Metabolic reprogramming: the emerging

concept and associated therapeutic

strategies
 Go J. Yoshida

Journal of Experimental & Clinical Cancer Researchvolume 34,

Article number: 111 (2015) | Download Citation

Abstract

Tumor tissue is composed of cancer cells and surrounding stromal cells with diverse
genetic/epigenetic backgrounds, a situation known as intra-tumoral heterogeneity.
Cancer cells are surrounded by a totally different microenvironment than that of normal
cells; consequently, tumor cells must exhibit rapidly adaptive responses to hypoxia and
hypo-nutrient conditions. This phenomenon of changes of tumor cellular bioenergetics,
called “metabolic reprogramming”, has been recognized as one of 10 hallmarks of
cancer. Metabolic reprogramming is required for both malignant transformation and
tumor development, including invasion and metastasis. Although the Warburg effect
has been widely accepted as a common feature of metabolic reprogramming,
accumulating evidence has revealed that tumor cells depend on mitochondrial
metabolism as well as aerobic glycolysis. Remarkably, cancer-associated fibroblasts in
tumor stroma tend to activate both glycolysis and autophagy in contrast to neighboring
cancer cells, which leads to a reverse Warburg effect. Heterogeneity of monocarboxylate
transporter expression reflects cellular metabolic heterogeneity with respect to the
production and uptake of lactate. In tumor tissue, metabolic heterogeneity induces
metabolic symbiosis, which is responsible for adaptation to drastic changes in the
nutrient microenvironment resulting from chemotherapy. In addition, metabolic
heterogeneity is responsible for the failure to induce the same therapeutic effect against
cancer cells as a whole. In particular, cancer stem cells exhibit several biological features
responsible for resistance to conventional anti-tumor therapies. Consequently, cancer
stem cells tend to form minimal residual disease after chemotherapy and exhibit
metastatic potential with additional metabolic reprogramming. This type of altered
metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy.
Collectively, complex and dynamic metabolic reprogramming should be regarded as a
reflection of the “robustness” of tumor cells against unfavorable conditions. This review
focuses on the concept of metabolic reprogramming in heterogeneous tumor tissue, and
further emphasizes the importance of developing novel therapeutic strategies based on
drug repositioning.

Introduction
Tumor tissue consists of a heterogeneous cellular population. Stromal cells such as
neurons, vascular endothelial cells, fibroblasts, and macrophages in cancer tissue drive
chemotherapy resistance [1] as well as tumor survival and progression [2, 3]. Even in
pure populations of tumor cells, heterogeneity is present as a result of genetic mutation
and epigenetic modulations. This cellular heterogeneity can be explained by a
hierarchical model, in which cancer stem-like cells (CSCs) can provide transient
amplifying cells and differentiated non-CSCs involved in establishing the tumor tissue
[4, 5]. CSCs possess several biological features of “stemness”, a combination of
phenotypes including plasticity in the transition between quiescent (G0 phase) and
proliferative states [6] and resistance to redox stress and chemotherapeutic agents
[7, 8]. Importantly, accumulating evidence suggests that metabolic reprogramming is
crucial in order for CSCs to maintain unlimited self-renewal potential and hyper-
adaptation to drastic changes in the tumor microenvironment [9–11].

Intra-tumoral heterogeneity due to the presence of CSCs is primarily responsible for our
inability to induce the same therapeutic effect among cancer cells as a whole [12, 13].
CSCs are very likely to contribute to the formation of minimal residual disease (MRD)
[1]. The term ‘MRD’ is most often used in the context of hematological malignant
disorders [14], but the underlying concept is quite convenient in discussion of clinically
undetectable resistant clones after conventional anti-tumor therapies [1]. Thus, MRD is
expected to contribute prominently to latent relapse and distant metastasis (Fig. 1).

