Review

Mitochondria in cancer cells:

what is so special about them?
Vladimir Gogvadze, Sten Orrenius and Boris Zhivotovsky
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden

The past decade has revealed a new role for the by malignant cells is widely used nowadays for the
mitochondria in cell metabolism – regulation of cell visualization of tumors by positron emission tomography,
death pathways. Considering that most tumor cells emphasizing the importance of Warburg’s observation.
are resistant to apoptosis, one might question whether However, the discovery of oncogenes, tumor suppressor
such resistance is related to the particular properties of genes, and other recent advances in tumor biology, shifted
mitochondria in cancer cells that are distinct from those the focus of cancer research away from studies of energy
of mitochondria in non-malignant cells. This scenario metabolism to other areas.
was originally suggested by Otto Warburg, who put Today, we are witnessing a renaissance of Warburg’s
forward the hypothesis that a decrease in mitochondrial fundamental observation. Studies during the past decade
energy metabolism might lead to development of can- have shed light on some of the peculiarities of mitochon-
cer. This review is devoted to the analysis of mitochon- drial function in cancer cells, and suggest that the Warburg
drial function in cancer cells, including the mechanisms effect is more closely related to alterations in signaling
underlying the upregulation of glycolysis, and how inter- pathways that govern glucose uptake and utilization than
vention with cellular bioenergetic pathways might make to mitochondrial defects per se.
tumor cells more susceptible to anticancer treatment The impact of mitochondrial activities on cellular
and induction of apoptosis. physiology is not restricted to ATP production for meta-
bolic demands. Mitochondria also produce reactive ox-
Introduction ygen species (ROS), which are involved in the regulation
To date, there are six known essential alterations in cell of many physiological processes, but which might also be
physiology that collectively might dictate malignant harmful to the cell if produced excessively. Furthermore,
transformation: self-sufficiency in growth signals, insen- mitochondria are crucial for the regulation of intracellu-
sitivity to growth-inhibitory (antigrowth) signals, limit- lar Ca2+ homeostasis, and they are key participants in the
less replicative potential, sustained angiogenesis, tissue regulation of cell death pathways. Obviously, these func-
invasion and metastasis, and evasion of programmed cell tions are of crucial importance for tumor cell physiology,
death (apoptosis) [1]. In addition, there is a growing body growth and survival. This review is devoted to the
of evidence suggesting that one of the early recogni- analysis of mitochondrial function in cancer cells. In
zed peculiarities of tumor cells (i.e. their dependence particular, we focus on the mechanisms underlying the
on glycolysis for ATP generation) might be added to this upregulation of glycolysis, and we describe how interven-
list. tion with cellular bioenergetic pathways might make
In 1926, Otto Warburg found that cancer cells produce tumor cells more susceptible to anticancer treatment
most of their ATP through glycolysis, even under aerobic and induction of apoptosis.
conditions [2], and there was a correlation between glyco-
lytic ATP production and aggressiveness of the tumor cells
Alterations of energy-supplying pathways in tumors
[3]. Warburg assumed that such ‘aerobic glycolysis’ was a
One of the main characteristics of cancer cells is their fast
universal property of malignant cells and suggested that
proliferation. As such, rapidly growing tumors easily
cancer is caused by impaired mitochondrial metabolism.
become hypoxic owing to the inability of the local vascula-
He hypothesized that these cells could be eliminated
ture to supply an adequate amount of oxygen. Similar
through the inhibition of mitochondrial oxidative phos-
hypoxic conditions are usually lethal to non-malignant cells.
phorylation (e.g. by moderate doses of ionizing radiation),
However, tumor cells can successfully escape hypoxia-
which would reduce the activity of these organelles below a
mediated death as a result of lowered expression or
threshold level critical for cell survival, whereas mitochon-
mutation of p53 [5]. Owing to the inability of mitochondria
dria in normal cells would still be able to produce enough
to provide enough ATP for cell survival under hypoxic
ATP. However, further studies challenged this idea and
conditions, tumor cells must upregulate the glycolytic path-
revealed that tumor mitochondria do respire and produce
way. This occurs by induction of hypoxia-inducible factor 1
ATP [4].
(HIF-1) [6]. HIF-1 stimulates key steps of glycolysis, but
Independent of whether mitochondrial respiration is
regulates genes that control angiogenesis, cell survival and
low or not, cancer cells do exhibit high rates of glycolysis
invasion. However, it should be mentioned that, in certain
– aerobic or anaerobic. The extensive glucose utilization
tumors, high levels of HIF-1 are observed also under oxyge-
Corresponding author: Zhivotovsky, B. ([email protected]). nated conditions. This indicates that, in addition to hypoxia,
0962-8924/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2008.01.006 Available online 4 March 2008 165
Review Trends in Cell Biology Vol.18 No.4

other factors (e.g. hormones and growth factors) might cause cells can become glycolytic as a result of suppression of
stabilization of HIF-1 expression [7]. mitochondrial energy production [15]. Similarly, inhibition
Stimulation of glycolysis can also occur by activation of of respiration in some human lung cancer cell lines was
phosphoinositide 3-kinase (PI3K) and its downstream tar- found to significantly upregulate glycolysis. However,
get, Akt (also known as protein kinase B), which are when glycolysis was suppressed, tumor cells were unable
engaged in a pathway that transmits survival signals from to sufficiently upregulate mitochondrial oxidative phos-
various cell surface receptors. Activation of Akt triggers phorylation, indicating partial mitochondrial impairment
increases in cell size, enhanced glycolytic activity and [16].
metabolism, and cell survival [8], and is commonly Low mitochondrial contribution to cellular ATP pro-
observed in cancer cells [9]. Akt was found to regulate duction under aerobic conditions is not a prerogative of
multiple steps in glycolysis through post-transcriptional tumor cells only; it is also seen in a variety of fast-growing
mechanisms, including localization of the glucose trans- normal cells [17]. Inhibition of mitochondrial respiration
porter to the cell surface and maintenance of hexokinase by stimulated glycolysis is a phenomenon known as the
function in the absence of extrinsic factors. Crabtree effect (reviewed in [18]), and is observed in cells
HIF-1 induction can also be triggered by the mitochon- that have approximately equal glycolytic and respiratory
dria themselves. When mitochondrial respiration in tumor capacities for ATP synthesis. Various mechanisms have
cells is downregulated, accumulation of Krebs cycle sub- been suggested to explain the Crabtree effect in tumor cells
strates might serve as a signal for stimulation of glycolysis [19,20].
[10]. Succinate was shown to inhibit HIF-1a prolyl hydro-
xylases in the cytosol, leading to stabilization and acti- HIF-1 and suppression of mitochondrial activity
vation of HIF-1a. Succinate accumulation in mitochondria The role of HIF-1 is not restricted to upregulation of the
results from inhibition of succinate dehydrogenase. enzymes stimulating glucose utilization. Recent findings
Mutations in this enzyme are involved in familial pre- demonstrate that, in addition, HIF-1 suppresses mitochon-
disposition to benign tumors; therefore, succinate dehydro- drial function in tumor cells, suggesting that it modulates
genase can be considered as a classical tumor suppressor the reciprocal relationship between glycolysis and oxi-
[11]. A similar stabilizing effect was described for lactate dative phosphorylation.
and pyruvate [12]. Analogously, dysfunction of mitochon- The switch between glycolysis and oxidative phos-
dria can lead to activation of Akt. Defects in mitochondrial phorylation is controlled by the relative activities of two
respiration cause enhanced levels of NADH, which can enzymes, pyruvate dehydrogenase (PDH) and lactate
subsequently inactivate PTEN (phosphatase and tensin dehydrogenase (LDH) (Figure 1). The activity of PDH is
homologue; a lipid phosphatase that antagonizes PI3K controlled by pyruvate dehydrogenase kinase 1 (PDK1).
function and therefore inhibits downstream signaling HIF-1 was shown to induce PDK1 and thereby inactivate
through Akt) through a redox modification mechanism PDH and, as a result, to suppress the Krebs cycle and
[13]. mitochondrial respiration (Figure 2) [21,22]. Suppression
In addition to upregulating the glycolytic pathway, HIF- of pyruvate oxidation through HIF-1-mediated PDK1
1 can initiate apoptosis by stabilization of p53 and/or upregulation might, in turn, protect cells from production
induction of certain pro-apoptotic proteins, such as BNIP3 of cytotoxic amounts of ROS. Thus, in HIF-1-deficient
(Bcl-2 and 19 kDa-interacting protein 3). These changes
concur with hypoxia-mediated induction of anti-apoptotic
proteins, such as IAP2 (inhibitor of apoptosis 2), and down-
regulation of the pro-apoptotic protein Bax (reviewed in
[14]). Therefore, during hypoxia, a complicated balance
emerges between factors that stimulate or suppress apop-
tosis.

