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2. disease
3. cancer

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
mitochondria in cell metabolism – regulation of cell
death pathways. Considering that most tumor cells
are resistant to apoptosis, one might question whether
such resistance is related to the particular properties of
mitochondria in cancer cells that are distinct from those
of mitochondria in non-malignant cells. This scenario
was originally suggested by Otto Warburg, who put
forward the hypothesis that a decrease in mitochondrial
energy metabolism might lead to development of cancer. This review is devoted to the analysis of mitochondrial function in cancer cells, including the mechanisms
underlying the upregulation of glycolysis, and how intervention with cellular bioenergetic pathways might make
tumor cells more susceptible to anticancer treatment
and induction of apoptosis.
Introduction
To date, there are six known essential alterations in cell
physiology that collectively might dictate malignant
transformation: self-sufficiency in growth signals, insensitivity to growth-inhibitory (antigrowth) signals, limitless replicative potential, sustained angiogenesis, tissue
invasion and metastasis, and evasion of programmed cell
death (apoptosis) [1]. In addition, there is a growing body
of evidence suggesting that one of the early recognized peculiarities of tumor cells (i.e. their dependence
on glycolysis for ATP generation) might be added to this
list.
In 1926, Otto Warburg found that cancer cells produce
most of their ATP through glycolysis, even under aerobic
conditions [2], and there was a correlation between glycolytic ATP production and aggressiveness of the tumor cells
[3]. Warburg assumed that such ‘aerobic glycolysis’ was a
universal property of malignant cells and suggested that
cancer is caused by impaired mitochondrial metabolism.
He hypothesized that these cells could be eliminated
through the inhibition of mitochondrial oxidative phosphorylation (e.g. by moderate doses of ionizing radiation),
which would reduce the activity of these organelles below a
threshold level critical for cell survival, whereas mitochondria in normal cells would still be able to produce enough
ATP. However, further studies challenged this idea and
revealed that tumor mitochondria do respire and produce
ATP [4].
Independent of whether mitochondrial respiration is
low or not, cancer cells do exhibit high rates of glycolysis
– aerobic or anaerobic. The extensive glucose utilization
Corresponding author: Zhivotovsky, B. ([email protected]).
by malignant cells is widely used nowadays for the
visualization of tumors by positron emission tomography,
emphasizing the importance of Warburg’s observation.
However, the discovery of oncogenes, tumor suppressor
genes, and other recent advances in tumor biology, shifted
the focus of cancer research away from studies of energy
metabolism to other areas.
Today, we are witnessing a renaissance of Warburg’s
fundamental observation. Studies during the past decade
have shed light on some of the peculiarities of mitochondrial function in cancer cells, and suggest that the Warburg
effect is more closely related to alterations in signaling
pathways that govern glucose uptake and utilization than
to mitochondrial defects per se.
The impact of mitochondrial activities on cellular
physiology is not restricted to ATP production for metabolic demands. Mitochondria also produce reactive oxygen species (ROS), which are involved in the regulation
of many physiological processes, but which might also be
harmful to the cell if produced excessively. Furthermore,
mitochondria are crucial for the regulation of intracellular Ca2+ homeostasis, and they are key participants in the
regulation of cell death pathways. Obviously, these functions are of crucial importance for tumor cell physiology,
growth and survival. This review is devoted to the
analysis of mitochondrial function in cancer cells. In
particular, we focus on the mechanisms underlying the
upregulation of glycolysis, and we describe how intervention with cellular bioenergetic pathways might make
tumor cells more susceptible to anticancer treatment
and induction of apoptosis.
Alterations of energy-supplying pathways in tumors
One of the main characteristics of cancer cells is their fast
proliferation. As such, rapidly growing tumors easily
become hypoxic owing to the inability of the local vasculature to supply an adequate amount of oxygen. Similar
hypoxic conditions are usually lethal to non-malignant cells.
However, tumor cells can successfully escape hypoxiamediated death as a result of lowered expression or
mutation of p53 [5]. Owing to the inability of mitochondria
to provide enough ATP for cell survival under hypoxic
conditions, tumor cells must upregulate the glycolytic pathway. This occurs by induction of hypoxia-inducible factor 1
(HIF-1) [6]. HIF-1 stimulates key steps of glycolysis, but
regulates genes that control angiogenesis, cell survival and
invasion. However, it should be mentioned that, in certain
tumors, high levels of HIF-1 are observed also under oxygenated 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
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other factors (e.g. hormones and growth factors) might cause
stabilization of HIF-1 expression [7].