Fig. 1

Cancer stem cells and MRD formation. Heterogeneous tumor tissue with combined-
modality therapy leads to the formation of MRD, which is clinically undetectable.
Transiently reduced heterogeneity is observed in MRD, which is enriched in CSCs.
Relapse or metastasis results in re-acquisition of a heterogeneous population that is
more potentially aggressive in terms of its degree of “stemness”

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Aberrant proliferation of cancer cells is supported by enhanced adaptation to nutrient
microenvironment mediated by alterations in energy metabolism. Consequently,
metabolic reprogramming is believed to be one of the hallmarks of tumor cells in
parallel with genomic instability, tumor-provoking chronic inflammation, escape from
the immune system, etc. [5]. Although aerobic glycolysis, termed the Warburg effect, is a
characteristic metabolic feature of cancer cells [15, 16], recent investigations revealed
that other metabolic features, in particular, the reverse Warburg effect [17, 18],
metabolic symbiosis [19, 20], and addiction to glutamine metabolism [21, 22], create
challenges for anti-cancer treatment due to adaptive or acquired chemoresistance. This
review article focuses on the relationship between metabolic reprogramming and tumor
heterogeneity, as well as on the development of promising therapeutic strategies by drug
repositioning targeting metabolic reprogramming.

Conventional Warburg effect and emerging concepts

In 1924, Otto Warburg discovered that tumor cells tend to produce large amounts of
lactate from glucose, regardless of the available oxygen level [15, 16]. This situation is
similar to anaerobic glycolysis, implying that oxidative phosphorylation (OXPHOS) is
replaced by glycolysis in normal differentiated cells under hypoxia [23, 24]. However,
cancer cells appear to engage in glycolytic metabolism before they are exposed to
hypoxic conditions [15, 16]. OXPHOS in mitochondria generates as many as 36 mol ATP
from 1 mol glucose, whereas the conversion of glucose to pyruvate or lactate produces
only 2 or 4 mol ATP, respectively [25, 26]. It remains unclear why cancer cells largely
depend on this “inefficient” metabolic pathway, even when enough oxygen is available
[27, 28]. In striking contrast to normal cells, cancer cells preferentially uptake and
convert glucose into lactate even in the presence of sufficient oxygen [29]. This
seemingly “inefficient” metabolic characteristic relies largely on aberrant upregulation
of GLUT1, a glucose transporters abundantly expressed in cancer cells [30, 31], although
one contradictory study reported that GLUT1 is not necessarily involved in the Warburg
effect depending on the degree of tumor invasiveness [32]. Inefficient ATP synthesis
becomes an obstacle for cancer cells only when their energy resources are scarce.
However, this is not the case in proliferating cancer cells with aberrant angiogenesis
[29]. Tumor cells finely regulate ATP synthesis by regulating substrate uptake, as well as
enzymes related to glycolysis, which enables them adapt to the nutrient
microenvironment [33]. Moreover, the regulation of adenosine monophosphate-
activated protein kinase (AMPK) signal transduction, a sensor of energy status, is
intimately connected to the Warburg effect, one form of metabolic reprogramming of
cancer cells [34, 35]. Indeed, genetic ablation of AMPK activates mammalian target of
rapamycin (mTOR) signal with ectopic expression of hypoxia-inducible factor-1 alpha
(HIF-1 alpha), resulting in rapid cellular proliferation accompanied by activation of
aerobic glycolysis [35]. This strongly suggests the importance of cancer metabolic
reprogramming in maintaining the interaction between the oxygen-sensing
transcription factor and the nutrient-sensing signal pathway.