Possible mechanisms of mitochondrial silencing in

cancer cells
When rapidly growing tumors shift their ATP production
to glycolysis, in response to HIF-1 or other factors, mito-
chondrial activity slows down. Under these circumstances,
mitochondria consume less oxygen and their ATP pro-
duction decreases. Analysis of possible alterations in the
oxidative phosphorylation machinery in some tumors Figure 1. Glucose utilization pathway. When glucose enters the cell, it is
phosphorylated by hexokinase to glucose-6-phosphate, which is further
revealed downregulation of the catalytic subunit of the metabolized by glycolysis to pyruvate. Under aerobic conditions, most of the
mitochondrial ATP synthase (b-F1-ATPase). This was pyruvate in non-malignant cells enters the mitochondria, with only a small amount
observed in most human carcinomas. Remarkably, the being metabolized to lactic acid. In mitochondria, pyruvate dehydrogenase (PDH)
converts pyruvate into acetyl-CoA, which feeds into the Krebs cycle. Oxidation of
expression level of the b-F1-ATPase protein correlated Krebs cycle substrates by the mitochondrial respiratory chain builds up the
inversely with the rate of aerobic glycolysis. Furthermore, mitochondrial membrane potential (Dc) – the driving force for ATP synthesis. By
inhibition of oxidative phosphorylation by oligomycin in contrast, in tumor cells, the oxidative (mitochondrial) pathway of glucose
utilization is suppressed, and most of the pyruvate is converted into lactate.
lung carcinoma was shown to trigger a rapid increase in Thus, the fate of pyruvate is determined by the relative activities of two key
aerobic glycolysis. This finding demonstrated that tumor enzymes – lactate dehydrogenase and pyruvate dehydrogenase.

166
Review Trends in Cell Biology Vol.18 No.4

[28,29]. Inhibition of glycolysis by glucose withdrawal was

shown to serve as a signal for the phosphorylation and
activation of p53. Therefore, under conditions of light to
modest cellular stress, such as those caused by glucose
deprivation, activation of p53 could increase SCO2 expres-
sion and thereby stimulate mitochondrial respiration and
ATP production. Another newly discovered target of p53 is
TIGAR (TP53-induced glycolysis and apoptosis regulator).
Expression of TIGAR lowered fructose-2,6-bisphosphate
levels in cells, resulting in the inhibition of glycolysis, while
stimulating NADPH generation through the pentose phos-
phate shunt [30].

ROS impairment of mitochondrial function

Figure 2. Mechanisms of mitochondrial silencing in tumors. The activity of PDH is
The hypoxic environment of proliferating tumor tissue
regulated by pyruvate dehydrogenase kinase 1 (PDK1), the enzyme that facilitates ROS production (Box 1). Cellular hypoxia and
phosphorylates and inactivates pyruvate dehydrogenase. HIF-1 inactivates PDH re-oxygenation are two essential elements of ischemia-
through PDK1 induction, resulting in suppression of the Krebs cycle and
mitochondrial respiration. In addition, HIF-1 stimulates expression of the lactate reperfusion injury, and massive production of ROS is
dehydrogenase A gene, facilitating conversion of pyruvate into lactate by lactate normally observed during re-oxygenation of hypoxic tissue.
dehydrogenase (LDH). Mutation of p53 can suppress the mitochondrial respiratory However, ROS levels can also be increased by hypoxia,
activity through downregulation of the Synthesis of Cytochrome c Oxidase 2
(SCO2) gene, the product of which is required for the assembly of cytochrome c when electron transport complexes are in the reduced state
oxidase (COX) of the mitochondrial respiratory chain. Thus, mutation of p53 can [31]. Therefore, under hypoxic conditions and, in particu-
suppress mitochondrial respiration and shift cellular energy metabolism towards
lar, after normalization of oxygen supply, production of
glycolysis.
ROS in tumor cells can be enhanced to an extent that might
induce damage to vital cellular components, including
mouse embryonic fibroblasts the level of ROS increased mitochondrial DNA (mtDNA). This might trigger a vicious
drastically, leading to cell death. ROS levels and cell death
were markedly reduced in subclones transfected with an
expression vector encoding PDK1 (reviewed in [23]). Box 1. Production of ROS by mitochondria
HIF-1 was also shown to stimulate expression of the In any cell, the majority of ROS are by-products of mitochondrial
gene encoding lactate dehydrogenase A, which facilitates respiration. Approximately 2% of the molecular oxygen consumed
during respiration is converted into the superoxide anion radical,
conversion of pyruvate into lactate [24]. This effect would
the precursor of most ROS. Normally, a four-electron reduction of
further diminish the utilization of pyruvate by mitochon- O2, resulting in the production of two molecules of water, is
dria, suppressing mitochondrial respiration. In addition, catalyzed by complex IV (COX) of the mitochondrial respiratory
HIF-1 can modulate cytochrome oxidase (COX) expression. chain. However, the electron transport chain contains several redox
Under hypoxic conditions, the subunit composition of COX centers (e.g. in complex I and III) that can leak electrons to molecular
oxygen, serving as the primary source of superoxide production in
is altered to optimize its activity; expression of the COX4–2
most tissues. The one-electron reduction of oxygen is thermodyna-
subunit is increased, whereas the COX4–1 subunit, which mically favorable for most mitochondrial oxidoreductases. Super-
optimizes COX activity under aerobic conditions, is oxide-producing sites and enzymes were recently analyzed in detail
degraded by activation of the mitochondrial protease in a comprehensive review [87]. ROS, if not detoxified, oxidize
LON [25]. cellular proteins, lipids, and nucleic acids and, by doing so, cause
cell dysfunction or death. A cascade of water and lipid soluble
antioxidants and antioxidant enzymes suppresses the harmful ROS
p53 and regulation of mitochondrial activity activity. An imbalance that favors the production of ROS over
Recent observations have revealed that p53, in addition to antioxidant defenses, defined as oxidative stress, is implicated in a
its role as a central regulator of the cellular stress response, wide variety of pathologies, including malignant diseases.
can modulate the balance between the glycolytic pathway It should be mentioned that mitochondria are not only a major
source of ROS but also a sensitive target for the damaging effects of
and mitochondrial oxidative phosphorylation [26]. The key oxygen radicals. ROS produced by mitochondria can oxidize proteins
component in this regulation is the gene encoding Synthesis and induce lipid peroxidation, compromising the barrier properties of
of Cytochrome c Oxidase 2 (SCO2), which, in conjunction biological membranes. One of the targets of ROS is mitochondrial
with the SCO1 protein, is required for the assembly of DNA (mtDNA), which encodes several proteins essential for the
function of the mitochondrial respiratory chain and, hence, for ATP
cytochrome c oxidase [27]. Analysis of potential p53 target
synthesis by oxidative phosphorylation. mtDNA, therefore, repre-
genes that can influence mitochondrial function showed that sents a crucial cellular target for oxidative damage, which might lead
SCO2, but not SCO1, was induced in a p53-dependent to lethal cell injury through the loss of electron transport and ATP
manner, as demonstrated by a nine-fold increase in tran- generation. mtDNA is especially susceptible to attack by ROS, owing
scripts. Mutation of p53 in tumors causes downregulation of to its close proximity to the electron transport chain, the major locus
for free-radical production, and the lack of protective histones. For
mitochondrial respiration as a result of COX deficiency and
example, mitochondrially generated ROS can trigger the formation of
a shift of cellular energy metabolism towards glycolysis. 8-hydroxydeoxyguanosine as a result of oxidative DNA damage; the
Conversely, stimulation of mitochondrial activity in tumor level of oxidatively modified bases in mtDNA is 10- to 20-fold higher
cells can be achieved by restoring the transcriptional func- than that in nuclear DNA. Oxidative damage induced by ROS is
tion of p53. Indeed, an interesting relationship between p53 probably a major source of mitochondrial genomic instability leading
to respiratory dysfunction.
and glucose metabolism has recently been established

