Cell. Mol. Life Sci.

DOI 10.1007/s00018-015-2100-2 Cellular and Molecular Life Sciences

REVIEW

Metabolic changes associated with tumor metastasis,

part 2: Mitochondria, lipid and amino acid metabolism
Paolo E. Porporato1 • Vale´ry L. Payen1 • Bjorn Baselet1,2 • Pierre Sonveaux1

Received: 31 July 2015 / Revised: 16 November 2015 / Accepted: 23 November 2015

© Springer International Publishing 2015

Abstract Metabolic alterations are a hallmark of cancer Keywords Tumor metastasis · Oxidative
controlling tumor progression and metastasis. Among the phosphorylation (OXPHOS) · Electron
various metabolic phenotypes encountered in tumors, this transport chain (ETC) · Reactive oxygen
review focuses on the contributions of mitochondria, lipid species (ROS) ·
and amino acid metabolism to the metastatic process. Tumor Tricarboxylic acid cycle (TCA cycle) · Lipogenesis ·
cells require functional mitochondria to grow, proliferate Glutaminolysis · Proline metabolism
and metastasize, but shifts in mitochondrial activities confer
pro-metastatic traits encompassing increased production of Abbreviations
mitochondrial reactive oxygen species (mtROS), enhanced aKG a-Ketoglutarate
resistance to apoptosis and the increased or de novo Aco Aconitase
production of metabolic intermediates of the TCA cycle ACLY ATP-citrate lyase
behaving as oncometabolites, including succinate, fumarate, CoA Coenzyme A
and D-2-hydroxyglutarate that control energy production, CS Citrate synthase
biosynthesis and the redox state. Lipid metabolism and the
D-2HG D-2-Hydroxyglutarate
metabolism of amino acids, such as glutamine, glutamate
EMT Epithelial-to-mesenchymal transition
and proline are also currently emerging as focal control
ETC Electron transport chain
points of cancer metastasis.
eSC Embryonic stem cell
FASN Fatty acid synthase
FH Fumarate hydratase
GDH Glutamate dehydrogenase
P. E. Porporato and V. L. Payen equally contributed to this GLS Glutaminase
manuscript. HGFR Hepatocyte growth factor receptor
HIF-1 Hypoxia-inducible factor-1
Submitted as a companion paper to ‘‘Payen VL, Porporato PE, IDH Isocitrate dehydrogenase
Baselet B, Sonveaux P. Metabolic changes associated with tumor
metastasis, part 1: Tumor pH, glycolysis and the pentose phosphate
KEAP1 Kelch-like ECH-associated protein 1
pathway.’’ KRAS Kirsten Rat Sarcoma
MCL-1 Myeloid cell leukemia-1
& Pierre Sonveaux mtROS Mitochondrial reactive oxygen species
[email protected]
mTORC1 Mammalian target of rapamycin complex 1
1
Pole of Pharmacology, Institut de Recherche Expe´rimentale NF-jB Nuclear factor-jB
et Clinique (IREC), Universite´ catholique de Louvain NRF2 Nuclear factor-like 2
(UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200 OXPHOS Oxidative phosphorylation
Brussels, Belgium
PGC-1 Peroxisome proliferator-activated
2
Radiobiology Unit, Belgian Nuclear Research Centre, receptor c coactivator-1
SCK·CEN, 2400 Mol, Belgium

1
3
 P. E. Porporato et al.

1
PHD Prolylhydroxylase http://globocan.iarc.fr.
PI3K Phosphoinositide 3-kinase
PKB/Akt Protein kinase B
ROS Reactive oxygen species
SDH Succinate dehydrogenase
SOD Superoxide dismutase
SRC2 Steroid receptor coactivator 2
SREBP Sterol regulatory element-binding protein
STAT3 Signal transducer and activator of
transcription 3
TCA (cycle) Tricarboxylic acid (cycle)
TET (enzyme) Ten-eleven translocation (enzyme)