Metabolic reprogramming in response to chemotherapy

Tumor heterogeneity in regard to mitochondrial metabolism, in seeming contradiction
to the Warburg effect, is considered to induce the diversity in activated metabolic
pathways [36] (Fig. 2). Notably, MRD in several kinds of cancers is enriched in CSCs,
leading to intra-tumoral heterogeneity and poor prognosis [1, 9, 10, 37]. Non-CSCs of
bladder cancer, for instance, release prostaglandin E2 (PGE2) when they undergo
apoptosis during the course of chemotherapy. PGE2 promotes the awakening of dormant
G0-phased CSCs into the proliferative state [9]. Given that PGE2-mediated metabolic
activation in mitochondria has been demonstrated in non-malignant cells [38], it is
possible that activated CSCs undergo altered metabolic reprogramming (Fig. 3).
Similarly, the survivors after transient depletion of a driver oncogene (i.e., activated
mutant KRAS G12D in pancreatic cancer) tend to depend heavily on OXPHOS in
mitochondria rather than aerobic glycolysis. Comprehensive analysis of metabolic
pathways of survivors after chemotherapy revealed the prominent expression of genes
that regulate mitochondrial function, autophagy and lysosome degradation activity, as
well as a strong reliance on mitochondrial respiration and diminished dependence on
the Warburg effect [10]. Autophagy is a metabolic-recycling pathway involving
proteasome-independent degradation of cellular components (e.g., old and
dysfunctional mitochondria), which is partially responsible for cancer chemoresistance
[39].

Fig. 2

Tumor heterogeneity in metabolism. The degree of addiction to glucose or glutamate

differs among various types of cancer cells. Tumor cells robustly importing glucose via
the GLUT1 transporter are responsible for the high intensity of FDG-PET in the clinical
settings. Cancer cells that express high levels of GLUT1 also induce a low-pH acidic
tumor microenvironment, thereby increasing the invasive potential of tumors

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Fig. 3
Iatrogenic activation of CSCs with altered metabolic reprogramming. Non-CSCs are
susceptible to chemotherapy and undergo apoptosis. Released PGE2 awakens the
dormant CSCs localized in the niche. Proliferating CSCs are likely to exhibit additional
metabolic reprogramming, concomitant with up-regulation of OXPHOS-related
molecules

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Furthermore, malignant melanoma cells that survive and proliferate after treatment
with mutant BRAF (V600E) inhibitor tend to exhibit relative dependence on
mitochondrial metabolism [11]. Because BRAF suppresses oxidative phosphorylation
(OXPHOS), MRD cells up-regulate proliferator-activated receptor-gamma coactivator-1
(PGC1-alpha). The BRAF (V600E)-MITF-PGC1-alpha axis promotes the biogenesis of
mitochondria and causes BRAF-mutant melanoma cells to become addicted to
mitochondrial metabolism [11]. Because histone H3 lysine 4 (H3K4)-demethylase
JARID1B-highly expressing melanoma cells proliferate slowly and are highly dependent
on mitochondrial metabolism [11, 40], chemotherapy-induced metabolic
reprogramming in tumor tissue is likely to be responsible for the enrichment of CSCs in
MRD.

Metabolic interaction driven by tumor heterogeneity

Initially, the concept of Warburg effect was believed to be confined to cancer cells. More
recently, the emerging concept of the “reverse Warburg effect”, however, has attracted
considerable attention. Tumor cell-derived reactive oxygen species (ROS) decrease the
expression of caveolin-1 in cancer-associated fibroblasts (CAFs). CAFs are the major
component of tumor stroma, and as such they express alpha-smooth muscle actin
(alpha-SMA) and are widely recognized to drive tumor progression and metastasis [41].
Loss of caveolin-1 in CAFs results in elevated ROS levels, which in turn stabilize HIF-1
alpha [17, 42]. In brief, cancer cells create “pseudo-hypoxic” conditions for fibroblasts.
Because the transcription factor HIF-1 alpha promotes glycolysis and provides tumor
cells with lactate and glutamate, elevated production of ROS in cancer cells indirectly
induces uptake of intermediate metabolites of the tricarboxylic acid (TCA) cycle in
mitochondria. CAFs consume more glucose and secrete more lactate than normal
fibroblasts. Furthermore, CAFs depend significantly on autophagy, and the activation of
autophagy in tumor stroma leads to chemoresistance [18, 42] (Fig. 4).