Stimulation of glycolysis can also occur by activation of
phosphoinositide 3-kinase (PI3K) and its downstream target, Akt (also known as protein kinase B), which are
engaged in a pathway that transmits survival signals from
various cell surface receptors. Activation of Akt triggers
increases in cell size, enhanced glycolytic activity and
metabolism, and cell survival [8], and is commonly
observed in cancer cells [9]. Akt was found to regulate
multiple steps in glycolysis through post-transcriptional
mechanisms, including localization of the glucose transporter to the cell surface and maintenance of hexokinase
function in the absence of extrinsic factors.
HIF-1 induction can also be triggered by the mitochondria themselves. When mitochondrial respiration in tumor
cells is downregulated, accumulation of Krebs cycle substrates might serve as a signal for stimulation of glycolysis
[10]. Succinate was shown to inhibit HIF-1a prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1a. Succinate accumulation in mitochondria
results from inhibition of succinate dehydrogenase.
Mutations in this enzyme are involved in familial predisposition to benign tumors; therefore, succinate dehydrogenase can be considered as a classical tumor suppressor
[11]. A similar stabilizing effect was described for lactate
and pyruvate [12]. Analogously, dysfunction of mitochondria can lead to activation of Akt. Defects in mitochondrial
respiration cause enhanced levels of NADH, which can
subsequently inactivate PTEN (phosphatase and tensin
homologue; a lipid phosphatase that antagonizes PI3K
function and therefore inhibits downstream signaling
through Akt) through a redox modification mechanism
[13].
In addition to upregulating the glycolytic pathway, HIF1 can initiate apoptosis by stabilization of p53 and/or
induction of certain pro-apoptotic proteins, such as BNIP3
(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 downregulation of the pro-apoptotic protein Bax (reviewed in
[14]). Therefore, during hypoxia, a complicated balance
emerges between factors that stimulate or suppress apoptosis.
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, mitochondrial activity slows down. Under these circumstances,
mitochondria consume less oxygen and their ATP production decreases. Analysis of possible alterations in the
oxidative phosphorylation machinery in some tumors
revealed downregulation of the catalytic subunit of the
mitochondrial ATP synthase (b-F1-ATPase). This was
observed in most human carcinomas. Remarkably, the
expression level of the b-F1-ATPase protein correlated
inversely with the rate of aerobic glycolysis. Furthermore,
inhibition of oxidative phosphorylation by oligomycin in
lung carcinoma was shown to trigger a rapid increase in
aerobic glycolysis. This finding demonstrated that tumor
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cells can become glycolytic as a result of suppression of
mitochondrial energy production [15]. Similarly, inhibition
of respiration in some human lung cancer cell lines was
found to significantly upregulate glycolysis. However,
when glycolysis was suppressed, tumor cells were unable
to sufficiently upregulate mitochondrial oxidative phosphorylation, indicating partial mitochondrial impairment
[16].
Low mitochondrial contribution to cellular ATP production under aerobic conditions is not a prerogative of
tumor cells only; it is also seen in a variety of fast-growing
normal cells [17]. Inhibition of mitochondrial respiration
by stimulated glycolysis is a phenomenon known as the
Crabtree effect (reviewed in [18]), and is observed in cells
that have approximately equal glycolytic and respiratory
capacities for ATP synthesis. Various mechanisms have
been suggested to explain the Crabtree effect in tumor cells
[19,20].
HIF-1 and suppression of mitochondrial activity
The role of HIF-1 is not restricted to upregulation of the
enzymes stimulating glucose utilization. Recent findings
demonstrate that, in addition, HIF-1 suppresses mitochondrial function in tumor cells, suggesting that it modulates
the reciprocal relationship between glycolysis and oxidative phosphorylation.
The switch between glycolysis and oxidative phosphorylation is controlled by the relative activities of two
enzymes, pyruvate dehydrogenase (PDH) and lactate
dehydrogenase (LDH) (Figure 1). The activity of PDH is
controlled by pyruvate dehydrogenase kinase 1 (PDK1).
HIF-1 was shown to induce PDK1 and thereby inactivate
PDH and, as a result, to suppress the Krebs cycle and
mitochondrial respiration (Figure 2) [21,22]. Suppression
of pyruvate oxidation through HIF-1-mediated PDK1
upregulation might, in turn, protect cells from production
of cytotoxic amounts of ROS. Thus, in HIF-1-deficient
Figure 1. Glucose utilization pathway. When glucose enters the cell, it is
phosphorylated by hexokinase to glucose-6-phosphate, which is further
metabolized by glycolysis to pyruvate. Under aerobic conditions, most of the
pyruvate in non-malignant cells enters the mitochondria, with only a small amount
being metabolized to lactic acid. In mitochondria, pyruvate dehydrogenase (PDH)
converts pyruvate into acetyl-CoA, which feeds into the Krebs cycle. Oxidation of
Krebs cycle substrates by the mitochondrial respiratory chain builds up the
mitochondrial membrane potential (Dc) – the driving force for ATP synthesis. By
contrast, in tumor cells, the oxidative (mitochondrial) pathway of glucose
utilization is suppressed, and most of the pyruvate is converted into lactate.