Introduction

While intensive research aims to characterize primary

tumor biology for the sake of new therapeutic and
diagnostic tools, less attention has been paid until
recently to the biology of metastases. Metastasis,
however, is estimated to be respon- sible for *90 % of
cancer-associated deaths [1], representing a yearly toll
of *8,200,000 patients worldwide (Globoscan 2012).1
Growing evidence points to a metabolic control of tumor
progression affecting many phenotypic traits of
malignancy, including metastasis. While the specific
contributions of tumor pH, glycolysis and the pentose
phosphate pathway to the metastatic process are
addressed in a companion paper, this review focuses on
mitochondrial, lipid and amino acid metabolism.
Defects of mitochondrial function have long been sus-
pected to contribute to the development and progression of
cancer. Almost a century ago, Otto Warburg [2] initiated
research on mitochondrial alterations in cancer and pro-
posed a mechanism to explain the differences in energy
metabolism between normal and cancer cells. He
suggested that mitochondrial alterations could provide
unique thera- peutic targets in various cancer types [3]. The
concept promoted by Warburg that mitochondrial damage
is the cause of cancer is no longer tenable as a general
concept [4]. However, specific cancer-associated mutations
have been reported in nuclear-encoded mitochondrial
enzymes of the tricarboxylic acid (TCA) cycle, including
fumarate hydratase (FH) [5], succinate dehydrogenase
(SDH) [5] and isocitrate dehydrogenase (IDH) [6]. SDH
deficiency has been linked to hereditary paraganglioma
and pheochro- mocytoma, and FH inactivation promotes
leiomyoma, leiomyosarcoma and renal cell carcinoma [7,
8]. Besides these mutations, several other cancer-related
mitochondrial alterations have been identified, and
mitochondria are now emerging as key players in tumor
transformation and
 Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino…
progression. This is not surprising since mitochondria are apoptosis, which mitochondria achieve by regulating the
not passive bystanders involved in bioenergetics. They release of cyto- chrome c and calcium. Mitochondria
rather act as metabolic and signaling hubs, interconnecting further host several signaling pathways involved in tumor
metabolism and cell signaling. transformation and growth. For example, the mitochondrial
From a metabolic standpoint, one of the main fraction of signal transducer and activator of transcription 3
activities of mitochondria is to perform the TCA cycle (STAT3) pro- motes OXPHOS and pancreatic cancer
where the acetyl group of acetyl-coenzyme A (acetyl- initiation [11, 12], ERK activation promotes tumor cell
CoA), mostly derived from pyruvate, is progressively resistance to apoptosis by inhibiting the opening of the
oxidized to CO2 to provide reducing equivalents for permeability transition pore [13], and c-Src regulates
oxidative phosphorylation (OXPHOS) (Fig. 1). In OXPHOS by phosphorylat- ing several ETC subunits [14].
addition to pyruvate, the TCA cycle can be fueled by These signaling pathways are directly related to
products of anaplerotic reactions (from Greek [up] mitochondrial metabolism. It is therefore not surprising
and pkgqo´x [fill in]), among which a-ketoglutarate that mitochondria exert critical roles not only in
(aKG) from glutaminolysis is a major substrate [9]. tumorigenesis but also in cancer metas- tasis, which is the
OXPHOS occurs at the mitochondrial elec- tron topic of this review.
transport chain (ETC) and represents a highly efficient
pathway for ATP generation. Importantly, the TCA
cycle also generates intermediates connecting the cycle Oxidative phosphorylation and mitochondrial
to other metabolic pathways by means of the so-called reactive oxygen species
cataplerotic reactions (from Greek jasa [down] and
pkgqo´x [deplete]) that drain the TCA cycle from its Mitochondria are involved in OXPHOS, which couples
metabolites. These reactions provide substrates for redox reactions of the ETC to ATP synthesis (Fig. 1).
biosynthesis, thus sup- porting normal cellular During this process, electrons derived from NADH and
functions, cell growth and proliferation [10]. FADH2 are transferred to molecular oxygen through
Besides metabolism sensu stricto, mitochondria are sequential redox reactions that generate a proton gradient
also critical regulators of compartmentalized cellular across the inner mitochondrial membrane. Four macro-
signaling. One typical example is the modulation of molecular protein complexes located at the inner
mitochondrial membrane are required for driving the
 MCL-1 HIF-1
Src NF-κB
Tumor cell mitochondrion Pyruvate
SNAIL Pyk2
NRF-2 Src Bcl2

Mitohormesis

Metastasis + +

+ +
2H 2H 2H+

ROS
I Q
Q III Cyt C IV ETC
II ROS

Pyruvate NADH NAD+

2 H+ + ½ O2 H2O ADP + Pi ATP
Targeted
Antioxidants
+H
+ 2
FAD
+
FADH 2H+
2H+
Metformin

Pyruvate
CoASH + NAD+
Fatty acid
dehydrogenase
Fatty acid synthase
NADH + H+ + CO 2

Acetyl-CoA
Metastasis
synthesis

H 2O Citrate
Oxaloacetate CoASH

NADH + H+ Citrate synthase

Malate Aconitase
NAD+ dehydrogenase

Malate Isocitrate
Malate NAD+

TCA
Fumarate Isocitrate
H2O hydratase dehydrogenase
Fumarate
hydratas NADH + H+ + CO2

cycle
e
H2O

NRF2 Fumarate Fumarate α-Ketoglutarate

Succinate α-Ketoglutarate
dehydrogenase dehydrogenase NAD+ + CoASH
FADH2
HIF-1

FAD NADH + H+ + CO2

Succinate Succinyl-CoA Succinyl-CoA

synthetase
Glutamate
Succinate
Metastasis dehydrogenase

Glutamate
GTP + GDP + Pi NAD(P)+ NAD(P)H + H+
CoASH
+ H2O + NH3

Glutamate Isocitrate
dehydrogenase
NH3
α-Ketoglutarate Isocitrate
968 Glutaminase

