ArticlePDF Available


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.
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
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)
, 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
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.
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
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.
1. Dowson, D. Proc. Inst. Mech. Eng. J 223, 261–273
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:// (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
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
© 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
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
. 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
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
establish that
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
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
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.
1. Warburg, O. Science 123, 309–314 (1956).
2. Hsu, P. P. & Sabatini, D. M. Cell 134, 703–707
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.
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
10. Krüger, A. et al. Antioxid. Redox Signal. 15, 311–324
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.
Phosphoenol pyruvate
Oxidative respiration
cancer growth
8 DECEMBER 2011 | VOL 480 | NATURE | 191
© 2011 Macmillan Publishers Limited. All rights reserved
... This metabolic reorganization entails redirecting energy flow away from the mitochondria to fuel glycolysis and the PPP. (28,(56)(57)(58) The PPP plays a critical, non-redundant role in the supply of the building blocks. Thus, redirecting energy flow to the non-oxidative branch of the PPP has the critical benefit of enabling the required nucleotide biosynthesis via the production of ribose 5-phosphate.(59) ...
Full-text available
BACKGROUND: A lot of contemporary cancer research has concentrated on genetic influence. However, cancer also involves biochemical changes, such as metabolic adaptation to support the aberrant cell proliferation. CONTENT: The fast cell proliferation in cancer cells enforce a metabolic re-arrangement to promote their long-term survival. The increased glucose uptake and fermentation of glucose to lactate are common features of this altered metabolism known as “the Warburg effect”. These metabolic pathways regulation enable cancer cells to produce adenosine triphosphate (ATP) in an efficient way. Epigenetic and metabolic changes also both affect molecular rewiring in cancer cells and promote cancer development and progression. SUMMARY: Metabolic rewiring and epigenetic remodeling establishing a direct link between metabolism and nuclear transcription to promote the survival of tumor cells. A further understanding of how metabolic remodeling can result in epigenetic changes in tumors, affecting cancer cell differentiation, proliferation, and/or apoptosis, will lead to a new strategy for cancer therapy. KEYWORDS: cancer metabolism, epigenetics, metabolic reprogramming, molecular rewiring
... Once the redox balance is disrupted, the increased ROS levels cause macromolecular damage and cancer cell death. [23] In this study, we report a novel {BiW 8 O (dmap = N-(4-pyridyl)dimethylamine) synthesized using a one-step synthesis method. For the first time, we identified pyroptosis to be a new mechanism involved in POM-induced cancer cell death. ...
Full-text available
We successfully synthesized {BiW8}, a 10‐nuclear heteroatom cluster modified {BiW8O30}. At 24 h post‐incubation, the IC50 values of {BiW8} against HUVEC, MG63, RD, Hep3B, HepG2, and MCF7 cells were 895.8, 127.3, 344.3, 455.0, 781.3, and 206.3 μM, respectively. The IC50 value of {BiW8} on the MG63 cells was more than 2‐fold lower than that of the other raw materials. Through morphological and functional features, we demonstrated pyroptosis as a newly identified mechanism of cell death induced by {BiW8}. {BiW8} increased 2‐fold reactive oxygen species (ROS) levels in MG63 cells at 24 h post‐incubation. Compared with 0 h, the glutathione (GSH) content decreased by 59%, 65%, 75%, 94%, and 97% at 6, 12, 24, 36 and 48 h post‐incubation, respectively. Furthermore, multiple antitumor mechanisms of {BiW8} were identified via transcriptome analysis and chemical simulation, including activation of pyroptosis, suppression of GSH generation, depletion of GSH, and inhibition of DNA repair.
... Pyruvate is channelled at higher rates into the TCA cycle, in which it is fully oxidized to CO2, resulting in oxidative ATP production and the formation of TCA intermediates required for amino acid biosynthesis at higher rate. The increase in oxidative metabolism coincides with increased flux into the oxidative pentose phosphate pathway, producing higher levels of NADPH both required for anabolism and anti-oxidant enzymes (61,62). ...