Thus, the fate of pyruvate is determined by the relative activities of two key
enzymes – lactate dehydrogenase and pyruvate dehydrogenase.
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[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 expression 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 phosphate shunt [30].
Figure 2. Mechanisms of mitochondrial silencing in tumors. The activity of PDH is
regulated by pyruvate dehydrogenase kinase 1 (PDK1), the enzyme that
phosphorylates and inactivates pyruvate dehydrogenase. HIF-1 inactivates PDH
through PDK1 induction, resulting in suppression of the Krebs cycle and
mitochondrial respiration. In addition, HIF-1 stimulates expression of the lactate
dehydrogenase A gene, facilitating conversion of pyruvate into lactate by lactate
dehydrogenase (LDH). Mutation of p53 can suppress the mitochondrial respiratory
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
oxidase (COX) of the mitochondrial respiratory chain. Thus, mutation of p53 can
suppress mitochondrial respiration and shift cellular energy metabolism towards
glycolysis.
mouse embryonic fibroblasts the level of ROS increased
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]).
HIF-1 was also shown to stimulate expression of the
gene encoding lactate dehydrogenase A, which facilitates
conversion of pyruvate into lactate [24]. This effect would
further diminish the utilization of pyruvate by mitochondria, suppressing mitochondrial respiration. In addition,
HIF-1 can modulate cytochrome oxidase (COX) expression.
Under hypoxic conditions, the subunit composition of COX
is altered to optimize its activity; expression of the COX4–2
subunit is increased, whereas the COX4–1 subunit, which
optimizes COX activity under aerobic conditions, is
degraded by activation of the mitochondrial protease
LON [25].
p53 and regulation of mitochondrial activity
Recent observations have revealed that p53, in addition to
its role as a central regulator of the cellular stress response,
can modulate the balance between the glycolytic pathway
and mitochondrial oxidative phosphorylation [26]. The key
component in this regulation is the gene encoding Synthesis
of Cytochrome c Oxidase 2 (SCO2), which, in conjunction
with the SCO1 protein, is required for the assembly of
cytochrome c oxidase [27]. Analysis of potential p53 target
genes that can influence mitochondrial function showed that
SCO2, but not SCO1, was induced in a p53-dependent
manner, as demonstrated by a nine-fold increase in transcripts. Mutation of p53 in tumors causes downregulation of
mitochondrial respiration as a result of COX deficiency and
a shift of cellular energy metabolism towards glycolysis.
Conversely, stimulation of mitochondrial activity in tumor
cells can be achieved by restoring the transcriptional function of p53. Indeed, an interesting relationship between p53
and glucose metabolism has recently been established
ROS impairment of mitochondrial function
The hypoxic environment of proliferating tumor tissue
facilitates ROS production (Box 1). Cellular hypoxia and
re-oxygenation are two essential elements of ischemiareperfusion injury, and massive production of ROS is
normally observed during re-oxygenation of hypoxic tissue.
However, ROS levels can also be increased by hypoxia,
when electron transport complexes are in the reduced state
[31]. Therefore, under hypoxic conditions and, in particular, after normalization of oxygen supply, production of
ROS in tumor cells can be enhanced to an extent that might
induce damage to vital cellular components, including
mitochondrial DNA (mtDNA). This might trigger a vicious
Box 1. Production of ROS by mitochondria
In any cell, the majority of ROS are by-products of mitochondrial
respiration. Approximately 2% of the molecular oxygen consumed
during respiration is converted into the superoxide anion radical,
the precursor of most ROS. Normally, a four-electron reduction of
O2, resulting in the production of two molecules of water, is
catalyzed by complex IV (COX) of the mitochondrial respiratory
chain. However, the electron transport chain contains several redox
centers (e.g. in complex I and III) that can leak electrons to molecular
oxygen, serving as the primary source of superoxide production in
most tissues. The one-electron reduction of oxygen is thermodynamically favorable for most mitochondrial oxidoreductases. Superoxide-producing sites and enzymes were recently analyzed in detail
in a comprehensive review [87]. ROS, if not detoxified, oxidize
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
activity. An imbalance that favors the production of ROS over
antioxidant defenses, defined as oxidative stress, is implicated in a
wide variety of pathologies, including malignant diseases.
