFM experiments typically
require very small loading forces (nano-
newtons) to maintain a contact area of only
a few nanometres in diameter in order to see
the atomic-scale modulation of friction. But,
perhaps, with suitably designed patterned
ridges and friction sensors, this ability to sense
the atomic-level contribution to the friction
modulation could be extended from the cur-
rent nanometre-sized contact zones of AFMs
to millimetre-sized contact zones, allowing
future robotic fingers to feel the atomic-level
contribution to surface texture.
C. Mathew Mate is at the Hitachi San
Jose Research Center, San Jose, California
95135, USA. Robert W. Carpick is in the
Department of Mechanical Engineering
and Applied Mechanics, University of
Pennsylvania, Philadelphia, Pennsylvania
19104, USA.
e-mails: mathew.mate@hitachigst.com;
carpick@seas.upenn.edu
1. Dowson, D. Proc. Inst. Mech. Eng. J 223, 261–273
(2009).
2. Wandersman, E., Candelier, R., Debrégeas, G. &
Prevost, A. Phys. Rev. Lett. 107, 164301 (2011).
3. Romano, J. M., Hsiao, K., Niemeyer, G., Chitta, S.
& Kuchenbecker, K. J. IEEE Trans. Robotics http://
dx.doi.org/10.1109/tro.2011.2162271 (2011).
4. Mate, C. M. Tribology on the Small Scale: A Bottom
Up Approach to Friction, Lubrication, and Wear
63–66 (Oxford Univ. Press, 2008).
5. Persson, B. N. J. Sliding Friction: Physical Principles
and Applications (Springer, 1998).
6. Mate, C. M., McClelland, G. M., Erlandsson, R. &
Chiang, S. Phys. Rev. Lett. 59, 1942–1945 (1987).
Low roughness High roughness
Sliding distance Sliding distance
F/Fave
0.98
0.99
1.00
1.01
1.02
Friction
force
Loading force
Epidermal ridges
Rough surface
a b
 
Figure 1 | The friction force. a,When a fingertip is rubbed against a rough surface, the net friction force
acting on the epidermal ridges increases with the loading force that the finger exerts on the ridges to press
them into contact with the surface. b,Wandersman etal.2 measure the net friction force that acts on an
elastomer block as it slides against glass surfaces of differing roughness. The elastomer block has ridges
similar in structure and elasticity to the epidermal ridges on a finger. Shown here is the instantaneous
friction force F, normalized to the average friction force Fave, as a function of sliding distance. λ is the
spacing of the ridges on the elastomer block and is 218 micrometres. The force has a slight oscillating
component that has the same period as the separation between the ridges and increases with the degree
of roughness on the glass. (Part b modified from ref. 2.)
190 | NATURE | VOL 480 | 8 DECEMBER 2011
NEWS & VIEWS
RESEARCH
© 2011 Macmillan Publishers Limited. All rights reserved
oxidative respiration occurs downstream of
glycolysis, and so does not compete with gly-
colysis for carbon equivalents and would not
interfere with a high glycolytic flux. Moreover,
unlike respiring cells, which shuffle pyruvate
from the cytoplasm into the mitochondria —
the organelles within which oxidative respi-
ration occurs — cancer cells actively excrete
the lactate they generate from pyruvate. This
contradicts the proposal that cancer cells shut
down respiration to save carbon equivalents
for biosynthesis. Finally, even some non-can-
cerous cells that do not make use of lactate
(including yeast, Tcells and induced pluri-
potent stem cells) undergo a Warburg-like
metabolic restructuring during rapid growth.
Anastasiou and colleagues’ results4 bring
the redox balance centre stage to explain this
metabolic reconfiguration. They show that the
glycolytic enzyme pyruvate kinase — a main
regulator of the Warburg effect — facilitates
tumour growth by preventing accumulation of
ROS, and so avoiding oxidative damage.
In all living cells, ROS leak from the chain
of reactions that constitute oxidative respira-
tion, or are generated as by-products of both
fatty-acid metabolism and biosynthetic redox
reactions. Under normal physiological condi-
tions this is not a problem, because ROS levels
are kept low and in equilibrium with reducing
molecules. In fact, a certain amount of ROS
is necessary for normal physiology. But if the
normal redox balance is disrupted, or ROS
accumulate, oxidation and disturbed bio-
chemical reactions damage macromolecules,
ultimately leading to cell death. Therefore,
cancer cells rely on a complex anti-oxidative
machinery that can dynamically supply reduc-
ing equivalents and clear ROS when required
3
.