Fig. 4

Interaction of caveolin 1-deficient CAFs with tumor cells. Cancer cells induce a pseudo-
hypoxic microenvironment rich in ROS derived from metabolic reprogramming. By
contrast, CAFs negative for caveolin 1 provide tumor cells with lactate, pyruvate, and
ketone bodies. Notably, although cancer cells depend heavily on mitochondrial
metabolism, CAFs exhibit the Warburg effect and activation of the autophagic pathway

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As mentioned above, fibroblasts surrounding epithelial cancer cells undergo metabolic

reprogramming resembling the phenotype associated with the Warburg effect.
Metabolic symbiosis between epithelial cancer cells and CAFs requires that each cell
express a different subtype of monocarboxylate transporter (MCT). Epithelial cancer
cells express MCT1, which contributes to uptake of lactate provided by caveolin1-null
CAFs expressing MCT4 [17, 43]. Tumor cells synthesize pyruvate from lactate, providing
the TCA cycle with an intermediate metabolite. Notably, an extracellular space rich in
lactate reflects acidic conditions, which in turn lead to the formation of pseudo-hypoxic
conditions.
It should be emphasized, however, that this reverse Warburg effect is not necessarily
present in all tumor types. Tumors expressing high levels of MCT4 or mesenchymal
phenotype do not tend to exhibit the reverse Warburg phenomenon. Instead, cancer
cells exhibit hierarchical metabolic heterogeneity: MCT4-expressing tumor cells
perform glycolysis and secrete lactate via MCT4, whereas MCT1-expressing cells import
lactate via MCT1 and perform OXPHOS. In addition, the amount of glucose uptake is
lower in MCT1-positive cancer cells than in MCT4-positive cells [19, 20] (Fig. 5). This
metabolic heterogeneity is referred to as metabolic symbiosis, and this kind of lactate
shuttle is also observed between neurons and astrocytes in the normal brain tissue [44].
It is notable that normal and cancerous tissues share finely regulated mechanisms of
metabolic symbiosis.

Fig. 5

Metabolic symbiosis between oxidative/aerobic tumor cells and hypoxic/glycolytic cells.

Tumor heterogeneity induces a lactate shuttle between hypoxic and oxidative cancer
cells. While MCT4-positive hypoxic cells contribute to formation of an acidic
microenvironment by aerobic glycolysis and secretion of lactate, MCT1-expressing
oxidative cells utilize lactate as a substrate of the TCA cycle, and consequently exhibit
stem-like characteristics. Notably, in contrast with MCT1-positive cancer cells, glucose
uptake is robust in MCT4-expressing cells

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Cancer stem-like cells in metabolic symbiosis

Importantly, well-oxygenated/aerobic cancer cells expressing high levels of MCT1
efficiently produce metabolic intermediates, as well as ATP, by utilizing lactate derived
from hypoxic/glycolytic cells expressing high levels of MCT4. Redox stress is a major
hallmark of cancer tissues that drives robust metabolism in adjacent proliferating
MCT1-positive cancer cells, which are rich in mitochondria, mediated by the paracrine
transfer of mitochondrial fuels such as lactate, pyruvate, and ketone bodies [19, 20]
(Figs. 4 and 5).

Most importantly, genotoxic stress due to chemotherapy or irradiation, which increase

ROS levels, promotes a CSC-like phenotype [45–47]. Because CSCs exhibit a rapidly
proliferating and poorly differentiated phenotype, MCT1-positive cancer cells are likely
to harbor stem-like phenotypes in heterogeneous populations of tumor cells. After all,
activated mitochondrial metabolism produces enough energy not only for self-renewal
by proliferation but also for invasion/distant metastasis, both of which are activated in
CSCs.