It should be mentioned that mitochondria are not only a major
source of ROS but also a sensitive target for the damaging effects of
oxygen radicals. ROS produced by mitochondria can oxidize proteins
and induce lipid peroxidation, compromising the barrier properties of
biological membranes. One of the targets of ROS is mitochondrial
DNA (mtDNA), which encodes several proteins essential for the
function of the mitochondrial respiratory chain and, hence, for ATP
synthesis by oxidative phosphorylation. mtDNA, therefore, represents a crucial cellular target for oxidative damage, which might lead
to lethal cell injury through the loss of electron transport and ATP
generation. mtDNA is especially susceptible to attack by ROS, owing
to its close proximity to the electron transport chain, the major locus
for free-radical production, and the lack of protective histones. For
example, mitochondrially generated ROS can trigger the formation of
8-hydroxydeoxyguanosine as a result of oxidative DNA damage; the
level of oxidatively modified bases in mtDNA is 10- to 20-fold higher
than that in nuclear DNA. Oxidative damage induced by ROS is
probably a major source of mitochondrial genomic instability leading
to respiratory dysfunction.
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cycle (i.e. hypoxia, ROS production, mtDNA mutations,
malfunction of the mitochondrial respiratory chain,
further stimulation of ROS production etc.), thus impairing
mitochondrial function and causing a shift to glycolytic
ATP production.
Consequences of upregulation of glycolysis in tumor
cells
The seemingly most obvious reason for a glycolytic shift in
cancer cells is that molecular oxygen becomes unavailable
in fast-proliferating cells, and thus the mitochondria cannot function properly in ATP production. Nevertheless,
even after restoration of oxygen supply, tumor cells tend
to utilize glucose and to keep mitochondrial activity suppressed. Apparently, ATP production is not the only reason
why tumor cells favor this energetically unprofitable pathway. Furthermore, mounting evidence demonstrates that
the amount of glucose entering cancer cells exceeds their
bioenergetic demands. The high rate of glycolysis in most
tumors not only compensates for mitochondrial dysfunction but also is required to support tumor cell proliferation.
High intracellular glucose concentrations enable the cell to
redirect the accumulated glycolytic end-product, pyruvate,
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 proliferation 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 competitive advantage for invasion, because the acidic environment 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-caspase3 and other effector caspases. By contrast, the intrinsic
pathway involves permeabilization of the outer mitochondrial membrane (OMM) followed by the release of cytochrome 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 activation of pro-caspase-9. Active caspase-9, in turn, cleaves
and activates pro-caspase-3 and pro-caspase-7; these effector caspases are responsible for the cleavage of a variety of
cellular proteins, leading to the characteristic biochemical
and morphological features of apoptotic cell death. Therefore, permeabilization of the OMM is considered to be a
crucial event during the early phase of the apoptotic process [34]. Multiple observations support the opinion that
the glycolytic shift makes tumor mitochondria less susceptible to permeabilization of the OMM and, hence, less
susceptible to activation of the mitochondrial pathway of
apoptosis. What, then, are the mechanisms of OMM permeabilization in apoptosis, and how could stimulation of
the glycolytic pathway make mitochondria resistant to
permeabilization?
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Mitochondrial membrane stabilization in glycolytic
tumor cells
The role of Bcl-2 proteins in OMM permeabilization
The Bcl-2 family proteins are a group of evolutionarily
conserved regulators of apoptosis. More than thirty Bcl-2
family-related proteins have been identified to date. They
include Bcl-2-like survival factors as well as Bax-like and
BH3-only death factors [35]. Permeabilization of the OMM
requires the oligomeric form of Bax. Oligomerization of
Bax can result from its binding to the truncated form of the
BH3-only protein Bid, tBid, which is cleaved by various
proteases, including caspase-8 (Figure 3a). Anti-apoptotic
proteins (e.g. Bcl-2, Bcl-XL, Mcl-1, and Bcl-w) interact with
the pro-apoptotic proteins Bax and Bak to prevent their
oligomerization (Figure 3b). Hence, the balance between
pro-apoptopic and anti-apoptotic proteins in the OMM is
crucial for apoptosis induction, and it appears that in many
tumors the mitochondrial apoptotic pathway is suppressed
owing to a disproportion between anti-apoptotic and proapoptotic mediators, in favor of the former [36].