Migration
Metastasis
H2O
NADPH NADP+
Glutamine + CO2

Fig. 1 Simplified scheme highlighting the contribution of mitochon- byproduct, mitochondrial reactive oxygen species (mtROS).
dria, lipid and amino acid metabolism to tumor metastasis. The Increased mtROS levels have been proposed to increase resistance
scheme depicts a mitochondrion where enzymes are represented in to stress (mitohormesis). Furthermore, several anaplerotic reactions
italicized blue font and their substrates in bold black. Upon entering replenish the TCA cycle. Many of these reactions promote tumor
into the mitochondria, pyruvate is broken down during the catabolic metastasis, as indicated in red. Other abbreviations: HIF-1 hypoxia-
part of the tricarboxylic acid (TCA) cycle. This produces reducing inducible factor-1, MCL-1 myeloid cell leukemia-1, NF-kB nuclear
agents that fuel the electron transport chain (ETC) to generate the factor-kB, NRF2 nuclear factor-like 2
proton motive force needed for the production of ATP and, as a

generation of the gradient, which triggers the activity of the While O2 is fully reduced to water to foster ATP syn-
ATP-synthase complex at the inner mitochondrial mem- thesis in mitochondria, a small proportion is converted into
brane. Thus, protons transferred from the intermembrane superoxide [15, 16] (Fig. 1). Superoxide is a radical anion
space to the mitochondrial matrix through ATP-synthase and a highly reactive oxygen species (ROS) acting as a
along their concentration gradient provide the energy for strong oxidant. In normal circumstances, superoxide is
ATP generation in mitochondria. detoxified by superoxide dismutases (SODs) that rapidly
convert it to H2O2. SODs are excellent catalysts that are cardiolipin at the inner mitochondrial membrane where it
rate-limited primarily by the speed of diffusion of the transfers electrons from complex III to IV of the ETC.
substrate in solution [17]. When superoxide is produced Following oxidation, this interaction is repressed and
at a supraphysiological rate and ROS rise to a critical cytochromec is released from mitochondria, thus triggering
level, they can oxidize cytochrome c and impair its apoptosis [19]. However, mitochondrial ROS (mtROS) are
binding to the inner mitochondrial membrane [18]. not only triggering
Cytochrome c is normally bound to the phospholipid
apoptosis. At non-lethal levels, they are essential for cel- acquisition of metastatic traits, with circulating tumor cells
lular adaptation to stress [20] and to hypoxia through characterized by an intermediate metabolic phenotype
activation of transcription factor hypoxia-inducible factor- compared to primary and secondary tumors (see Figure 1
1 (HIF-1) [21], as well as for the induction of autophagy in companion paper). One of the advantages conferred by
[22] and mitochondrial biogenesis by activation of the an elevation of OXPHOS activity could be a stronger
transcriptional coactivator peroxisome proliferator-acti- resistance to apoptosis through the induction of a pro-ox-
vated receptor c coactivator-1 (PGC-1) [23]. idant state [38]. Altered mitochondrial metabolism has also
The initial observation by Warburg that some tumor been proposed to promote metastasis by inducing stress
cells perform glycolysis at a high rate even in presence of tolerance during nutrient deprivation [39].
oxygen prompted him to formulate the hypothesis In strong contrast to studies advocating for a contri-
according to which mitochondria are not functional in bution of OXPHOS to cancer metastasis, a number of
tumors [3]. Except for some specific cases, this hypothesis independent authors reported that interfering with mito-
has not been con- firmed [24]. Still, the perception of the chondrial activity can promote metastasis. In particular,
role of mitochondria in tumor cells has often been reduced overexpression of oncogenes such as BAX inhibitor-1
to the provision of biosynthetic intermediates for cellular [40, 41] or loss of metastasis suppressor genes such as
proliferation [25]. But mitochondria are also emerging as KISS1 [42] induces metastasis together with a switch
essential mediators of tumorigenesis. In fact, complete from an oxidative to a glycolytic metabolism. Mito-
abolition of ETC activity was shown to prevent chondrial DNA (mtDNA) mutations can also promote
tumorigenesis in a Kirsten Rat Sar- coma (KRAS)-driven metastatic dissemination from prostate to bones and the
mouse model of lung cancer [26], in murine breast cancer invasive growth of melanoma cells in vivo [43, 44].
and melanoma models [27], and it inhibited the in vivo Accordingly, specific mtDNA mutations are a marker of
growth of human breast cancer cells [28]. In models of poor prognosis in breast cancer and melanoma patients
pancreatic cancer, mitochondrial targeting of STAT3 [45, 46]. As a final example, mitochondrial stress result-
stimulated ETC activity and tumor transformation [11, 12], ing from mtDNA depletion or treatment with ionophores
further emphasizing the critical role of mitochon- dria in that uncouple ETC activity from ATP generation pro-
cancer. Along the same lines, cancer cells responsible for moted an invasive behavior in human lung cancer cells
tumor relapse following oncogene ablation specifically and C2C12 myoblasts [47, 48].