Pyruvate kinase is a regulator of cellular
anti-oxidative metabolism. Of the four human
isoforms of this enzyme, PKM2 plays a cru-
cial part in cancer metabolism. Like other
metabolic enzymes, PKM2 levels increase in
tumours
5
. However, this protein has a unique
regulatory role in that its decreased catalytic
activity is associated with tumour progression
and the development of the Warburg effect6,7.
When pyruvate kinase activity is low — as
in cancer cells or in respiring yeast — its sub-
strate, phosphoenol pyruvate, accumulates
8,9
.
This inhibits the glycolytic enzyme triose
phosphate isomerase and leads to activation
of a pathway alternative to glycolysis — the
pentose phosphate pathway9. Increased activ-
ity of this pathway protects against ROS in at
least two ways. First, it provides NADPH, a
reducing factor that is required for the activity
of antioxidant enzymes and for the recycling of
the anti-oxidant peptide glutathione. NADPH
also compensates for the redox imbalance
caused by increased nucleotide and fatty-acid
synthesis3. Second, the pentose phosphate
pathway regulates gene expression in favour
of adaptation to oxidative stress10.
Anastasiou and co-workers
4
establish that
CORRECTION
In the News & Views article ‘Ageing:
Generations of longevity’ by Susan E.
Mango (Nature 479, 302–303; 2011), it
was stated that transient exposure of rats
to a high-sugar/low-protein diet leads to
glucose intolerance. This should have read
“transient exposure of rats to a high-sugar/
high-fat diet leads to glucose intolerance”.
activation of the pentose phosphate pathway
and its anti-oxidative activity are essential for
cancer-cell growth (Fig.1). They report that,
in lung cancer cells, oxidation of PKM2 on
the cysteine amino-acid residue 358 (Cys358)
keeps its activity low. This increases both the
concentration of glucose-6-phosphate — the
metabolite that connects glycolysis to the oxi-
dative, NADP
+
-reducing branch of the pentose
phosphate pathway — and flux through the
pentose phosphate pathway.
The authors interfered with the pyruvate-
kinase-triggered activation of the pentose
phosphate pathway by increasing PKM2
activity in the presence of oxidants. To do this,
they mutated the enzymes Cys358 to a serine
residue or used small-molecule activators. This
treatment had remarkable effects on cancer-
cell growth. Accumulation of ROS caused
oxidative damage and slowed the prolifera-
tion of cancer cells both in tissue culture and
in tumours grafted into immunocompromised
mice.
These data suggest that inducing the
Warburg effect promotes cancer growth by
activating the pentose phosphate pathway,
maintaining the balance of redox equivalents,
providing NADPH and activating antioxidant
defence systems. The findings have notable
implications for understanding the energetic
balance during cancer development: block-
ing pyruvate kinase to redirect the metabolic
flux is energetically costly under conditions
of low respiratory activity because it dimin-
ishes the step that is responsible for the net
yield of the cellular energy molecule ATP by
glycolysis. This indicates that maintenance of
the redox balance is more limiting for tumour
growth than are energy levels or biosynthetic
metabolism.
Could this metabolic reconfiguration be
exploited for therapeutic purposes? Poten-
tially, yes. But targeting a fundamental redox-
balancing process must be cancer-cell specific,
otherwise it would heavily damage other
metabolically active cell types, including liver
cells, immune cells and neurons. Yet, PKM2,
triose phosphate isomerase, the pentose phos-
phate pathway and its associated metabolites
are not cancer-cell specific. Nevertheless, a
promising strategy might be to induce ROS
overload in cancer cells, thereby making them
vulnerable to oxidative damage by neutraliz-
ing the protective effects of the Warburg effect.
To develop such strategies it will be essential
to pursue comprehensive quantitative and
qualitative investigations to understand all
the ROS-producing biochemical reactions in
the cancer cell.
Nana-Maria Grüning and Markus Ralser
are at the Max Planck Institute for Molecular
Genetics, 14195 Berlin, Germany. M.R. is
also in the Department of Biochemistry and
Cambridge Systems Biology Centre, University
of Cambridge, Cambridge, CB2 1GA, UK.
e-mails: gruening@molgen.mpg.de;
mr559@cam.ac.uk
1. Warburg, O. Science 123, 309–314 (1956).
2. Hsu, P. P. & Sabatini, D. M. Cell 134, 703–707
(2008).
3. Cairns, R. A., Harris, I. S. & Mak, T. W. Nature Rev.
Cancer 11, 85–95 (2011).