An imbalance among cellular levels of Bcl-2 family
proteins can also contribute to OMM stabilization indirectly
(e.g. through binding of Bcl-2 to the voltage-dependent anion
Figure 3. Stabilization of mitochondria against OMM permeabilization in tumor
cells. OMM permeabilization is a key event in apoptotic cell death. (a) During
apoptosis, tBid-mediated oligomerization of Bax causes OMM permeabilization
and release of cytochrome c (red circles). (b) Bcl-2 protein binds Bax and prevents
its oligomerization. A shift in the balance between pro- apoptotic and antiapoptotic proteins in cancer cells, in favor of the latter, reduces the availability 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
using mitochondrially generated ATP but keeps VDAC in the open state,
preventing its interaction with tBid (de).
Review
channel [VDAC] [37], a protein located in the OMM and
responsible for most of the metabolite fluxes between the
cytosol and the mitochondria [38]). Closure of VDAC upon
growth factor withdrawal induces apoptosis by inhibition of
ADP–ATP exchange and a resultant decrease in metabolite
fluxes over the mitochondrial membranes, which can cause
mitochondrial deterioration and cytochrome c release [39].
The anti-apoptotic protein Bcl-XL prevents apoptosis by
maintaining VDAC in an open configuration. However, it
is not clear how the closure of VDAC would cause OMM
permeabilization, although it has been suggested that
VDAC generally shows a higher permeability to Ca2+ in
the closed state than in the open state [40]. Hence, Ca2+
influx could possibly trigger the induction of mitochondrial
permeability transition (MPT), another mechanism of OMM
permeabilization due to opening of a non-specific pore in the
inner mitochondrial membrane (IMM), commonly known as
the MPT pore.
Opening of the MPT pore can be facilitated by inorganic
phosphate, oxidation of NAD(P)H, ATP depletion, low pH,
and ROS (reviewed in [41]). The MPT pore is thought to
consist of a multimeric complex, involving VDAC in the
OMM, adenine nucleotide translocase (ANT), an integral
protein of the IMM, and a matrix protein, cyclophilin D
(CyP-D). This complex is located at contact sites between
the mitochondrial inner and outer membranes. In
addition, other proteins, including kinases (e.g. hexokinase, creatine kinase) and the peripheral benzodiazepine
receptor, can bind to the pore complex and modulate its
permeability [42]. MPT is followed by the influx of water
and ions into the matrix, causing mitochondrial swelling,
rupture of the OMM, and the release of intermembrane
space proteins such as cytochrome c into the cytosol.
Mitochondria from tumor cells are relatively less susceptible to Ca2+-induced MPT. The difference in sensitivity
might be due to the relatively higher expression of the Bcl2 protein in the tumor cells [43], although the precise
mechanism of Bcl-2-mediated resistance is still unclear.
It has recently been reported that permeabilization of
the OMM can also result from the opening of so-called
mitochondrial apoptosis-induced channels (MACs) [44].
MACs provide specific pores in the OMM for the passage
of intermembrane space proteins, in particular cytochrome
c, into the cytosol. Interestingly, the permeability of MACs
was also shown to be dependent on the presence of Bcl-2
family proteins. Thus, Bax was an essential constituent of
MACs in some systems; electrophysiological characteristics of MACs were very similar to those of channels
formed by Bax, and depletion of Bax significantly diminished MAC activity. By contrast, overexpression of Bcl-2
was shown to block formation of MACs and release of
cytochrome c [45]. Opening of MACs does not affect the
integrity of the IMM or disrupt mitochondrial intactness,
in contrast to MPT.
Both Bax- (or Bak-) and MPT-dependent release of
cytochrome c is facilitated by ROS. Cytochrome c is normally bound to the outer surface of the IMM by both
electrostatic and hydrophobic interactions with the unique
mitochondrial phospholipid, cardiolipin. Oxidation of cardiolipin causes the dissociation of cytochrome c [46], which
might provide a plausible explanation for the anti-apopto-
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Vol.18 No.4
tic effects reported for multiple mitochondrial antioxidant
enzymes [47].
Hexokinase and OMM stability
Hexokinase plays a leading role in the process by which
mitochondria are protected from OMM permeabilization in
glycolytic tumor cells. Four isoforms of hexokinase are
known: hexokinase-I, hexokinase-II, hexokinase -III and
hexokinase -IV, also known as glucokinase. Among glycolytic enzymes, hexokinases, in particular hexokinase-I and
hexokinase-II, are exceptional in their ability to bind
directly to mitochondria [48]. By contrast, the type III
isozyme lacks the hydrophobic N-terminal sequence
known to be crucial for the binding of type I and type II
isozymes to mitochondria [49].