167
Review Trends in Cell Biology Vol.18 No.4

cycle (i.e. hypoxia, ROS production, mtDNA mutations, Mitochondrial membrane stabilization in glycolytic
malfunction of the mitochondrial respiratory chain, tumor cells
further stimulation of ROS production etc.), thus impairing The role of Bcl-2 proteins in OMM permeabilization
mitochondrial function and causing a shift to glycolytic The Bcl-2 family proteins are a group of evolutionarily
ATP production. conserved regulators of apoptosis. More than thirty Bcl-2
family-related proteins have been identified to date. They
Consequences of upregulation of glycolysis in tumor include Bcl-2-like survival factors as well as Bax-like and
cells BH3-only death factors [35]. Permeabilization of the OMM
The seemingly most obvious reason for a glycolytic shift in requires the oligomeric form of Bax. Oligomerization of
cancer cells is that molecular oxygen becomes unavailable Bax can result from its binding to the truncated form of the
in fast-proliferating cells, and thus the mitochondria can- BH3-only protein Bid, tBid, which is cleaved by various
not function properly in ATP production. Nevertheless, proteases, including caspase-8 (Figure 3a). Anti-apoptotic
even after restoration of oxygen supply, tumor cells tend proteins (e.g. Bcl-2, Bcl-XL, Mcl-1, and Bcl-w) interact with
to utilize glucose and to keep mitochondrial activity sup- the pro-apoptotic proteins Bax and Bak to prevent their
pressed. Apparently, ATP production is not the only reason oligomerization (Figure 3b). Hence, the balance between
why tumor cells favor this energetically unprofitable path- pro-apoptopic and anti-apoptotic proteins in the OMM is
way. Furthermore, mounting evidence demonstrates that crucial for apoptosis induction, and it appears that in many
the amount of glucose entering cancer cells exceeds their tumors the mitochondrial apoptotic pathway is suppressed
bioenergetic demands. The high rate of glycolysis in most owing to a disproportion between anti-apoptotic and pro-
tumors not only compensates for mitochondrial dysfunc- apoptotic mediators, in favor of the former [36].
tion but also is required to support tumor cell proliferation. An imbalance among cellular levels of Bcl-2 family
High intracellular glucose concentrations enable the cell to proteins can also contribute to OMM stabilization indirectly
redirect the accumulated glycolytic end-product, pyruvate, (e.g. through binding of Bcl-2 to the voltage-dependent anion
toward lipid synthesis, which is necessary for membrane
assembly. Indeed, inhibition of ATP citrate lyase, a key
enzyme that catalyzes the conversion of citrate to cytosolic
acetyl-CoA and thereby links glucose metabolism to lipid
synthesis, was reported to suppress tumor cell prolifer-
ation and survival in vitro and also reduced in vivo tumor
growth and induced differentiation [32]. In addition, a shift
to the glycolytic pathway with production of lactate creates
an acidic environment that gives the cancer cells a com-
petitive advantage for invasion, because the acidic environ-
ment is toxic for non-malignant cell populations [33].
Another important consequence of the glycolytic shift in
tumor cells is their acquired resistance to apoptotic cell
death. Of the two major apoptotic pathways known, the
extrinsic (receptor-mediated) pathway engages initiator
pro-caspase-8, which subsequently activates pro-caspase-
3 and other effector caspases. By contrast, the intrinsic
pathway involves permeabilization of the outer mitochon-
drial membrane (OMM) followed by the release of cyto-
chrome c and other proteins from the intermembrane space
of mitochondria. Once in the cytosol, cytochrome c interacts
with its adaptor molecule, apoptotic protease activating
factor-1 (Apaf-1), resulting in the recruitment and acti-
vation of pro-caspase-9. Active caspase-9, in turn, cleaves
and activates pro-caspase-3 and pro-caspase-7; these effec-
tor caspases are responsible for the cleavage of a variety of
cellular proteins, leading to the characteristic biochemical
and morphological features of apoptotic cell death. There-
fore, permeabilization of the OMM is considered to be a
crucial event during the early phase of the apoptotic pro-
cess [34]. Multiple observations support the opinion that Figure 3. Stabilization of mitochondria against OMM permeabilization in tumor
the glycolytic shift makes tumor mitochondria less suscept- cells. OMM permeabilization is a key event in apoptotic cell death. (a) During
ible to permeabilization of the OMM and, hence, less apoptosis, tBid-mediated oligomerization of Bax causes OMM permeabilization
and release of cytochrome c (red circles). (b) Bcl-2 protein binds Bax and prevents
susceptible to activation of the mitochondrial pathway of its oligomerization. A shift in the balance between pro- apoptotic and anti-
apoptosis. What, then, are the mechanisms of OMM per- apoptotic proteins in cancer cells, in favor of the latter, reduces the availability of
meabilization in apoptosis, and how could stimulation of Bax and prevents OMM permeabilization. (c) Upregulation of hexokinase in tumors
and its binding to VDAC in the OMM not only facilitates glucose phosphorylation
the glycolytic pathway make mitochondria resistant to using mitochondrially generated ATP but keeps VDAC in the open state,
permeabilization? preventing its interaction with tBid (de).

