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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 etal.
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 surface’s 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 etal.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 etal.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, Tcells 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 enzyme’s 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