4. Anastasiou, D. et al. Science http://dx.doi.
org/
10.1126/science.1211485
(2011).
5. Bluemlein, K. et al. Oncotarget 2, 393–400 (2011).
6. Hitosugi, T. et al. Sci. Signal. 2, ra73 (2009).
7. Christofk, H. R. et al. Nature 452, 230–233 (2008).
8. Vander Heiden, M. G. et al. Science 329,
1492–1499 (2010).
9. Grüning, N.-M. et al. Cell Metab. 14, 415–427
(2011).
10. Krüger, A. et al. Antioxid. Redox Signal. 15, 311–324
(2011).
Figure 1 | Restructuring cellular metabolism.
Glucose is converted to pyruvate by the
cytoplasmic process of glycolysis, generating
energy. When oxygen is present, pyruvate enters
mitochondria, where it generates more energy
through the process of oxidative respiration.
But, in proliferating cells — and under anaerobic
conditions — pyruvate is converted to lactate.
In cancer and respiring yeast, reduced activity
of pyruvate kinase, the enzyme that catalyses the
final step of glycolysis, mediates redox balance
by activating the pentose phosphate pathway9.
Anastasiou et al.4 show that activation of this
pathway is crucial for cancer cells, and facilitates
tumour growth by limiting ROS accumulation
and, therefore, oxidative stress.
Glucose
Glycolysis
Phosphoenol pyruvate
Energy
Oxidative respiration
Cancer
Pyruvate
kinase
Lactate
Pyruvate
Pentose
phosphate
pathway
ROS
Cancer-cell
proliferation,
cancer growth
Mitochondrion
Cytoplasm
8 DECEMBER 2011 | VOL 480 | NATURE | 191
NEWS & VIEWS RESEARCH
© 2011 Macmillan Publishers Limited. All rights reserved
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Chapter
Cancer cell metabolic pathways (aerobic glycolysis, Warburg effect) may be used as targets for the development of new drugs with more specific therapeutic strategies. Reactive oxygen species (ROS) are often involved in these metabolic pathways. Their generation, as well as the defensive reactions against them, present attractive targets. In this chapter, the major aspects of aerobic glycolysis in cancer cells are summarized first, while presenting the principles of ROS biochemistry. ROS formation, and the defense mechanisms against them, are rather heterogeneous in various cancer cell types. The basic mechanisms, therefore, are described first in two well-defined non-malignant cell types, erythrocytes and neutrophils. This is followed by a description of the more complex situation in cancer cells, where the influence of anti-/pro-oxidative microenvironments on cellular proliferation and survival is discussed. In the second part, potential targets for ROS-based therapeutics are presented and the mechanisms of some of them (dichloroacetate, iron dependency, arsenic trioxide, and high-dose intravenous (i.v.) ascorbic acid) are described in more detail.
Chapter
Reactive oxygen/nitrogen species are presently recognized not only as damaging by-products of aerobic respiration or inflammatory reactions, but also critical mediators of redox signalling in different organs, including liver. The molecules of oxidants produced within cells, as well as the chemical principles sustaining cellular redox-regulated processes are herein described. Cysteine residues of some proteins act as sensors of redox milieu and are oxidized in reversible reactions leading to the formation of sulfenic acid and disulfides, the initial steps of thiol oxidation. Central to reversibility of redox-signaling processes are glutathione, thioredoxins, and peroxiredoxins systems, controlling intracellular local hydrogen peroxide levels and thiol/disulfide balance. The role of hydrogen peroxide channels as aquaporins/peroxiporins is described. Lastly, some of the most important redox-based molecular machines are described in detail, including tyrosine phosphatases, receptor or cytosolic kinases, metabolic enzymes, and several transcriptions factors. Moreover, some redox-sensitive non-protein substrates, endowed with signalling features, are described. The redox signalling area of research is promptly expanding and continuous challenging studies are examining new pathways and clarifying their importance in cellular hepatic pathophysiology.
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Control of intracellular reactive oxygen species (ROS) concentrations is critical for cancer cell survival. We show that, in human lung cancer cells, acute increases in intracellular concentrations of ROS caused inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of Cys(358). This inhibition of PKM2 is required to divert glucose flux into the pentose phosphate pathway and thereby generate sufficient reducing potential for detoxification of ROS. Lung cancer cells in which endogenous PKM2 was replaced with the Cys(358) to Ser(358) oxidation-resistant mutant exhibited increased sensitivity to oxidative stress and impaired tumor formation in a xenograft model. Besides promoting metabolic changes required for proliferation, the regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress.