168
Review Trends in Cell Biology Vol.18 No.4

channel [VDAC] [37], a protein located in the OMM and tic effects reported for multiple mitochondrial antioxidant
responsible for most of the metabolite fluxes between the enzymes [47].
cytosol and the mitochondria [38]). Closure of VDAC upon
growth factor withdrawal induces apoptosis by inhibition of Hexokinase and OMM stability
ADP–ATP exchange and a resultant decrease in metabolite Hexokinase plays a leading role in the process by which
fluxes over the mitochondrial membranes, which can cause mitochondria are protected from OMM permeabilization in
mitochondrial deterioration and cytochrome c release [39]. glycolytic tumor cells. Four isoforms of hexokinase are
The anti-apoptotic protein Bcl-XL prevents apoptosis by known: hexokinase-I, hexokinase-II, hexokinase -III and
maintaining VDAC in an open configuration. However, it hexokinase -IV, also known as glucokinase. Among glyco-
is not clear how the closure of VDAC would cause OMM lytic enzymes, hexokinases, in particular hexokinase-I and
permeabilization, although it has been suggested that hexokinase-II, are exceptional in their ability to bind
VDAC generally shows a higher permeability to Ca2+ in directly to mitochondria [48]. By contrast, the type III
the closed state than in the open state [40]. Hence, Ca2+ isozyme lacks the hydrophobic N-terminal sequence
influx could possibly trigger the induction of mitochondrial known to be crucial for the binding of type I and type II
permeability transition (MPT), another mechanism of OMM isozymes to mitochondria [49].
permeabilization due to opening of a non-specific pore in the Tumors are characterized by upregulation of hexoki-
inner mitochondrial membrane (IMM), commonly known as nase-I (in brain tumors) and hexokinase-II (in almost all
the MPT pore. other tumors). Interaction with VDAC enables hexokinase
Opening of the MPT pore can be facilitated by inorganic to use exclusively intra-mitochondrial ATP to phosphor-
phosphate, oxidation of NAD(P)H, ATP depletion, low pH, ylate glucose, thereby promoting a high rate of glycolysis
and ROS (reviewed in [41]). The MPT pore is thought to (Figure 3c) (reviewed in [50]). The interaction of hexoki-
consist of a multimeric complex, involving VDAC in the nase with VDAC not only facilitates glucose phosphoryl-
OMM, adenine nucleotide translocase (ANT), an integral ation but also keeps VDAC in the open state, which
protein of the IMM, and a matrix protein, cyclophilin D counteracts OMM permeabilization. Another consequence
(CyP-D). This complex is located at contact sites between of hexokinase–VDAC interaction is that hexokinase
the mitochondrial inner and outer membranes. In occupies binding sites for pro-apoptotic proteins on the
addition, other proteins, including kinases (e.g. hexoki- OMM and thereby prevents induction of apoptosis
nase, creatine kinase) and the peripheral benzodiazepine (Figure 3de) [51].
receptor, can bind to the pore complex and modulate its Finally, hexokinase has been implicated in the regula-
permeability [42]. MPT is followed by the influx of water tion of MPT pore opening [52]. In contrast to hexokinase-II,
and ions into the matrix, causing mitochondrial swelling, hexokinase-I was shown to trigger the closure of VDAC,
rupture of the OMM, and the release of intermembrane thus suppressing mitochondrial activity and stimulating
space proteins such as cytochrome c into the cytosol. glycolytic ATP production [53]. The product of glucose
Mitochondria from tumor cells are relatively less suscept- phosphorylation, glucose-6-phosphate, mitigates the inhi-
ible to Ca2+-induced MPT. The difference in sensitivity bition of VDAC by hexokinase-I, and mitochondrial ATP
might be due to the relatively higher expression of the Bcl- production can be restored. This happens when glycolysis
2 protein in the tumor cells [43], although the precise is suppressed downstream of glucose-6-phosphate for-
mechanism of Bcl-2-mediated resistance is still unclear. mation. Therefore, the interaction of hexokinase-I with
It has recently been reported that permeabilization of VDAC might be regarded as a mechanism that protects
the OMM can also result from the opening of so-called the mitochondria from MPT induction. However, a recent
mitochondrial apoptosis-induced channels (MACs) [44]. genetic study indicated that mitochondrial VDAC is dis-
MACs provide specific pores in the OMM for the passage pensable for MPT induction and apoptotic cell death [54]. It
of intermembrane space proteins, in particular cytochrome appears that the role of VDAC in permeabilization of OMM
c, into the cytosol. Interestingly, the permeability of MACs during apoptosis requires further study.
was also shown to be dependent on the presence of Bcl-2
family proteins. Thus, Bax was an essential constituent of ANT and OMM stability
MACs in some systems; electrophysiological character- Another factor contributing to the mitochondrial resist-
istics of MACs were very similar to those of channels ance against MPT induction in tumor cells is the altered
formed by Bax, and depletion of Bax significantly dimin- expression profile of ANT, a key component of the pore
ished MAC activity. By contrast, overexpression of Bcl-2 complex. Analysis of ANT isoform expression in several
was shown to block formation of MACs and release of transformed human cell lines demonstrated predominant
cytochrome c [45]. Opening of MACs does not affect the expression of ANT2 [55], an isoform lacking the apoptotic
integrity of the IMM or disrupt mitochondrial intactness, activity of ANT1 [56]. Transient overexpression of ANT3,
in contrast to MPT. or ANT1, was shown to induce apoptosis [57]. Thus, as with
Both Bax- (or Bak-) and MPT-dependent release of hexokinase-I binding to VDAC, the overexpression of
cytochrome c is facilitated by ROS. Cytochrome c is nor- ANT2 in tumors might contribute to mitochondrial resist-
mally bound to the outer surface of the IMM by both ance to OMM permeabilization.
electrostatic and hydrophobic interactions with the unique
mitochondrial phospholipid, cardiolipin. Oxidation of car- Akt-mediated OMM stabilization
diolipin causes the dissociation of cytochrome c [46], which As mentioned above, the serine–threonine kinase Akt–
might provide a plausible explanation for the anti-apopto- PKB is a major downstream effector of growth factor-