Tumors are characterized by upregulation of hexokinase-I (in brain tumors) and hexokinase-II (in almost all
other tumors). Interaction with VDAC enables hexokinase
to use exclusively intra-mitochondrial ATP to phosphorylate glucose, thereby promoting a high rate of glycolysis
(Figure 3c) (reviewed in [50]). The interaction of hexokinase with VDAC not only facilitates glucose phosphorylation but also keeps VDAC in the open state, which
counteracts OMM permeabilization. Another consequence
of hexokinase–VDAC interaction is that hexokinase
occupies binding sites for pro-apoptotic proteins on the
OMM and thereby prevents induction of apoptosis
(Figure 3de) [51].
Finally, hexokinase has been implicated in the regulation of MPT pore opening [52]. In contrast to hexokinase-II,
hexokinase-I was shown to trigger the closure of VDAC,
thus suppressing mitochondrial activity and stimulating
glycolytic ATP production [53]. The product of glucose
phosphorylation, glucose-6-phosphate, mitigates the inhibition of VDAC by hexokinase-I, and mitochondrial ATP
production can be restored. This happens when glycolysis
is suppressed downstream of glucose-6-phosphate formation. Therefore, the interaction of hexokinase-I with
VDAC might be regarded as a mechanism that protects
the mitochondria from MPT induction. However, a recent
genetic study indicated that mitochondrial VDAC is dispensable for MPT induction and apoptotic cell death [54]. It
appears that the role of VDAC in permeabilization of OMM
during apoptosis requires further study.
ANT and OMM stability
Another factor contributing to the mitochondrial resistance against MPT induction in tumor cells is the altered
expression profile of ANT, a key component of the pore
complex. Analysis of ANT isoform expression in several
transformed human cell lines demonstrated predominant
expression of ANT2 [55], an isoform lacking the apoptotic
activity of ANT1 [56]. Transient overexpression of ANT3,
or ANT1, was shown to induce apoptosis [57]. Thus, as with
hexokinase-I binding to VDAC, the overexpression of
ANT2 in tumors might contribute to mitochondrial resistance to OMM permeabilization.
Akt-mediated OMM stabilization
As mentioned above, the serine–threonine kinase Akt–
PKB is a major downstream effector of growth factor169
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mediated cell survival. Activation of the Akt–PKB pathway is well known to protect cells from apoptosis [58],
although the precise mechanisms of this protection are
unclear to date. However, Akt activation inhibited cytochrome c release from mitochondria and thereby prevented
the activation of caspases [59]. By contrast, Akt was not
able to suppress apoptosis following cytoplasmic microinjection of cytochrome c, indicating that the anti-apoptotic
effect of Akt occured upstream of OMM permeabilization.
How, then, could Akt enhance OMM stability?
It has been demonstrated that Akt activation inhibits
p53-mediated expression of Bax, thereby suppressing the
probability of OMM permeabilization [60]. In addition, the
active, but not the inactive, form of Akt was shown to
phosphorylate the pro-apoptotic protein Bad, preventing
its interaction with the OMM and reducing its pro-apoptotic activity [61,62]. Following PI3K activation, Akt
rapidly accumulates in mitochondria [63], where it resides
in both the outer and inner membranes, as well as in the
matrix. Active Akt might also affect the oligomerization of
Bax, a prerequisite step in OMM permeabilization. However, the expression of mitochondria-targeted, active Akt
did not change the level of monomeric Bax, whereas Bax
dimerization was markedly reduced [64]. In addition, Akt
was shown to promote the translocation of hexokinase to
mitochondria, where it interacts with mitochondrial
VDAC. Moreover, genetic evidence suggests that Akt is
also required for a sustained association between hexokinase and the mitochondria [65], which would subsequently
facilitate hexokinase–VDAC interaction and its effects on
MPT pore opening. Targeted disruption of this association
impaired the ability of growth factors and Akt to inhibit
cytochrome c release and apoptosis.
Contribution of loss of p53 function to OMM
stabilization
Mutations, or downregulation, of the transcription factor
p53 not only contribute to the suppression of mitochondrial
respiratory activity, as described above, but might also
play an important role in mitochondrial resistance to
permeabilization. p53 regulates the expression of the
BH3-only proteins, p53 upregulated modulator of apoptosis (PUMA) and Noxa (Latin for damage), which promote
OMM permeabilization during apoptosis [66,67]. PUMA
and NOXA bind to anti-apoptotic proteins, thereby liberating previously bound Bax and Bak from such complexes.