Full-text available
Alternative splicing (AS) has been suggested as one of the major processes expanding the diversity of proteomes in multicellular organisms. Mutually exclusive exons (MXE) provide one form of AS that is less likely to disrupt protein structure and is over-represented in the proteome compared to other forms of AS. We used domain structure information from the CATH classification to perform a systematic structural analysis of the effects of MXE splicing in high quality animal genomes (e.g. human, fly, mouse and 2 fishes) and we were able to annotate approximately 50% of MXE events with structural information. For those MXE events which can be mapped to a structure, we found that although embedded in domains, they were strongly enriched in surface exposed residues. We also demonstrated that the variable residues between splicing events lie close to known and/or predicted functional sites. We present some examples of MXE events in proteins that have important roles in cells. This work presents the first large scale systematic study of the structural/functional effects of MXE splicing using predominantly domain based modelling and functional annotation tools. Our study supports and expands on previous work in this field and helps to build a picture of how MXE events facilitate evolution of new functions.
... This phenomenon is called the Warburg effect or aerobic glycolysis [47,48]. Over the years, it has been repeatedly confirmed that increased glucose uptake and reduction of oxidative phosphorylation are typical for many proliferating cells, including cancer cells [17,46]. Interestingly, the process of aerobic glycolysis is not characteristic of non-proliferating cells, which could indicate higher efficiency of this process and greater benefits for intensely dividing cells, although fewer ATP molecules are formed in its course than in the oxidative phosphorylation process (2 ATP molecules and 32 ATP molecules, respectively) [25]. ...
A thorough understanding of the processes occurring in cancer cells is necessary to make cancer treatment as effective as possible. Changes in cellular metabolism in relation to normal cells are considered particularly important. One of the most interesting and promising areas is glucose metabolism and the factors affecting this process, with special emphasis on the potential role of hexokinases, especially the isoform II of this enzyme. Hexokinases (HK) are transferase enzymes involved in the process of glycolysis. Hexokinase II (HK II) plays an important role in initiating and maintaining the glycolysis process at a high level of efficiency, which is crucial for the growth and proliferation of cancer cells. An increase in the number of copies of the HK II gene and increased transcription of this enzyme resulting in the suppression of apoptosis and the enhancement of cell proliferation have been found in tumor cells. Hexokinase II also participates in the Crabtree effect by affecting the amount of ATP and thus the efficiency of the Ca2+ removal process outside the cell membrane by Ca2+ ATPase. Overexpression of HK II has thus far been found in pancreatic cancer, gastric cancer, breast cancer, squamous cell carcinoma of the larynx, glioblastoma multiforme, ovarian cancer and biliary tract cancer, indicating the possible key role of this enzyme in their formation and progression and providing the basis for seeking potential benefits of cancer treatment using HK II as a target of new drugs.
... The choice between fermentative and oxidative metabolism also affects redox homoeostasis, with the electron transport chain and glycolysis respectively having different effects on the release of reducing or oxidizing molecules, during ATP generation [54]. The maintenance of redox balance is indeed one reason why microbes use overflow metabolism when there is excess glucose available, as secreted metabolites can act as electron sinks for NADH, to regenerate NAD þ for glycolysis to occur [55]. ...
Full-text available
All biosynthetically active cells release metabolites, in part due to membrane leakage and cell lysis, but also in part due to overflow metabolism and ATP-dependent membrane export. At the same time, cells are adapted to sense and take up extracellular nutrients when available, to minimize the number of biochemical reactions that have to operate within a cell in parallel, and ultimately, to gain metabolic efficiency and biomass. Within colonies, biofilms or tissues, the co-occurrence of metabolite export and import enables the sharing of metabolites as well as metabolic specialization of single cells. In this review we discuss emerging biochemical concepts that give reasoning for why cells overproduce and release metabolites, and how these form the foundations for cooperative metabolite exchange activity between cells. We place particular emphasis on discussing the role of overflow metabolism in cells that exhibit either the Warburg or Crabtree effect. Furthermore, we discuss the profound physiological changes that cells undergo when their metabolism switches from metabolite synthesis to uptake, providing an explanation why metabolic specialization results in non-genotypic heterogeneity at the single cell level.