169
Review Trends in Cell Biology Vol.18 No.4

mediated cell survival. Activation of the Akt–PKB path- might be most useful in cells with mitochondrial defects, or
way is well known to protect cells from apoptosis [58], under hypoxic conditions, when the mitochondrial contri-
although the precise mechanisms of this protection are bution to cellular bioenergetics is minimal. Under such
unclear to date. However, Akt activation inhibited cyto- circumstances inhibition of glycolysis would be expected
chrome c release from mitochondria and thereby prevented to severely deplete ATP [69]. Indeed, in a variety of cancer
the activation of caspases [59]. By contrast, Akt was not cells, inhibition of glycolysis, for example with 2-deoxyglu-
able to suppress apoptosis following cytoplasmic microin- cose (2-DG), a non-metabolizable glucose analogue [70], or 3-
jection of cytochrome c, indicating that the anti-apoptotic bromopyruvate [71], was shown to cause a marked drop in
effect of Akt occured upstream of OMM permeabilization. ATP level, especially in clones of cells with mitochondrial
How, then, could Akt enhance OMM stability? respiratory defects. Among the effects of the ATP depletion
It has been demonstrated that Akt activation inhibits were rapid dephosphorylation of the pro-apoptotic protein
p53-mediated expression of Bax, thereby suppressing the Bad, migration of Bax to the mitochondria, and massive cell
probability of OMM permeabilization [60]. In addition, the death [72]. Similar to the effects of inhibiting key steps in the
active, but not the inactive, form of Akt was shown to glycolytic pathway, suppression of glucose transport might
phosphorylate the pro-apoptotic protein Bad, preventing also sensitize tumor cells to anticancer agents. For example,
its interaction with the OMM and reducing its pro-apop- a glucose transporter inhibitor, phloretin, was reported to
totic activity [61,62]. Following PI3K activation, Akt markedly enhance the anticancer effects of daunorubicin
rapidly accumulates in mitochondria [63], where it resides [73]. Combining inhibitors of glycolysis with conventional
in both the outer and inner membranes, as well as in the chemotherapeutic drugs might provide a novel therapeutic
matrix. Active Akt might also affect the oligomerization of strategy to overcome drug resistance in hypoxia. Appar-
Bax, a prerequisite step in OMM permeabilization. How- ently, under these conditions, the ultimate fate of the cancer
ever, the expression of mitochondria-targeted, active Akt cell will depend on how efficiently mitochondrial oxidative
did not change the level of monomeric Bax, whereas Bax phosphorylation can substitute for the inhibited glycolysis
dimerization was markedly reduced [64]. In addition, Akt in providing the ATP needed for cellular demands.
was shown to promote the translocation of hexokinase to
mitochondria, where it interacts with mitochondrial Shifting cellular metabolism from glycolysis to glucose
VDAC. Moreover, genetic evidence suggests that Akt is oxidation
also required for a sustained association between hexoki- Recent findings demonstrate that stimulation of mitochon-
nase and the mitochondria [65], which would subsequently drial activity and restoration of the mechanisms of ATP
facilitate hexokinase–VDAC interaction and its effects on generation characteristic of non-malignant cells might be
MPT pore opening. Targeted disruption of this association an efficient tool in anticancer strategy. In particular, shift-
impaired the ability of growth factors and Akt to inhibit ing cellular metabolism towards mitochondrial ATP pro-
cytochrome c release and apoptosis. duction might overcome the effects of HIF-1-mediated
upregulation of the glycolytic pathway. Several attempts
Contribution of loss of p53 function to OMM have been made to prevent the formation of lactate and to
stabilization redirect pyruvate metabolism towards oxidation in the
Mutations, or downregulation, of the transcription factor mitochondria. Thus, inhibition of PDK1 and, hence, acti-
p53 not only contribute to the suppression of mitochondrial vation of PDH, by dichloroacetate, was shown to shift
respiratory activity, as described above, but might also metabolism from glycolysis to glucose oxidation. As a
play an important role in mitochondrial resistance to result, such treatment decreased mitochondrial membrane
permeabilization. p53 regulates the expression of the potential (DC) and increased mitochondrial production of
BH3-only proteins, p53 upregulated modulator of apopto- ROS in cancer cells, but not in normal cells [74]. A similar
sis (PUMA) and Noxa (Latin for damage), which promote effect was achieved by inhibition of LDH (Figure 4).
OMM permeabilization during apoptosis [66,67]. PUMA Inhibition of LDH, or stimulation of PDH through the
and NOXA bind to anti-apoptotic proteins, thereby liberat- inhibition of PDK1, could be particularly useful in tumors
ing previously bound Bax and Bak from such complexes. with impaired mitochondrial bioenergetics. However, in
Co-immunoprecipitation studies showed that NOXA binds cancer cells with functionally competent mitochondria,
to Bcl-2 and Bcl-XL, but not to Bax. Interestingly, p53 can this approach might be insufficient, because mitochondrial
also regulate OMM permeabilization through direct acti- ATP synthesis would compensate for the inhibited glycoly-
vation of Bax [68]. Although the precise mechanism of this sis. Therefore, under these circumstances, supplementary
activation is still obscure, it is clear that loss of p53 function suppression of mitochondrial activity might be needed to
in tumor cells can result in stabilization of the OMM kill cancer cells. Indeed, non-toxic doses of apoptolidin, an
through downregulation of pro-apoptotic Bcl-2 family inhibitor of mitochondrial ATP synthase, were found to
proteins by multiple mechanisms. trigger cell death in malignant cell lines when applied
together with the LDH inhibitor oxamate [75]. Similar
Promotion of cancer cell death through the results were obtained when 2-DG was used instead of
manipulation of cellular ATP-generating pathways oxamate to inhibit glycolysis. Hence, combined strategies
Suppression of the glycolytic pathway involving manipulation of both the glycolytic and the
The dependence of tumor cells on glycolysis for ATP gener- mitochondrial pathways might be useful tools in the elim-
ation offers a rationale for therapeutic strategies aimed at ination of cancer cells that would otherwise survive thanks
selective inhibition of the glycolytic pathway. This approach to mitochondrial ATP production.

170
 Review Trends in Cell Biology Vol.18 No.4

Can oxidative stress be employed in anticancer therapy?