Co-immunoprecipitation studies showed that NOXA binds
to Bcl-2 and Bcl-XL, but not to Bax. Interestingly, p53 can
also regulate OMM permeabilization through direct activation of Bax [68]. Although the precise mechanism of this
activation is still obscure, it is clear that loss of p53 function
in tumor cells can result in stabilization of the OMM
through downregulation of pro-apoptotic Bcl-2 family
proteins by multiple mechanisms.
Promotion of cancer cell death through the
manipulation of cellular ATP-generating pathways
Suppression of the glycolytic pathway
The dependence of tumor cells on glycolysis for ATP generation offers a rationale for therapeutic strategies aimed at
selective inhibition of the glycolytic pathway. This approach
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might be most useful in cells with mitochondrial defects, or
under hypoxic conditions, when the mitochondrial contribution to cellular bioenergetics is minimal. Under such
circumstances inhibition of glycolysis would be expected
to severely deplete ATP [69]. Indeed, in a variety of cancer
cells, inhibition of glycolysis, for example with 2-deoxyglucose (2-DG), a non-metabolizable glucose analogue [70], or 3bromopyruvate [71], was shown to cause a marked drop in
ATP level, especially in clones of cells with mitochondrial
respiratory defects. Among the effects of the ATP depletion
were rapid dephosphorylation of the pro-apoptotic protein
Bad, migration of Bax to the mitochondria, and massive cell
death [72]. Similar to the effects of inhibiting key steps in the
glycolytic pathway, suppression of glucose transport might
also sensitize tumor cells to anticancer agents. For example,
a glucose transporter inhibitor, phloretin, was reported to
markedly enhance the anticancer effects of daunorubicin
[73]. Combining inhibitors of glycolysis with conventional
chemotherapeutic drugs might provide a novel therapeutic
strategy to overcome drug resistance in hypoxia. Apparently, under these conditions, the ultimate fate of the cancer
cell will depend on how efficiently mitochondrial oxidative
phosphorylation can substitute for the inhibited glycolysis
in providing the ATP needed for cellular demands.
Shifting cellular metabolism from glycolysis to glucose
oxidation
Recent findings demonstrate that stimulation of mitochondrial activity and restoration of the mechanisms of ATP
generation characteristic of non-malignant cells might be
an efficient tool in anticancer strategy. In particular, shifting cellular metabolism towards mitochondrial ATP production might overcome the effects of HIF-1-mediated
upregulation of the glycolytic pathway. Several attempts
have been made to prevent the formation of lactate and to
redirect pyruvate metabolism towards oxidation in the
mitochondria. Thus, inhibition of PDK1 and, hence, activation of PDH, by dichloroacetate, was shown to shift
metabolism from glycolysis to glucose oxidation. As a
result, such treatment decreased mitochondrial membrane
potential (DC) and increased mitochondrial production of
ROS in cancer cells, but not in normal cells [74]. A similar
effect was achieved by inhibition of LDH (Figure 4).
Inhibition of LDH, or stimulation of PDH through the
inhibition of PDK1, could be particularly useful in tumors
with impaired mitochondrial bioenergetics. However, in
cancer cells with functionally competent mitochondria,
this approach might be insufficient, because mitochondrial
ATP synthesis would compensate for the inhibited glycolysis. Therefore, under these circumstances, supplementary
suppression of mitochondrial activity might be needed to
kill cancer cells. Indeed, non-toxic doses of apoptolidin, an
inhibitor of mitochondrial ATP synthase, were found to
trigger cell death in malignant cell lines when applied
together with the LDH inhibitor oxamate [75]. Similar
results were obtained when 2-DG was used instead of
oxamate to inhibit glycolysis. Hence, combined strategies
involving manipulation of both the glycolytic and the
mitochondrial pathways might be useful tools in the elimination of cancer cells that would otherwise survive thanks
to mitochondrial ATP production.
Review
Figure 4. Shifting metabolism from glycolysis to glucose oxidation. Utilization of
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,
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
mitochondria. Thus, inhibition of PDK1 by dichloroacetate might stimulate the
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
activities will stimulate mitochondrial ATP production and might be lethal to tumor
cells, even if these inhibitors are used at non-toxic doses. In addition, stimulation of
mitochondrial function, for example though overexpression of mitochondrial
frataxin, a protein associated with Friedreich ataxia, was shown to stimulate
oxidative metabolism and inhibited growth in several cancer cell lines [86].