Thus, the pharmacological blockage of MCT1 is useful for the treatment of cancer. MCT1
inhibition disrupts metabolic symbiosis, and MCT1-positive aerobic cancer cells can no
longer uptake lactate [20], which suggests that MCT1-positive CSCs play a fundamental
role in maintaining the hierarchy in tumor cellular society, in contrast to MCT4-positive
cells (Fig. 5).

Acquisition of stem-like and malignant phenotypes with metabolic reprogramming

The cooperation of amino acid transporters is necessary for cancer cells to undergo
metabolic reprogramming and maintain stem-like phenotypes. For example, triple-
negative breast cancer (TNBC) cells, which lack estrogen receptor, progesterone
receptor, and the tyrosine kinase receptor HER2, exhibit addiction to glutamine
metabolism due to coordination between the xCT and ASCT2 amino acid transporters
[48, 49]: xCT uptakes cystine in exchange for glutamine, for use in GSH synthesis [7],
whereas ASCT2 uptakes glutamine in a collaborative manner [50]. Glutamine is
simultaneously imported via ASCT2 transporter and exported in exchange for leucine
via the LAT1/4F2 (CD98 heavy chain) antiporter [48]. The glutamine uptake pathway
contributes to the synthesis of alpha-KG, promoting the TCA cycle in mitochondria, as
well as glutamate, thereby promoting synthesis of nucleotides required for cellular
proliferation [48] (Fig. 6). Thus, metabolic reprogramming, which is orchestrated by the
elevated expression and interaction of amino acid transporters, contributes to the
activation of glutamine metabolic reprogramming and protects tumor cells against
accumulation of oxidative stress mediated by cystine metabolic reprogramming.

Fig. 6
Metabolic reprogramming of amino acids due to coordinated transporters. ASCT2/LAT1
and xCT/CD98hc transporter complexes in tumor cells activate the mTORC1-SIRT4-
GDH axis and glutathione synthesis, respectively. The former pathway promotes
conversion of glutamate into alpha-KG, a substrate of the TCA cycle, whereas the latter
pathway maintains redox status

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Remarkably, circulating tumor cells (CTCs) that have undergone metabolic

reprogramming provide themselves with a microenvironment that is favorable for
colonization and distant metastasis. Recent work showed that CTCs derived from colon
adenocarcinoma and positive for CD110, the thrombopoietin receptor, can home to the
pre-metastatic niche and colonize metastatic hepatic tissue due to elevated lysine
catabolism [51, 52]. Lysine degradation provides CD110-positive CTCs with glutamate
and acetyl-CoA, which contributes to the synthesis of anti-oxidant GSH and p300-
dependent LRP6 acetylation, respectively [52, 53]. This metabolic reprogramming
promotes the metastatic potential of CTCs via a reduction in ROS levels, elevation of
self-renewal potential, and activation of the Wnt/beta-catenin signal pathway [52].
Thus, CTCs resemble CSCs during the process of metastasis, at least in terms of the
‘education’ of the pre-metastatic niche. Most importantly, this metastatic phenotype is
supported by lysine metabolic reprogramming.

A subpopulation of cancer cells that depend heavily on aerobic glycolysis robustly

uptakes and consumes glucose, whereas another subpopulation engages in OXPHOS
and glutaminolysis with activated mitochondrial metabolism. The efficiency of lactate
production in the former (MCT4-positive) subpopulation is much higher than in the
latter (MCT1-positive) subpopulation, which relies on OXPHOS and glutamine-derived
TCA cycle in the mitochondria [54] (Fig. 5). Thus, tumor cells tend to decrease
microenvironmental pH via elevated lactate secretion. The acidic tumor
microenvironment induces expression of matrix metalloproteinases (MMPs), especially
MMP-2 and MMP-9 [55]. Thus, metabolic reprogramming remarkably enhances the
invasion and metastatic potentials of cancer cells.