Modulation of cellular redox balance through pharmaco-
logical stimulation of ROS production and/or depletion of
protective reducing metabolites (e.g. Glutathione [GSH]
and NADPH) can lead to oxidative stress, destabilization of
mitochondria and induction of apoptosis [83]. The antic-
ancer effect of multiple conventional treatments (e.g. ioniz-
ing radiation, etoposide and arsenates) is based on their
ability to stimulate ROS production. For example, the
chemotherapeutic agent arsenic trioxide was found to
cause oxidative modification of thiol groups in ANT and
subsequent release of cytochrome c through MPT induction
at high doses. By contrast, clinically achievable concen-
trations of the drug stimulated cytochrome c release and
apoptosis through a Bax- or Bak-dependent mechanism
Figure 4. Shifting metabolism from glycolysis to glucose oxidation. Utilization of [84,85].
pyruvate is controlled by the relative activities of two enzymes, PDH and LDH. In
cancer cells, PDH activity is suppressed by PDH kinase-mediated phosphorylation,
Concluding remarks
and, therefore, instead of entering the Krebs cycle, pyruvate is converted into lactate.
Several attempts have been made to redirect pyruvate towards oxidation in the Tumorigenesis is a complex process involving the acti-
mitochondria. Thus, inhibition of PDK1 by dichloroacetate might stimulate the vation of oncogenes, inactivation of tumor suppressors,
activity of PDH and, hence, direct pyruvate to the mitochondria. A similar effect can
be achieved by inhibition of LDH by oxamate. Overall, suppression of PDK1 and LDH
and deregulation of cell death programs. The findings that
activities will stimulate mitochondrial ATP production and might be lethal to tumor pro-apoptotic genes might act as tumor suppressors and
cells, even if these inhibitors are used at non-toxic doses. In addition, stimulation of that anti-apoptotic genes can serve as oncogenes suggested
mitochondrial function, for example though overexpression of mitochondrial
frataxin, a protein associated with Friedreich ataxia, was shown to stimulate
that the balance between pro-apoptotic and anti-apoptotic
oxidative metabolism and inhibited growth in several cancer cell lines [86]. genes modulates tumor growth. How to selectively activate
apoptosis in transformed cells remains a primary strategic
Alteration of mitochondrial metabolism problem in cancer therapy, and extensive studies are being
The resistance of cancer cells to treatment is often associ- performed to find efficient mechanisms of apoptosis induc-
ated with flaws in their apoptotic program. Successful tion in tumor cells. Despite the heterogeneity of tumors,
elimination of tumor cells, therefore, largely depends on which dictates an individual approach to anticancer treat-
the ability of anticancer treatment to stimulate silent or ment, almost all tumor cells demonstrate enhanced uptake
suppressed apoptotic pathways. Mitochondria are promis- and utilization of glucose, a phenomenon known as the
ing targets for such an approach. Hence, agents that Warburg effect. Stimulation of the glycolytic pathway in
suppress mitochondrial respiration, or uncouple oxidative tumors not only compensates for the decline in ATP pro-
phosphorylation, have been shown to provoke cell death, duction due to impaired mitochondrial function but is also
although such compounds fail to kill cells depleted of responsible for enhanced mitochondrial stability and
mitochondrial DNA and therefore lacking an intact respir- resistance to apoptosis induction. Stabilization of mito-
atory chain. The anti-apoptotic protein Bcl-2 did not block chondria is not limited to the upregulation of anti-apopto-
apoptosis induced by respiratory chain inhibitors [76]. tic Bcl-2 proteins observed in a variety of tumors.
Suppression of mitochondrial respiratory chain activity Amazingly, pathways that lead to upregulation of glycoly-
also sensitized the cells to traditional apoptotic stimuli. sis can also cause suppression of mitochondrial activity.
Thus, in HeLa cells treated with respiratory inhibitors, For instance, HIF-1 not only stimulates the influx and
lower concentrations of Fas were sufficient to induce apop- utilization of glucose in tumor cells but also stabilizes
tosis than were required in untreated cells [77]. mitochondria through multiple pathways. Hence, target-
All-trans retinoic acid (ATRA) is another potential reg- ing the mitochondria appears to be a promising strategy for
ulator of mitochondrial metabolism. This natural deriva- the induction of apoptosis in tumor cells. Activation of the
tive of vitamin A disrupted mitochondrial function in the mitochondrial pathway reverts cellular energy metabolism
myeloid cell line P39 long before any detectable signs of to the phenotype characteristic of non-malignant cells and
apoptosis appeared. ATRA suppressed mitochondrial also promotes ROS production by the mitochondria, which
respiration, decreased Dc and, as a result, induced MPT might increase the susceptibility of the tumor cells to
[78]. Similarly, a-tocopheryl succinate (a-TOS), a redox- undergo apoptotic cell death. The existing interplay be-
silent analogue of vitamin E, was shown to selectively kill tween apoptotic regulators and mitochondrial energy
malignant cells at concentrations that were non-toxic to metabolism should therefore be considered in the search
normal cells and tissues [79]. The pro-apoptotic effect of a- for novel anticancer drugs. Another approach might be
TOS has been linked to its interaction with complex II of based on destabilizing mitochondria and sensitizing them
the mitochondrial respiratory chain [80], stimulation of to MPT induction. Thus, the success of a coordinated attack
ROS production [81], and promotion of the translocation of on cancer must be based on the concerted modulation of
Bax from the cytosol to the mitochondria, causing cyto- cellular energy metabolism, mitochondrial stability, and
chrome c release and caspase activation [82]. Thus, the other mechanisms responsible for the resistance to apop-
results obtained to date make a-TOS an attractive candi- tosis characteristic of tumor cells. Further investigation of
date for antitumor strategy. the role of the mitochondria in tumor cell metabolism