... Oxidative stress is considered to be the primary cause of cancer and occur as a result of an imbalance between the increasing demand for oxygen and nutrients by rapidly proliferating tumor cells and an inadequate, dysfunctional blood supply resulting from tumor angiogenesis [35][36][37]. Cancer cells demonstrate the Warburg effect, according to which even in the presence of sufficient oxygen cell prefer glycolysis for their energy production [38][39][40]. Oxidative stress results in increased level of reactive oxygen species (ROS), but the cancer cells can adjust against ROS levels by using this metabolic shift that can save them from apoptosis due to oxidative damage thus rapid proliferation is there [41,42]. Antioxidative enzymes (APOX, CAT, and SOD) effect the proliferation of a cell in a positive way, but when these antioxidants are given in compliance with some anti-proliferative therapy, it enhances the efficacy of the therapy by reducing the levels of ROS. ...
Full-text available
Cassia fistula Seed Extract Enhances Apoptosis in HeLa Cell Line via activating Annexin V and p53 Sana Javaid Awan*, Kanza Tariq, Ghazanfer Ali Nasir, Wajjiha Batool, Muneeb Ahmed Sheraz, Sajjad Ahmed, Tahir Maqbool, Usman Ali, Farheen Ansari Institute of Molecular Biology and Biotechnology, The University of Lahore, Pakistan Abstract Cancer is one of the top causes of death in the prosperous countries. Conventional plants are a precious source of novel cytotoxic agents and are still performing superior role in health concerns. The study was aimed to evaluate the effect of in vitro anticancer activity of Cassia fistula (CF) seed extracts against the HeLa cell line and umbilical cord-derived mesenchymal stem cells (UC-MSCs). CF seeds were extracted using three solvents (ethanol, ethyl acetate and petroleum ether). For the estimation of anti-proliferation in HeLa cells and UC-MSCs, MTT assay and for cell viability, trypan blue and crystal violet assays were done. Angiogenic potential was checked via immunocytochemistry and ELISA of vascular endothelial growth factor (VEGF). Immunocytochemistry of annexin-V and p53 was performed for the estimation of apoptosis in HeLa cells and UC-MSCs. Furthermore, ELISA for annexin-V, lactate dehydrogenase (LDH) assay and antioxidant enzymes activity assays were also performed. The seed extract showed reduced viability, angiogenesis and proliferation of HeLa cells with increased apoptosis. Whereas, anti-oxidative enzymes showed higher activity in seed extract treated cancer cells as compared to untreated cells. It was observed that the CF seed extract could induce apoptosis and improve the antioxidant status of HeLa cells along with the inhibition of proliferation and angiogenesis, especially, when extraction was done with ethyl acetate. Keywords Angiogenesis and apoptosis, Cassia fistula, cancer, plant extract.
From basic principles to insights into pioneering research, this introductory textbook provides the fundamentals of cancer biology that will enable students of biology and medicine to enter the field with confidence. It opens with a discussion of global cancer patterns, how cancers arise, and the risk factors involved. A description of the normal signalling pathways within cells then explains how DNA mutations affect proteins and what this means for the development and behaviour of tumours. Later chapters discuss methods for tumour detection, biomarker identification and the impact of genome sequencing, before reviewing the development of anti-cancer drugs and exciting current advances in treatment. With 50% new material, including two new chapters on genetic analysis of cancer and cancer chemotherapy, improved pedagogy, examples of revolutionising technologies in drug design and delivery, and useful online resources, this textbook offers an accessible and engaging account of cancer biology for undergraduate and graduate students.
Full-text available
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known to contain an active-site cysteine residue undergoing oxidation in response to hydrogen peroxide, leading to rapid inactivation of the enzyme. Here we show that human and mouse cells expressing a GAPDH mutant lacking this redox switch retain catalytic activity but are unable to stimulate the oxidative pentose phosphate pathway and enhance their reductive capacity. Specifically, we find that anchorage-independent growth of cells and spheroids is limited by an elevation of endogenous peroxide levels and is largely dependent on a functional GAPDH redox switch. Likewise, tumour growth in vivo is limited by peroxide stress and suppressed when the GAPDH redox switch is disabled in tumour cells. The induction of additional intratumoural oxidative stress by chemo- or radiotherapy synergized with the deactivation of the GAPDH redox switch. Mice lacking the GAPDH redox switch exhibit altered fatty acid metabolism in kidney and heart, apparently in compensation for the lack of the redox switch. Together, our findings demonstrate the physiological and pathophysiological relevance of oxidative GAPDH inactivation in mammals.