rely on OXPHOS for survival [29]. Consistently, the It has been reported that either increased or reduced
antidiabetic drug metformin, a dual AMPK activator and OXPHOS activity promotes metastatic dissemination. A
ETC Complex I inhibitor [30], acts synergistically with potential explanation of this conundrum is that two oppo-
chemotherapy to eradicate resistant tumor cells and site metabolic phenotypes might contribute to metastasis
promote cancer remission [31]. This observation has been by regulating different pathways. Indeed, on one hand,
recently linked to the activity of metformin as an inhibitor increased mitochondrial metabolism has been shown to
of ETC Complex I [30, 32]. promote resistance to apoptosis [35, 38, 49–51], whereas,
With regard to the specific contribution of OXPHOS to on the other hand, mitochondrial dysfunction can favor a
tumor metastasis, several groups challenged the view that pro-metastatic behavior either by promoting glycolytic
ETC is dispensable for tumor migration and metastasis [27, compensation [52] or by impacting the NAD?/NADH
33–37]. Disseminating cancer cells actually display redox ratio that regulates sirtuin activity, thereby directly
increased levels of mitochondrial respiration, at least in promoting tumor metastasis [53]. We recently proposed a
breast and melanoma models [35]. This is driven by the parallel but not mutually exclusive interpretation. In dif-
upregulation of PGC-1a, a master gene regulating mito- ferent tumor cell models, we indeed observed that either an
chondrial biogenesis and metabolism, making PGC-1a increased or a dysfunctional mitochondrial activity are
expression a marker of poor prognosis in invasive ductal equally capable of promoting an invasive tumor phenotype
breast carcinoma [35]. Another piece of evidence arguing [33]. We found that metabolic states of tumor cells corre-
for an important contribution of mitochondria to tumor sponding to increased TCA cycle activity or experimentally
metastasis derives from the work of Tan et al. [27] who induced ETC bottlenecking were associated with increased
demonstrated that active mitochondria are required for mtROS generation, and mtROS were a common mediator
tumor growth in vivo and that upon experimentally of metastasis for these two different metabolic phenotypes:
induced loss of mitochondrial DNA (q0 cells), cancer cells targeting mtROS with mitochon- dria-targeted antioxidants
are capable of restoring mitochondrial respiration by mitoTEMPO or mitoQ inhibited metastatic dissemination
‘‘steal- ing’’ mitochondria from host cells. Interestingly, this in a mouse melanoma B16F10 model and abolished
work further showed that tumor cells display an increased spontaneous metastatic dissemination in a model of MDA-
mitochondrial activity (elevated O2 consumption and MB-231 human breast cancer in mice
increased presence of cristae) along with the progressive
 [33]. Despite the fact that mtROS can promote apoptosis, rarely progress [72]. Oncocytomas normally occur in
depending on their production level, they also behave as endocrine and exocrine tissues (e.g., thyroid, parathyroid,
second messengers for retrograde mitochondrial signaling kidneys, salivary and pituitary glands), and are character-
to the nucleus [54] (Fig. 1). Because mtROS are short-lived ized by mitochondrial hyperplasia seen as a compensatory
and compartmentalized in mitochondria [20], they can mechanism caused by complete inactivation of Complex I
indeed spatially and temporally coordinate a localized activity [72–75]. Further evidence is required to define the
signaling cascade by oxidizing specific amino acid residues overall levels of mtROS in these tumors and their gly-
[55]. One recent example comes from studies in C. elegans colytic rate. Overall, metabolic analyses of oncocytomas
where mtROS promoted cellular adaptation to stress by point at the necessity to maintain residual ETC activity for
stimulating, e.g., the p38-nuclear factor-like 2 (NRF2) tumor invasiveness.
redox-sensitive pathway [56]. This in turn primed the
antioxidant machinery, resulting in increased lifespan of the
nematodes, a phenomenon that has been defined as TCA cycle
mitohormesis [56, 57]. In tumor cells, we found that
mtROS can cause metastasis by activating the proto- The TCA cycle comprises eight consecutive reaction steps,
oncogene Src and the focal adhesion kinase Pyk2, collec- starting from the condensation of acetyl-CoA with a
tively resulting in resistance to anoikis and increased molecule of oxaloacetate by citrate synthase (CS) to form
migration, invasion, metastasis take and spontaneous citrate (Fig. 1). Interestingly, CS expression was found to
metastasis [33, 58]. Consequently, targeting mtROS gen- be increased in pancreatic ductal adenocarcinoma [76] and
eration by complete inhibition of Complex I activity or in metastatic versus benign ovarian carcinoma [77]. Evi-
using specific mitochondria-targeted antioxidants was suf- dence is controversial for its role in metastasis, as it has
ficient to abolish metastasis formation in vivo. The fact that been shown that CS downregulation either decreases (as
mtROS are relevant for metastasis has been broadly seen after transient siRNA knock-down) [77] or increases