171
Review Trends in Cell Biology Vol.18 No.4

might help in the development of new therapeutic strat- 24 Semenza, G.L. et al. (1996) Hypoxia response elements in the aldolase
A, enolase 1, and lactate dehydrogenase A gene promoters contain
egies aimed at killing cancer cells and suppressing tumor
essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem.
growth. 271, 32529–32537
25 Fukuda, R. et al. (2007) HIF-1 regulates cytochrome oxidase subunits
Acknowledgements to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122
Work in the authors’ laboratory was supported by grants from The 26 Matoba, S. et al. (2006) p53 regulates mitochondrial respiration.
Swedish and Stockholm Cancer Societies, The Swedish Childhood Cancer Science 312, 1650–1653
Foundation, The Swedish Research Council, the EC-FP-6 (Oncodeath and 27 Buchwald, P. et al. (1991) Immunological identification of yeast SCO1
Chemores) and EC-FP-7 (APO-SYS). We apologize to authors whose protein as a component of the inner mitochondrial membrane. Mol.
primary references could not be cited owing to space limitations. Gen. Genet. 229, 413–420
28 Jones, R.G. et al. (2005) AMP-activated protein kinase induces a p53-
References dependent metabolic checkpoint. Mol. Cell 18, 283–293
1 Hanahan, D. and Weinberg, R.A. (2000) The hallmarks of cancer. Cell 29 Feng, Z. et al. (2005) The coordinate regulation of the p53 and
100, 57–70 mTOR pathways in cells. Proc. Natl. Acad. Sci. U.S.A. 102, 8204–
2 Warburg, O. Über den Stoffwechsel der Tumore. Berlin: Springer. 8209
Translated: The metabolism of tumors. Lindon: Arnold Constable. 1930 30 Bensaad, K. et al. (2006) TIGAR, a p53-inducible regulator of glycolysis
3 Simonnet, H. et al. (2002) Low mitochondrial respiratory chain content and apoptosis. Cell 126, 107–120
correlates with tumor aggressiveness in renal cell carcinoma. 31 Guzy, R.D. and Schumacker, P.T. (2006) Oxygen sensing by
Carcinogenesis 23, 759–768 mitochondria at complex III: the paradox of increased reactive
4 Weinhouse, S. (1976) The Warburg hypothesis fifty years later. Z. oxygen species during hypoxia. Exp. Physiol. 91, 807–819
Krebsforsch. Klin. Onkol. Cancer Res. Clin. Oncol. 87, 115–126 32 Hatzivassiliou, G. et al. (2005) ATP citrate lyase inhibition can
5 Moll, U.M. and Schramm, L.M. (1998) p53 – an acrobat in suppress tumor cell growth. Cancer Cell 8, 311–321
tumorigenesis. Crit. Rev. Oral Biol. Med. 9, 23–37 33 Gillies, R.J. and Gatenby, R.A. (2007) Adaptive landscapes and
6 Wang, G.L. and Semenza, G.L. (1993) General involvement of hypoxia- emergent phenotypes: why do cancers have high glycolysis? J.
inducible factor 1 in transcriptional response to hypoxia. Proc. Natl. Bioenerg. Biomembr. 39, 251–257
Acad. Sci. U.S.A. 90, 4304–4308 34 Gogvadze, V. et al. (2006) Multiple pathways of cytochrome c
7 Hagg, M. and Wennstrom, S. (2005) Activation of hypoxia-induced release from mitochondria in apoptosis. Biochim. Biophys. Acta
transcription in normoxia. Exp. Cell Res. 306, 180–191 1757, 639–647
8 Plas, D.R. and Thompson, C.B. (2005) Akt-dependent transformation: 35 Festjens, N. et al. (2004) Bcl-2 family members as sentinels of cellular
there is more to growth than just surviving. Oncogene 24, 7435–7442 integrity and role of mitochondrial intermembrane space proteins in
9 Elstrom, R.L. et al. (2004) Akt stimulates aerobic glycolysis in cancer apoptotic cell death. Acta Haematol. 111, 7–27
cells. Cancer Res. 64, 3892–3899 36 Abel, F. et al. (2005) Imbalance of the mitochondrial pro- and anti-
10 Gottlieb, E. and Tomlinson, I.P. (2005) Mitochondrial tumour apoptotic mediators in neuroblastoma tumours with unfavourable
suppressors: a genetic and biochemical update. Nat. Rev. Cancer 5, biology. Eur. J. Cancer 41, 635–646
857–866 37 Shimizu, S. et al. (2000) Bax and Bcl-xL independently regulate
11 Baysal, B.E. et al. (2000) Mutations in SDHD, a mitochondrial complex apoptotic changes of yeast mitochondria that require VDAC but not
II gene, in hereditary paraganglioma. Science 287, 848–851 adenine nucleotide translocator. Oncogene 19, 4309–4318
12 Lu, H. et al. (2002) Hypoxia-inducible factor 1 activation by aerobic 38 Colombini, M. (1983) Purification of VDAC (voltage-dependent anion-
glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. selective channel) from rat liver mitochondria. J. Membr. Biol. 74, 115–
Chem. 277, 23111–23115 121
13 Pelicano, H. et al. (2006) Mitochondrial respiration defects in cancer 39 Vander Heiden, M.G. et al. (2001) Bcl-xL promotes the open
cells cause activation of Akt survival pathway through a redox- configuration of the voltage-dependent anion channel and
mediated mechanism. J. Cell Biol. 175, 913–923 metabolite passage through the outer mitochondrial membrane. J.
14 Greijer, A.E. and van der Wall, E. (2004) The role of hypoxia inducible Biol. Chem. 276, 19414–19419
factor 1 (HIF-1) in hypoxia induced apoptosis. J. Clin. Pathol. 57, 1009– 40 Tan, W. and Colombini, M. (2007) VDAC closure increases calcium ion
1014 flux. Biochim. Biophys. Acta 1768, 2510–2515
15 Lopez-Rios, F. et al. (2007) Loss of the mitochondrial bioenergetic 41 Crompton, M. (1999) The mitochondrial permeability transition pore
capacity underlies the glucose avidity of carcinomas. Cancer Res. 67, and its role in cell death. Biochem. J. 341, 233–249
9013–9017 42 Crompton, M. (2000) Mitochondrial intermembrane junctional
16 Wu, M. et al. (2007) Multiparameter metabolic analysis reveals a close complexes and their role in cell death. J. Physiol. 529, 11–21
link between attenuated mitochondrial bioenergetic function and 43 Evtodienko, Y.V. et al. (1999) The Ca2+ threshold for the mitochondrial
enhanced glycolysis dependency in human tumor cells. Am. J. permeability transition and the content of proteins related to Bcl-2 in
Physiol. Cell Physiol. 292, C125–C136 rat liver and Zajdela hepatoma mitochondria. Mol. Cell. Biochem. 194,
17 Wang, T. et al. (1976) Aerobic glycolysis during lymphocyte 251–256
proliferation. Nature 261, 702–705 44 Kinnally, K.W. and Antonsson, B. (2007) A tale of two mitochondrial
18 Ibsen, K.H. (1961) The Crabtree effect: a review. Cancer Res. 21, channels, MAC and PTP, in apoptosis. Apoptosis 12, 857–868
829–841 45 Pavlov, E.V. et al. (2001) A novel, high conductance channel of
19 Sussman, I. et al. (1980) Regulation of cellular energy metabolism: the mitochondria linked to apoptosis in mammalian cells and Bax
Crabtree effect. Biochim. Biophys. Acta 591, 209–223 expression in yeast. J. Cell Biol. 155, 725–731
20 Wojtczak, L. et al. (1999) Effect of glucose and deoxyglucose on the 46 Ott, M. et al. (2002) Cytochrome c release from mitochondria proceeds
redistribution of calcium in ehrlich ascites tumour and Zajdela by a two-step process. Proc. Natl. Acad. Sci. U.S.A. 99, 1259–1263
hepatoma cells and its consequences for mitochondrial energetics. 47 Orrenius, S. et al. (2007) Mitochondrial oxidative stress: implications
Further arguments for the role of Ca(2+) in the mechanism of the for cell death. Annu. Rev. Pharmacol. Toxicol. 47, 143–183
crabtree effect. Eur. J. Biochem. 263, 495–501 48 Bustamente, E. et al. (1977) Hexokinase: the direct link between
21 Kim, J.W. et al. (2006) HIF-1-mediated expression of pyruvate mitochondrial and glycolytic reactions in rapidly growing cancer
dehydrogenase kinase: a metabolic switch required for cellular cells. Adv. Exp. Med. Biol. 92, 363–380
adaptation to hypoxia. Cell Metab. 3, 177–185 49 Wilson, J.E. (2003) Isozymes of mammalian hexokinase: structure,
22 Papandreou, I. et al. (2006) HIF-1 mediates adaptation to hypoxia by subcellular localization and metabolic function. J. Exp. Biol. 206, 2049–
actively downregulating mitochondrial oxygen consumption. Cell 2057
Metab. 3, 187–197 50 Mathupala, S.P. et al. (2006) Hexokinase II: cancer’s double-edged
23 Semenza, G.L. (2007) Oxygen-dependent regulation of mitochondrial sword acting as both facilitator and gatekeeper of malignancy when
respiration by hypoxia-inducible factor 1. Biochem. J. 405, 1–9 bound to mitochondria. Oncogene 25, 4777–4786