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In proliferating cells, a transition from aerobic to anaerobic metabolism is known as the Warburg effect, whose reversal inhibits cancer cell proliferation. Studying its regulator pyruvate kinase (PYK) in yeast, we discovered that central metabolism is self-adapting to synchronize redox metabolism when respiration is activated. Low PYK activity activated yeast respiration. However, levels of reactive oxygen species (ROS) did not increase, and cells gained resistance to oxidants. This adaptation was attributable to accumulation of the PYK substrate phosphoenolpyruvate (PEP). PEP acted as feedback inhibitor of the glycolytic enzyme triosephosphate isomerase (TPI). TPI inhibition stimulated the pentose phosphate pathway, increased antioxidative metabolism, and prevented ROS accumulation. Thus, a metabolic feedback loop, initiated by PYK, mediated by its substrate and acting on TPI, stimulates redox metabolism in respiring cells. Originating from a single catalytic step, this autonomous reconfiguration of central carbon metabolism prevents oxidative stress upon shifts between fermentation and respiration.
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The Warburg effect describes the circumstance that tumor cells preferentially use glycolysis rather than oxidative phosphorylation for energy production. It has been reported that this metabolic reconfiguration originates from a switch in the expression of alternative splice forms (PKM1 and PKM2) of the glycolytic enzyme pyruvate kinase (PK), which is also important for malignant transformation.However, analytical evidence for this assumption was still lacking. Using mass spectrometry, we performed an absolute quantification of PKM1 and PKM2 splice isoforms in 25 human malignant cancers, 6 benign oncocytomas, tissue matched controls, and several cell lines. PKM2 was the prominent isoform in all analyzed cancer samples and cell lines. However, this PKM2 dominance was not a result of a change in isoform expression, since PKM2 was also the predominant PKM isoform in matched control tissues. In unaffected kidney, lung, liver, and thyroid, PKM2 accounted for a minimum of 93% of total PKM, for 80% - 96% of PKM in colon,and 55% - 61% of PKM in bladder. Similar results were obtained for a panel of tumor and non-transformed cell lines, where PKM2 was the predominant form.Thus, our results reveal that an exchange in PKM1 to PKM2 isoform expression during cancer formation is not occurring, nor do these results support conclusions that PKM2 is specific for proliferating, and PKM1 for non-proliferating tissue.
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A shift in primary carbon metabolism is the fastest response to oxidative stress. Induced within seconds, it precedes transcriptional regulation, and produces reducing equivalents in form of NADPH within the pentose phosphate pathway (PPP). Here, we provide evidence for a regulatory signaling function of this metabolic transition in yeast. Several PPP-deficiencies caused abnormal accumulation of intermediate metabolites during the stress response. These PPP-deficient strains had strong growth deficits on media containing oxidants, but we observed that part of their oxidant-phenotypes were not attributable to the production of NADPH equivalents. This pointed to a second, yet unknown role of the PPP in the antioxidant response. Comparing transcriptome profiles obtained by RNA sequencing, we found gene expression profiles that resembled oxidative conditions when PPP activity was increased. Vice versa, deletion of PPP enzymes disturbed and delayed mRNA and protein expression during the antioxidant response. Thus, the transient activation of the PPP is a metabolic signal required for balancing and timing gene expression upon an oxidative burst. Consequently, dynamic rearrangements in central carbon metabolism seem to be of major importance for eukaryotic redox sensing, and represent a novel class of dynamic gene expression regulators.
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Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
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Proliferating cells, including cancer cells, require altered metabolism to efficiently incorporate nutrients such as glucose into biomass. The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of glucose by aerobic glycolysis and contributes to anabolic metabolism. Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. We demonstrate that phosphoenolpyruvate (PEP), the substrate for pyruvate kinase in cells, can act as a phosphate donor in mammalian cells because PEP participates in the phosphorylation of the glycolytic enzyme phosphoglycerate mutase (PGAM1) in PKM2-expressing cells. We used mass spectrometry to show that the phosphate from PEP is transferred to the catalytic histidine (His11) on human PGAM1. This reaction occurred at physiological concentrations of PEP and produced pyruvate in the absence of PKM2 activity. The presence of histidine-phosphorylated PGAM1 correlated with the expression of PKM2 in cancer cell lines and tumor tissues. Thus, decreased pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent histidine phosphorylation of PGAM1 and may provide an alternate glycolytic pathway that decouples adenosine triphosphate production from PEP-mediated phosphotransfer, allowing for the high rate of glycolysis to support the anabolic metabolism observed in many proliferating cells.
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