demonstrated, from the initial reports indicating that (following stable shRNA expression) [78] invasion. One
metastatic cells accumulate more ROS than untransformed possible explanation for these opposite observations might
cells [59] to the seminal work of Ishikawa et al. [60] be an adaptive phenotype following long-term knock-down
demonstrating that specific ROS-inducing mtDNA muta- of CS.
tions are sufficient to promote metastasis. In the latter The product of the CS reaction, citrate, is then converted
study, increased levels of mtROS activated the anti-apop- to isocitrate by aconitase (Aco). This reaction requires the
totic protein myeloid cell leukemia-1 (MCL-1), a member conversion of citrate into the enzyme-bound intermediate
of the Bcl-2 family promoting tumor cell aggressiveness. cis-aconitate. Aco reactivation is particularly relevant for
To date, several specific mtDNA mutations have been tumorigenesis in prostate cancer, where Aco is normally
reported to trigger tumor progression through the promo- inactivated by the high concentration of zinc ions present
tion of ROS production [61–63]. From a molecular in prostate cells [79]. In vitro, Aco activation has also been
standpoint, several downstream targets of mtROS have associated with the metastatic behavior of PC-3 M human
been identified, including FAK [64], PYK2 [58], SNAIL prostate cancer cells [80].
[65], p38 and NRF-2 [56, 66], nuclear factor-jB (NF-jB) Isocitrate is converted to aKG by IDHs, with the con-
activation mediated by c-Src oxidation [67] and HIF-1 comitant generation of NADH by IDH3 localized in
stabilization through mtROS-mediated prolylhydroxylase mitochondria and NADPH by IDH1 and IDH2 that traffic
(PHD) inactivation [21]. These mediators, in turn promote between the cytoplasm and mitochondria. aKG is not only
increased cell resistance to stress [68, 69]. Due to the a metabolic intermediate of the TCA cycle but also an
particular nature of ROS, it is important to consider mtROS important co-substrate of several enzymes, especially the
in a spatial context. Consequently, there are important vast family of oxygenases that performs functions ranging
caveats to consider when targeting mtROS with general from collagen synthesis to histone demethylation [81]. It is
antioxidants that can alter the total cellular ROS pool in therefore not surprising that aKG controls complex bio-
tumor and host cells and interfere with therapy, explaining logic functions, with, for example, high levels of aKG
the disappointing results of several clinical trials having promoting the maintenance of the pluripotency of embry-
treated cancer patients with general antioxidants [58, 70]. onic stem cells (eSCs) by regulating whole genome
Although, glycolytic compensation following mtDNA methylation [82]. One of the classes of oxygenases
mutation certainly contributes to the pro-metastatic phe- requiring aKG as a co-substrate is PHDs, i.e., prolylhy-
notype [42], it is not sufficient by itself [71]. In droxylases that behave as oxygen sensors. PHD2 in
oncocytoma, for example, total loss of Complex I activity particular tags HIF-1 subunit a for proteasome-mediated
was reported to correlate with the emergence of tumors that degradation under normoxia [83], and low levels of aKG
would therefore theoretically promote normoxic HIF-1 papillary renal cell cancers, sarcomas, pheochromocytomas
activation and tumor progression. aKG also mediates the and paragangliomas [98–100]. Mechanistically, succinate
activation of mammalian target of rapamycin complex 1 and fumarate are competitive inhibitors of aKG-dependent
(mTORC1) in synergy with leucine [84]. It increases the dioxygenases (i.e., enzymes that catalyze the incorporation
lifespan of C. elegans by promoting a moderate mito- of the two atoms of oxygen of O 2 into a substrate). They
chondrial inhibition through binding to ATP-synthase [85]. promote HIF-1 stabilization by inhibiting PHDs [97] and
Biological activities of aKG are thus numerous. Yet, induce a whole genome epigenetic dysregulation by
blocking the anaplerotic reactions supplementing aKG inhibiting both histone demethylases and the ten-eleven
(such as glutaminolysis and alanine transamination) inhi- translocation (TET) family of 5-methlycytosine hydroxy-
bits cell transformation and tumor invasion [26, 86], while lases [5, 101, 102]. Both metabolites thus share a common
supplementation with cell-permeable aKG is sufficient to way of inducing transformation [103]. In addition, fuma-
rescue the clonogenic potential of tumor cells [86]. High rate accumulation results in a spontaneous reaction leading
intracellular levels of aKG are likely pro-metastastic, but to posttranslational modification of cysteines in proteins
because aKG also promotes transformation, specific known as ‘succination’ (i.e., a chemical modification of
research is still required to discriminate between its impact proteins formed by a Michael addition reaction between
on tumor transformation and metastasis. Beyond the fact fumarate and thiol groups) [104]. Succination notably
that it catalyzes aKG production, the IDH reaction is of impairs the function of Kelch-like ECH-associated protein