Activation of glutamine metabolism driven by oncogene addiction

Mitochondria plays a much more important role in cancer metabolism than previously
expected, and glutaminolysis is the most common metabolic pathway regulated in this
organelle [56]. Glutaminolysis is the series of biochemical reactions by which glutamine
is catabolized into downstream metabolites, e.g., alpha-ketoglutarate (alpha-KG) and
glutamate. Via the TCA cycle, alpha-KG undergoes catabolism to malate, which is
transported into the cytoplasm and converted to pyruvate, and then ultimately to lactate
[22]. Mechanistically, mTORC1 signaling promotes glutamine anaplerosis via
upregulation of glutamate dehydrogenase (GDH) [57]. SIRT4 is a mitochondrial-
localized member of the sirtuin family of NAD-dependent enzymes that play
fundamental roles in metabolism, stress response and longevity [58]. In regard to
glutaminolysis, SIRT4 is a critical negative regulator for glutamine metabolism in
mitochondria [58], which is down-regulated at the transcriptional level when the mTOR
signaling pathway is activated [57]. Thus, mTOR inhibitors such as rapamycin are
expected to block mTORC1-SIRT4-GDH axis, which is essential for glutaminolysis [57]
(Fig. 6).

As mentioned above, tumor tissue consists of a cellular population that is heterogeneous

in terms of dependency on the Warburg effect and mitochondrial metabolism. Relative
to slow-cycling CSCs, proliferative cancer cells tend to take up a great deal of glutamine,
as well as glucose, for the generation of metabolites [54]. Both aerobic glycolysis and
glutaminolysis are frequently simultaneously activated in malignant cancer cells
[36, 59]. Seemingly paradoxically, however, some cancer cell lines cannot survive and
proliferate in the absence of glutamine, despite the fact that glutamine is a non-essential
amino acids that can be synthesized from glucose [60]. Glutamine is a primary substrate
for the TCA cycle and is required to maintain the redox state via the production of
nicotinamide adenine dinucleotide phosphate (NADPH). Glutaminolysis enables cancer
cells to reduce NADP+ to NADPH, a reaction that is catalyzed by malic enzymes. NADPH
is a required electron donor for reductive steps in lipid synthesis, nucleotide
metabolism, and maintenance of reduced GSH [21]. In this way, metabolic
reprogramming of glutaminolysis enables cancer cells to regulate redox state.

Oncogenic c-Myc mediates elevation of glutaminolysis in cancer cells. c-Myc promotes

both glutamine uptake and glutamine catabolism [61]. Because of c-Myc-mediated
metabolic reprogramming, cancer cells tend to exhibit “glutamine addiction” [48, 61].
This is a typical example of metabolic reprogramming in cancer cells with oncogene-
addiction [62, 63], suggesting a potential “Achilles’ heel” of tumor cells that are addicted
to glutamine metabolism in manner that is mediated by c-Myc.
Therapeutic strategies targeting metabolic reprogramming
Drug repositioning (DR), screening for anti-cancer therapeutic effects of conventionally
administered medications for non-malignant disorders, has attracted a great deal of
attention because the safety and frequency of side effects of these medicines have been
already proven [64]. Proton pump inhibitor (PPIs), for instance, are acid-activated pro-
drugs that inhibit H/K-ATPase expressed in gastric parietal cells and are conventionally
used for the treatment of gastric ulcer [65]. PPIs have exert synergistic effects on
chemotherapy [66] by modulating the acidic microenvironment [67] or down-regulating
microRNAs involved in chemotherapy resistance [68]. Other typical examples of DR
include sulfasalazine [7, 8, 69], itraconazole [70, 71], terfenadine [72, 73], and
simvastatin [74, 75] are described in Table 1. To address their anti-tumor therapeutic
effects in clinical settings, all of those drugs are being tested in clinical trials or
xenograft experiments.