Alteration of mitochondrial metabolism
The resistance of cancer cells to treatment is often associated with flaws in their apoptotic program. Successful
elimination of tumor cells, therefore, largely depends on
the ability of anticancer treatment to stimulate silent or
suppressed apoptotic pathways. Mitochondria are promising targets for such an approach. Hence, agents that
suppress mitochondrial respiration, or uncouple oxidative
phosphorylation, have been shown to provoke cell death,
although such compounds fail to kill cells depleted of
mitochondrial DNA and therefore lacking an intact respiratory chain. The anti-apoptotic protein Bcl-2 did not block
apoptosis induced by respiratory chain inhibitors [76].
Suppression of mitochondrial respiratory chain activity
also sensitized the cells to traditional apoptotic stimuli.
Thus, in HeLa cells treated with respiratory inhibitors,
lower concentrations of Fas were sufficient to induce apoptosis than were required in untreated cells [77].
All-trans retinoic acid (ATRA) is another potential regulator of mitochondrial metabolism. This natural derivative of vitamin A disrupted mitochondrial function in the
myeloid cell line P39 long before any detectable signs of
apoptosis appeared. ATRA suppressed mitochondrial
respiration, decreased Dc and, as a result, induced MPT
[78]. Similarly, a-tocopheryl succinate (a-TOS), a redoxsilent analogue of vitamin E, was shown to selectively kill
malignant cells at concentrations that were non-toxic to
normal cells and tissues [79]. The pro-apoptotic effect of aTOS has been linked to its interaction with complex II of
the mitochondrial respiratory chain [80], stimulation of
ROS production [81], and promotion of the translocation of
Bax from the cytosol to the mitochondria, causing cytochrome c release and caspase activation [82]. Thus, the
results obtained to date make a-TOS an attractive candidate for antitumor strategy.
Trends in Cell Biology
Vol.18 No.4
Can oxidative stress be employed in anticancer therapy?
Modulation of cellular redox balance through pharmacological 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 anticancer effect of multiple conventional treatments (e.g. ionizing 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 concentrations of the drug stimulated cytochrome c release and
apoptosis through a Bax- or Bak-dependent mechanism
[84,85].
Concluding remarks
Tumorigenesis is a complex process involving the activation of oncogenes, inactivation of tumor suppressors,
and deregulation of cell death programs. The findings that
pro-apoptotic genes might act as tumor suppressors and
that anti-apoptotic genes can serve as oncogenes suggested
that the balance between pro-apoptotic and anti-apoptotic
genes modulates tumor growth. How to selectively activate
apoptosis in transformed cells remains a primary strategic
problem in cancer therapy, and extensive studies are being
performed to find efficient mechanisms of apoptosis induction in tumor cells. Despite the heterogeneity of tumors,
which dictates an individual approach to anticancer treatment, almost all tumor cells demonstrate enhanced uptake
and utilization of glucose, a phenomenon known as the
Warburg effect. Stimulation of the glycolytic pathway in
tumors not only compensates for the decline in ATP production due to impaired mitochondrial function but is also
responsible for enhanced mitochondrial stability and
resistance to apoptosis induction. Stabilization of mitochondria is not limited to the upregulation of anti-apoptotic Bcl-2 proteins observed in a variety of tumors.
Amazingly, pathways that lead to upregulation of glycolysis can also cause suppression of mitochondrial activity.
For instance, HIF-1 not only stimulates the influx and
utilization of glucose in tumor cells but also stabilizes
mitochondria through multiple pathways. Hence, targeting the mitochondria appears to be a promising strategy for
the induction of apoptosis in tumor cells. Activation of the
mitochondrial pathway reverts cellular energy metabolism
to the phenotype characteristic of non-malignant cells and
also promotes ROS production by the mitochondria, which
might increase the susceptibility of the tumor cells to
undergo apoptotic cell death. The existing interplay between apoptotic regulators and mitochondrial energy
metabolism should therefore be considered in the search
for novel anticancer drugs. Another approach might be
based on destabilizing mitochondria and sensitizing them
to MPT induction. Thus, the success of a coordinated attack
on cancer must be based on the concerted modulation of
cellular energy metabolism, mitochondrial stability, and
other mechanisms responsible for the resistance to apoptosis characteristic of tumor cells. Further investigation of
the role of the mitochondria in tumor cell metabolism
171
Review
might help in the development of new therapeutic strategies aimed at killing cancer cells and suppressing tumor
growth.
Acknowledgements
Work in the authors’ laboratory was supported by grants from The
Swedish and Stockholm Cancer Societies, The Swedish Childhood Cancer
Foundation, The Swedish Research Council, the EC-FP-6 (Oncodeath and
Chemores) and EC-FP-7 (APO-SYS). We apologize to authors whose
primary references could not be cited owing to space limitations.
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