particular interest because heterozygous mutations of 1 (KEAP1), thus relieving transcription factor NRF2 from
IDH1 and IDH2 are quite common in gliomas [87]. These KEAP1-mediated inhibition and promoting an antioxidant
mutations can result in a neomorphic enzymatic activity response [105, 106]. In contrast, succination can also affect
that allows heterodimeric IDH complexes to catalyze the glutathione, promoting oxidative stress [107]. Despite the
conversion of aKG into the oncometabolite D-2-hydrox- vast influence of succinate and fumarate on epigenetic
yglutarate (D-2HG) [6]. Mutations of IDH1 and IDH2 regulation and signaling pathways, only a limited amount
genes have been found in colon cancer [88], acute myeloid of evidence links these oncometabolites to metastatic
leukemia [89] and enchondroma [90]. Despite the fact that progression. While the experimental re-expression of FH in
D-2HG promotes tumorigenesis by altering DNA-methy- a FH-deficient renal cell carcinoma line impaired tumor
lation genome-wide (primarily by antagonizing aKG- cell migration and invasion in vitro [108], treatment with
dependent dioxygenases) [91], limited evidence links the dimethylfumarate, a cell-permeable form of fumarate,
IDH1 and IDH2 mutations to an increased metastatic strongly reduced invasion and metastasis formation in
potential [92]. melanoma [109–111]. To date, only the loss of SDH5 has
In the TCA cycle, aKG is then sequentially converted to been clearly shown to drive the acquisition of a mes-
succinyl-CoA (with the generation of NADH), succinate enchymal and prometastatic phenotype in lung cancer
(with the concurrent generation of GTP) and fumarate (by cells, further correlating with reduced levels of SDH5 in a
SDH) (Fig. 1). FH then converts fumarate into malate, small group of metastatic versus non-metastatic lung
which is used to generate oxaloacetate by malate dehy- patients [112]. However, no evidence links this effect to the
drogenase. This final reaction produces one additional enzymatic activity of SDH. Rather, SDH5 was found to
molecule of NADH from NAD?. SDH is a macromolecular form a complex with glycogen synthase kinase (GSK-3b, a
complex composed of four different subunits located on mediator of b-catenin degradation) and protein phos-
the internal face of the inner mitochondrial membrane. A phatase A (PP2A): when present, SDH5 activates GSK-3b
major characteristic of this enzymatic complex is that it is and prevents the epithelial-to-mesenchymal transition
shared between the TCA cycle and the ETC where it (EMT). When SDH5 is lost, b-catenin accumulates,
composes Complex II. Indeed, following succinate oxida- translocates to the cell nucleus and promotes EMT [112].
tion, SDH covalently binds a molecule of FAD that is The TCA cycle is amphibolic: it not only mediates
reduced to FADH2, which is followed by the transfer of catabolic reactions aimed at energy production but also
two electrons from FADH2 to ubiquinone (also known as produces precursors for cell growth. Cancer cells are cap-
coenzyme Q [CoQ]), yielding ubiquinol [CoQH2] in the able of reducing aKG to isocitrate, which has been termed
ETC. Mutations of SDH5, the protein responsible for reductive or reverse TCA cycle [113], ultimately increasing
covalently attaching FAD to SDH, are causally linked to citrate and acetyl-CoA levels to promote lipogenesis.
tumorigenesis [7, 8, 93–96] as they lead to accumulation of Glutamine directly fuels this pathway, especially when
succinate, which has been identified as an oncometabolite oxygen is limiting or when mitochondria are dysfunctional
promoting transformation [97]. On the other hand, fuma- [114, 115]. The trigger for such ‘‘anti-clockwise’’ TCA
rate accumulation linked to FH deficiency promotes the cycle has been suggested to be an increased aKG/citrate
formation of hereditary uterine fibroids, skin leiomyomas, ratio [116]. Although this phenotype has been strongly
linked to tumor growth [114, 115, 117–119], little is known overexpression was sufficient to induce resistance to
about the specific contribution of reductive carboxylation apoptosis and the transformation of normal prostate cells in
to tumor metastasis. It has nevertheless been reported that mice [130]. Similarly, ACLY is required for tumor growth
steroid receptor coactivator 2 (SRC2) promotes lipogenesis and its inhibition is a promising strategy for tumor therapy
by stimulating glutamine utilization and reductive car- [131, 132].
boxylation in prostate cancer, and SRC2 is particularly Lipid synthesis is essential for the production of mem-
enriched in metastatic lesions in patients with prostate branes necessary for cell proliferation. In addition to
cancer [120, 121]. In animal models, SRC2 depletion promoting cell proliferation, data indicate that lipid synthe-
strongly reduced tumor cell viability, tumor growth and sis further contributes to tumor progression and metastasis,
spontaneous metastasis. Although, these data suggest that with a strong increase in FASN and ACLY expression in
the metabolic phenotype characterized by a pronounced breast cancer [132, 133], retinoblastoma [134], lung cancer
reductive carboxylation might promote the emergence of [132] and colon cancer [135]. Inhibition of FASN and