172
Review Trends in Cell Biology Vol.18 No.4

51 Pastorino, J.G. et al. (2002) Mitochondrial binding of hexokinase II 69 Pelicano, H. et al. (2006) Glycolysis inhibition for anticancer treatment.
inhibits Bax-induced cytochrome c release and apoptosis. J. Biol. Oncogene 25, 4633–4646
Chem. 277, 7610–7618 70 Halicka, H.D. et al. (1995) 2-Deoxy-D-glucose enhances sensitivity of
52 Beutner, G. et al. (1998) Complexes between porin, hexokinase, human histiocytic lymphoma U937 cells to apoptosis induced by tumor
mitochondrial creatine kinase and adenylate translocator display necrosis factor. Cancer Res. 55, 444–449
properties of the permeability transition pore. Implication for 71 Geschwind, J.F. et al. (2002) Novel therapy for liver cancer: direct
regulation of permeability transition by the kinases. Biochim. intraarterial injection of a potent inhibitor of ATP production. Cancer
Biophys. Acta 1368, 7–18 Res. 62, 3909–3913
53 Azoulay-Zohar, H. et al. (2004) In self-defence: hexokinase promotes 72 Xu, R.H. et al. (2005) Inhibition of glycolysis in cancer cells: a novel
voltage-dependent anion channel closure and prevents mitochondria- strategy to overcome drug resistance associated with mitochondrial
mediated apoptotic cell death. Biochem. J. 377, 347–355 respiratory defect and hypoxia. Cancer Res. 65, 613–621
54 Baines, C.P. et al. (2007) Voltage-dependent anion channels are 73 Cao, X. et al. (2007) Glucose uptake inhibitor sensitizes cancer cells to
dispensable for mitochondrial-dependent cell death. Nat. Cell Biol. daunorubicin and overcomes drug resistance in hypoxia. Cancer
9, 550–555 Chemother. Pharmacol. 59, 495–505
55 Chevrollier, A. et al. (2005) ANT2 isoform required for cancer cell 74 Bonnet, S. et al. (2007) A mitochondria-K+ channel axis is suppressed
glycolysis. J. Bioenerg. Biomembr. 37, 307–316 in cancer and its normalization promotes apoptosis and inhibits cancer
56 Bauer, M.K. et al. (1999) Adenine nucleotide translocase-1, a growth. Cancer Cell 11, 37–51
component of the permeability transition pore, can dominantly 75 Salomon, A.R. et al. (2000) Understanding and exploiting the
induce apoptosis. J. Cell Biol. 147, 1493–1502 mechanistic basis for selectivity of polyketide inhibitors of F(0)F(1)-
57 Zamora, M. et al. (2004) Adenine nucleotide translocase 3 (ANT3) ATPase. Proc. Natl. Acad. Sci. U.S.A. 97, 14766–14771
overexpression induces apoptosis in cultured cells. FEBS Lett. 563, 76 Wolvetang, E.J. et al. (1994) Mitochondrial respiratory chain inhibitors
155–160 induce apoptosis. FEBS Lett. 339, 40–44
58 Franke, T.F. et al. (1997) PI3K: downstream AKTion blocks apoptosis. 77 Asoh, S. et al. (1996) Expression of the apoptosis-mediator Fas is
Cell 88, 435–437 enhanced by dysfunctional mitochondria. J. Biochem. 120, 600–607
59 Kennedy, S.G. et al. (1999) Akt/Protein kinase B inhibits cell death by 78 Schmidt-Mende, J. et al. (2006) Early mitochondrial alterations in
preventing the release of cytochrome c from mitochondria. Mol. Cell. ATRA-induced cell death. Cell Death Differ. 13, 119–128
Biol. 19, 5800–5810 79 Neuzil, J. et al. (2001) Selective cancer cell killing by alpha-tocopheryl
60 Yamaguchi, A. et al. (2001) Akt activation protects hippocampal succinate. Br. J. Cancer 84, 87–89
neurons from apoptosis by inhibiting transcriptional activity of p53. 80 Neuzil, J. et al. (2007) Mitocans as anti-cancer agents targeting
J. Biol. Chem. 276, 5256–5264 mitochondria: lessons from studies with vitamin E analogues,
61 del Peso, L. et al. (1997) Interleukin-3-induced phosphorylation of BAD inhibitors of complex II. J. Bioenerg. Biomembr. 39, 65–72
through the protein kinase Akt. Science 278, 687–689 81 Neuzil, J. et al. (2006) Molecular mechanism of ‘mitocan’-induced
62 Datta, S.R. et al. (1997) Akt phosphorylation of BAD couples survival apoptosis in cancer cells epitomizes the multiple roles of reactive
signals to the cell-intrinsic death machinery. Cell 91, 231–241 oxygen species and Bcl-2 family proteins. FEBS Lett. 580, 5125–5129
63 Bijur, G.N. and Jope, R.S. (2003) Rapid accumulation of Akt in 82 Yu, W. et al. (2003) RRR-alpha-tocopheryl succinate-induced apoptosis
mitochondria following phosphatidylinositol 3-kinase activation. J. of human breast cancer cells involves Bax translocation to
Neurochem. 87, 1427–1435 mitochondria. Cancer Res. 63, 2483–2491
64 Mookherjee, P. et al. (2007) Mitochondrial-targeted active Akt protects 83 Engel, R.H. and Evens, A.M. (2006) Oxidative stress and apoptosis: a
SH-SY5Y neuroblastoma cells from staurosporine-induced apoptotic new treatment paradigm in cancer. Front. Biosci. 11, 300–312
cell death. J. Cell. Biochem. 102, 196–210 84 Larochette, N. et al. (1999) Arsenite induces apoptosis via a direct effect
65 Majewski, N. et al. (2004) Hexokinase-mitochondria interaction on the mitochondrial permeability transition pore. Exp. Cell Res. 249,
mediated by Akt is required to inhibit apoptosis in the presence or 413–421
absence of Bax and Bak. Mol. Cell 16, 819–830 85 Nutt, L.K. et al. (2005) Indirect effects of Bax and Bak initiate the
66 Nakano, K. and Vousden, K.H. (2001) PUMA, a novel proapoptotic mitochondrial alterations that lead to cytochrome c release during
gene, is induced by p53. Mol. Cell 7, 683–694 arsenic trioxide-induced apoptosis. Cancer Biol. Ther. 4, 459–467
67 Oda, E. et al. (2000) Noxa, a BH3-only member of the Bcl-2 family and 86 Schulz, T.J. et al. (2006) Induction of oxidative metabolism by
candidate mediator of p53-induced apoptosis. Science 288, 1053–1058 mitochondrial frataxin inhibits cancer growth: Otto Warburg
68 Chipuk, J.E. et al. (2004) Direct activation of Bax by p53 mediates revisited. J. Biol. Chem. 281, 977–981
mitochondrial membrane permeabilization and apoptosis. Science 303, 87 Andreyev, A.Y. et al. (2005) Mitochondrial metabolism of reactive
1010–1014 oxygen species. Biochemistry (Mosc.) 70, 200–214

Elsevier joins major health information initiative

Elsevier has joined with scientific publishers and leading voluntary health organizations to create
patientINFORM, a groundbreaking initiative to help patients and caregivers close a crucial information
gap. patientINFORM is a free online service dedicated to disseminating medical research.

Elsevier provides voluntary health organizations with increased online access to our peer-reviewed
biomedical journals immediately upon publication, together with content from back issues. The
voluntary health organizations integrate the information into materials for patients and link to the full
text of selected research articles on their websites.

patientINFORM has been created to enable patients seeking the latest information about treatment
options online access to the most up-to-date, reliable research available for specific diseases.

For more information, visit www.patientinform.org

173