We successfully synthesized {BiW8}, a 10‐nuclear heteroatom cluster modified {BiW8O30}. At 24 h post‐incubation, the IC50 values of {BiW8} against HUVEC, MG63, RD, Hep3B, HepG2, and MCF7 cells were 895.8, 127.3, 344.3, 455.0, 781.3, and 206.3 μM, respectively. The IC50 value of {BiW8} on the MG63 cells was more than 2‐fold lower than that of the other raw materials. Through morphological and functional features, we demonstrated pyroptosis as a newly identified mechanism of cell death induced by {BiW8}. {BiW8} increased 2‐fold reactive oxygen species (ROS) levels in MG63 cells at 24 h post‐incubation. Compared with 0 h, the glutathione (GSH) content decreased by 59%, 65%, 75%, 94%, and 97% at 6, 12, 24, 36 and 48 h post‐incubation, respectively. Furthermore, multiple antitumor mechanisms of {BiW8} were identified via transcriptome analysis and chemical simulation, including activation of pyroptosis, suppression of GSH generation, depletion of GSH, and inhibition of DNA repair.
Two nanosensors for simultaneous optical measurements of the bioanalytically and biologically relevant analytes temperature (“T”), oxygen (“O”), and pH (“P”) have been designed. These “TOP” nanosensors are based on 100 nm-sized silica-coated polystyrene nanoparticles (PS-NPs) doped with a near infrared emissive oxygen- and temperature-sensitive chromium(III) complex ([Cr(ddpd)2][BPh4]3, CrBPh4) and an inert reference dye (Nile Red, NR or 5,10,15,20-tetrakis-(pentafluorophenyl) porphyrin, TFPP) and are covalently labeled with pH-sensitive fluorescein isothiocyanate (FITC). These emitters can be excited at the same wavelength and reveal spectrally distinguishable emission bands allowing for ratiometric intensity-based and time-resolved studies in the visible and near infrared wavelength region. Studies in PBS buffer solutions and in a model body liquid demonstrate the applicability of these nanosensors for the sensitive fluorescence readout of TOP simultaneously at the same position.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
Glucose Metabolism Revisited Cancer cells are revved up to reproduce rapidly and typically consume glucose rapidly by glycolysis. Why then do cancer cells express an isoform of a rate-limiting enzyme in glycolysis, pyruvate kinase M2, which has decreased activity? Vander Heiden et al. (p. 1492 ) propose that consequent accumulation of phosphoenolpyruvate, with the help of an enzymatic activity that remains to be characterized, can lead to phosphate transfer to phosphoglycerate mutase, another glycolytic enzyme, providing the cell with a different way to make pyruvate. This may allow cancer cells to produce pyruvate without generating excess adenosine triphosphate, which can act through feedback to inhibit glycolyis.
It is hard to begin a discussion of cancer cell metabolism without first mentioning Otto Warburg . A pioneer in the study of respiration, Warburg made a striking discovery in the 1920s. He found that, even in the presence of ample oxygen, cancer cells prefer to ...
Friction, lubrication, adhesion, and wear are prevalent physical phenomena in everyday life and in many key technologies. This book incorporates a bottom-up approach to friction, lubrication, and wear. This is done by focusing on how these tribological phenomena occur on the small scale - the atomic to the micrometer scale - a field often called nanotribology. The book covers the microscopic origins of the common tribological concepts of roughness, elasticity, plasticity, friction coefficients, and wear coefficients. Some macroscale concepts (like elasticity) scale down well to the micro- and atomic-scale, while other macroscale concepts (like hydrodynamic lubrication) do not. In addition, this book also has chapters on topics not typically found in tribology texts: surface energy, surface forces, lubrication in confined spaces, and the atomistic origins of friction. These chapters cover tribological concepts that have become increasingly important at the small scale: capillary condensation, disjoining pressure, contact electrification, molecular slippage at interfaces, and atomic scale stick-slip. Numerous examples are provided throughout the book on how a nanoscale understanding of tribological phenomena is essential to the proper engineering of important new technologies such as MEMS, disk drives, and nanoimprinting.
I present a brief but broad overview of sliding friction with emphasis on experimental and theoretical results obtained during the past few years.