aggressive tumor cell clones prone to metastasis, further ACLY was found to impair the metastatic progression of
experiments are required to test this possibility. colon cancer cells by reducing CD44- and hepatocyte
growth factor receptor (HGFR)-mediated signaling, result-
ing in reduced tumor cell migration and clonogenicity on
Lipid metabolism soft agar [136]. Because lipid synthesis endows tumor cells
with an increased resistance to apoptosis [126], tumor cells
Lipid accumulation is so common in tumors that it can by can be expected to rewire their energy metabolism towards
itself be considered as a hallmark of cancer [122]. The increased lipid synthesis to overcome therapy, an
transcription factors, sterol regulatory element-binding adaptation that further confers a more aggressive
proteins -1 and -2 (SREBP-1/-2) are the main transcrip- phenotype. In con- trast, blockade of lipid synthesis can
tional regulators of the lipogenic program, inducing inhibit metastatic dissemination following anti-angiogenic
cholesterol and fatty acid biosynthesis [123, 124]. SREBPs therapy [137]. This observation holds great promise for
are downstream targets of the phosphoinositide 3-kinase future combination therapies since one of the major
(PI3K)–protein kinase B (PKB/Akt)–mTORC1 signaling drawbacks reducing the efficacy of anti-angiogenic therapy
pathway. Their inhibition represses tumor growth by is the induction of metastases [138]. One of the major
depleting lipid rafts at the plasma membrane, thereby future challenges will be the identification of the molecular
impairing Akt activation [125]. Conversely, upregulation mechanisms linking lipid synthesis to the acquisition of
of SREBP expression renders tumor cells more resistant to invasive traits.
apoptosis and makes them more aggressive, especially in Besides the role of lipid synthesis in promoting invasion
conditions where nutrient and oxygen availability are and metastasis, it is becoming clear that fatty acid oxida-
limited [126]. As a matter of fact, the SREBP signature is a tion by itself can also promote metastasis. Indeed, simple
marker of poor prognosis in glioblastoma [126]. Notably, depletion of exogenous lipids is sufficient to impair breast
the mucin 1 oncoprotein (which is overexpressed in breast cancer cell migration in vitro, even in the presence of
cancer and is important for metastatic progression [127, alternative oxidative fuels glucose and glutamine [139].
128]) and SRC2 (which is overexpressed in prostate Similarly, in the non-small cell lung cancer cell line A549,
metastatic lesions [120], see above) are upstream the addition of transforming growth factor b promotes
regulators of SREBPs and, thus, of lipid metabolism. tumor invasiveness by increasing mitochondrial lipid oxi-
Despite, further studies are required to establish a cause– dation [140]. In this model, forced lipid oxidation alone
consequence relationship, regulation of lipid metabolism was sufficient to induce EMT. In agreement, cancer-asso-
and cancer metastasis may thus be intertwined. ciated adipocytes are emerging as key regulators of
Acetyl-CoA is at the crossroad between the TCA cycle metastatic formation in both breast and ovarian cancers
and lipid synthesis, with its production being critical for where they fuel metastases by providing tumor cells with
both metabolic pathways. Essential gatekeepers regulating energy substrates [141, 142].
de novo lipid synthesis are ATP-citrate lyase (ACLY) that
converts citrate to oxaloacetate and acetyl-CoA, and fatty
acid synthase (FASN), a macromolecular complex that Amino acid metabolism
catalyzes the condensation of carbon skeletons into fatty
acids. With a few exceptions, e.g., in liver and mammary Amino acid metabolism is a central part of cellular meta-
glands, FASN expression is low in normal tissues, but it bolic homeostasis. Among all natural amino acids,
increases during transformation [129]. In the prostate, glutamine is one of the most characterized for its role in
FASN demonstrated pro-oncogenic properties, as forced tumor formation and metastasis [9]. This non-essential
amino acid is also one of the most abundant amino acids
present in bodily fluids and one of the most heavily during nutrient deprivation, either by stimulating ATP
depleted amino acid in tumor tissue, indicating the high production or by inducing ROS-mediated autophagy [154].
avidity of tumors for glutamine [143]. Glutaminolysis has This pro-oxidant activity of proline has been proposed to
been proposed to be as important as glucose metabolism in promote mitohormesis [56], i.e., adaptation to stress driven
tumors [144] and is primarily induced by the Myc onco- by mitochondria (see also above). It most probably
gene [145]. The first step of glutamine metabolism is explains the observation that increased proline metabolism
mediated by glutaminases GLS1 and GLS2 that catalyze correlates with invasiveness and resistance to oxidative
the conversion of glutamine to glutamate and ammonia stress in esophageal squamous cell cancer [155]. Along the
(NH3). Glutamate can further be deaminated to aKG by same lines, Comes et al. [156] recently reported that pro-
glutamate dehydrogenase (GDH), with the concurrent line supplementation on its own was sufficient to trigger a