Table 1 Typical examples of conventional drugs as anti-tumor agents

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Here, we will describe in detail the potential effects of metformin as an anti-cancer drug.
DR has revealed, for example, that metformin, an oral drug widely used to treat type 2
diabetes mellitus (DM) [76], prevents tumor growth and development. A large number
of retrospective clinical studies also show that metformin prevents carcinogenesis and
improves clinical prognosis [77–79]. Metformin activates AMPK signal transduction,
which not only decreases insulin resistance in type 2 DM [76] but also blocks AMPK-
mediated mTOR activation even in CSCs [77]. mTOR signals are regulated by amino-
acid transporters, characterized by the L-type amino acid transporter 1 (LAT1; SLC7A5)
and the glutamine/amino acid transporter (ASCT2; SLC1A5) [80, 81], which is why the
AMPK-mTOR axis functions as a sensor of dynamic change in the nutrient/growth
factor microenvironment. In particular, leucine uptake via LAT1 activates the mTOR
signal pathway [81, 82] leading to poor prognosis [83, 84]. Because EpCAM is a
functional CSC marker that forms a complex with amino-acid transporters such as LAT1
[82, 85], it is reasonable that the LAT1 expression level would be positively correlated
with poor prognosis [83, 84]. Therefore, the LKB1-AMPK-mTOR axis is orchestrated by
amino-acid concentration in the tumor microenvironment, and this axis promotes
metabolic reprogramming of cancer cells in response to the microenvironment.

Remarkably, recent investigations have revealed that this anti-type 2 DM drug

suppresses ectonucleotide pyrophosphatase/phosphodiesterase family member 1
(ENPP1). Consequently, metformin can inhibit the generation of the subpopulation of
cancer cells that express high levels of ABCG2, an ATP-binding cassette (ABC)
transporter responsible for active drug efflux. Mechanistically, the cytosolic domain of
ENPP1 is crucial for interaction with ABCG2 at the cellular membrane; thus ENPP1
contributes to drug resistance by promoting the stabilization of ABCG2 [86, 87]. In
addition, metformin induces microRNA-27b-mediated suppression of ENPP1, which
reduces chemoresistance and tumor seeding potential [86]. ENPP1 is widely accepted as
a cause of insulin resistance in type 2 DM [88], emphasizing the significance of drug
repositioning. Collectively, these observations indicate that this anti-DM agent is a
promising means to attenuate the malignant behavior of cancer cells, much like other
drugs conventionally administered for non-cancerous diseases.

Conclusions

The complex and dynamic metabolic reprogramming should be regarded as a reflection

of the “robustness” of tumor cells against unfavorable conditions. Hyper-adaptation due
to metabolic reprogramming of cancer cells is likely to give us a great opportunity to
attack the “shatter point” in heterogeneous tumor tissue. DR enables us to identify
“silver bullets” for the treatment of tumor tissues in metabolically heterogeneous cell
populations. To facilitate development of novel therapeutic strategies, the synergistic
effects of repositioned drugs with conventional anti-cancer agents should be evaluated
in clinical trials in the near future.

Abbreviations

alpha-KG:
Alpha-ketoglutarate
AMPK:
Adenosine monophosphate-activated protein kinase
CAFs:
Cancer-associated fibroblasts
CSC:
Cancer stem-like cell
CTC:
Circulating tumor cells
DM:
Diabetes mellitus
DR:
Drug-repositioning
ECM:
Extracellular matrix
ENPP1:
Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
GDH:
Glutamate dehydrogenase
HIF-1 alpha:
Hypoxic inducible factor-1 alpha
LAT1:
L-type amino acid transporter 1
MCT:
Monocarboxylate transporter
MMP:
 Matrix metalloproteinases
MRD:
Minimal residual disease
mTOR:
Mammalian target of rapamycin
NADPH:
Nicotinamide adenine dinucleotide phosphate
OXPHOS:
Oxidative phosphorylation
ROS:
Reactive oxygen species
TCA:
Tricarboxylic acid