production of one molecule of NADH by GDH1 or genome-wide methylation remodeling and the acquisition
NADPH by GDH2. aKG can then be used in oxidative of an EMT-like phenotype by eSC, promoting eSC
TCA cycling, reductive TCA cycling or as a co-factor for metastasis in vivo.
biochemical reactions, as detailed above. Alternatively, Finally, amino acid metabolism could also promote
glutamate can also be transaminated by the glutamic- metastasis via a tumor cell-extrinsic action. For example,
pyruvic transaminase or by glutamic-oxaloacetic transam- the seminal work of Uyttenhove et al. [157] revealed that
inases (GOT1 or GOT2). GOT2 generates aspartate in the cancer cells can escape immune defenses by stimulating
mitochondria, which may then generate oxaloacetate in the the degradation of tryptophan, an amino acid essential for
cytosol after a second transamination reaction catalyzed by T-cell replication. Indoleamine 2,3-dioxygenase is the main
GOT1. Oxaloacetate is channeled to malate dehydroge- enzyme involved in tryptophan degradation and constitutes
nase, resulting in the production of pyruvate and NADPH. a marker of tumor aggressiveness in ovarian [158], thyroid
This alternative pathway of glutamate has emerged as a [159], breast [160] and skin [161] cancers. In another
critical regulator of the redox balance in pancreatic ductal example, enhanced serine biosynthesis has been associated
adenocarcinoma [146]. Because glutamate can further be with the induction of osteoclastogenesis and increased
used for glutathione synthesis, glutamine metabolism is formation of bone metastases in breast cancer [162],
important not only for energy production but also for redox although the molecular rationale behind this obser- vation
regulation in cancer. Hence, GLS inhibition impairs tumor still remains to be elucidated.
cell migration and invasion [86] and promotes apoptosis in
cells undergoing EMT as a consequence of decreased
resistance to oxidative stress [147]. Concluding remarks
Interestingly, GDH1, the enzyme controlling NAD ?-
dependent glutamate deamination, has been reported to be In eukaryotic cells, mitochondria evolved as gatekeepers
overexpressed in metastases of gallbladder [148] and not only of energy producing metabolism (cataplerosis)
murine hepatocarcinoma [149]. GDH1 is important for but also of biosynthetic metabolism (anaplerosis) and
redox homeostasis as it controls aKG production and the apoptosis. While a vast amount of experimental data point
subsequent generation of fumarate, which activates the at the key role of mitochondria in promoting tumor cell
antioxidant enzyme glutathione peroxidase 1 [150]. Thus, growth and proliferation in primary tumors, a rather
GDH1 has been shown to promote tumor progression by limited number of studies directly addressed their con-
increasing tumor cell resistance to oxidative stress. Its tribution to the metastatic process. The emerging picture
specific contribution to the metastatic process remains to is that while mitochondrial metabolism is hijacked by
be determined. tumor cells to promote cell growth, proliferation, redox
A more complex story of amino acids and their role in homeostasis and survival, mitochondria could also act as
cancer metastasis is that of proline. On one hand, proline bioenergetic sensors conferring migratory, invasive and
oxidase, which catalyzes proline degradation, has been metastatic phenotypes to cancer cells exposed to harsh
identified as a mitochondrial tumor suppressor due to its microenvironmental conditions. Together with de novo
pro-apoptotic properties coupled to increased ROS gener- produced D-2-hydroxyglutarate following specific IDH
ation [151]. Interestingly, the Myc oncogene inhibits mutations, mtROS and TCA cycle intermediates increas-
proline degradation [145], by participating in the accu- ingly produced in (pre)metastatic tumor cells, as well as
mulation of proline in growing tumors [143, 152]. Proline glutamate originating from glutaminolysis, could be
further accumulates in tumors following degradation of the viewed as molecules involved in retrograde signaling
extracellular matrix [153] and elevated proline synthesis in from mitochondria to the cell, suggesting that in certain
glutamine catabolism [145]. On the other hand, proline circumstances, mitochondria could drive cancer
degradation can turn into an important source of energy metastasis.
 The origins of the changes affecting mitochondrial le Cancer (2012-186), the Belgian Federal Agency for Nuclear
metabolism in premetastatic cells, in metastatic progenitor Control (FANC-AFCN), the Louvain Foundation and the UCL Fonds
cells and tumor cells populating the metastatic lesion and Spe´ciaux de la Recherche (FSR). Pierre Sonveaux is a F.R.S.-FNRS
Research Associate, Paolo E. Porporato a F.R.S.-FNRS Postdoctoral
whether they can/must be reversed at specific steps of the Fellow and Vale´ry L. Payen a F.R.S.-FNRS PhD Fellow. Bjorn
metastatic process remain to be determined. They could be Baselet is a grantee of the Belgian Nuclear Research Center
dependent or independent from mutations affecting geno- (SCK·CEN).
mic or mitochondrial DNA. The observation that a
metabolic switch from OXPHOS to glycolysis can also
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