Japanese Dental Science Review (2018) 54, 8—21

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Japanese Dental Science Review

journal homepage: www.elsevier.com/locate/jdsr

Review Article

Cancer metabolism: New insights into

classic characteristics
Yasumasa Kato a,∗, Toyonobu Maeda a, Atsuko Suzuki a,
Yuh Baba b

a
Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, 31-1 Misumido,
Tomita-machi, Koriyama 963-8611, Japan
b
Department of General Clinical Medicine, Ohu University School of Dentistry, 31-1 Misumido,
Tomita-machi, Koriyama 963-8611, Japan

Received 27 February 2017; accepted 1 August 2017

KEYWORDS Summary Initial studies of cancer metabolism in the early 1920s found that cancer cells were
Glycolysis; phenotypically characterized by aerobic glycolysis, in that these cells favor glucose uptake and
Warburg effect; lactate production, even in the presence of oxygen. This property, called the Warburg effect, is
Glutamine considered a hallmark of cancer. The mechanism by which these cells acquire aerobic glycolysis
metabolism; has been uncovered. Acidic extracellular fluid, secreted by cancer cells, induces a malignant
Acidic extracellular phenotype, including invasion and metastasis. Cancer cells survival depends on a critical balance
pH of redox status, which is regulated by amino acid metabolism. Glutamine is extremely impor-
tant for oxidative phosphorylation and redox regulation. Cells highly dependent on glutamine
and that cannot survive with glutamine are called glutamine-addicted cells. Metabolic repro-
gramming has been observed in cancer stem cells, which have the property of self-renewal and
are resistant to chemotherapy and radiotherapy. These findings suggest that studies of cancer
metabolism can reveal methods of preventing cancer recurrence and metastasis.
© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ Corresponding author. Fax: +81 249328978.

E-mail address: yasumasa-kato@umin.ac.jp (Y. Kato).

https://doi.org/10.1016/j.jdsr.2017.08.003
1882-7616/© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Cancer metabolism 9

Contents

1. Introduction ................................................................................................................ 9
2. Glucose metabolism and its regulation......................................................................................9
2.1. Hypoxia .............................................................................................................. 9
2.2. Histone deacetylases (HDACs)........................................................................................9
2.3. Tyrosine and serine/threonine kinases .............................................................................. 11
2.4. Oncogenes and tumor-suppressor genes.............................................................................11
2.4.1. Ras....................................................................................................11
2.4.2. c-Myc ...................................................................................................... 11
2.4.3. The never in mitosis gene A-related kinase 2 (NEK2) ....................................................... 12
2.4.4. p53 ........................................................................................................ 12
2.4.5. c-Met and ErbB2 ........................................................................................... 12
3. Acidic metabolites.........................................................................................................12
3.1. Lactate ............................................................................................................. 12
3.2. Carbon dioxide and carbonic anhydrases (CAs)......................................................................13
3.3. Ketone bodies ...................................................................................................... 13
4. Acidic pHe signaling and metastasis........................................................................................13
5. Amino acid usage in cancer ................................................................................................ 14
5.1. Glutamine .......................................................................................................... 14
5.2. Redox regulation....................................................................................................15
5.3. Activation of mTORC1 .............................................................................................. 15
6. Perspective ................................................................................................................ 16
Conflict of interest ........................................................................................................ 16
Acknowledgments ......................................................................................................... 16
References ................................................................................................................ 16

2. Glucose metabolism and its regulation

1. Introduction 2.1. Hypoxia

Initial studies of cancer metabolism in the early 1920s Tumor cells utilize glycolysis to supply energy, even under
showed that the cancer phenotype for glucose metabolism aerobic conditions, resulting in the conversion of pyruvate
is unique, with increased abilities to take up glucose and to lactate in the extracellular space. Hypoxia stimulates lac-
produce lactate, even under aerobic conditions [1]. This tate production in tumors by activating hypoxia-inducible
pathway, called aerobic glycolysis or the Warburg effect, transcription factor 1␣ (HIF1␣)-dependent expression of
results in extracellular fluid around tumor tissue having genes such as glucose transporter 1 (GLUT1), hexokinase
acidic pH [1,2]. Indeed, the extracellular pH (pHe ) of most 2 (HK2), pyruvate kinase (PK) M2, pyruvate dehydroge-
tumor tissues is around 6.5—6.9, and may be even lower nase kinase 1 (PDK1), enolase 1 (ENO1), and lactate
(e.g., 5.7) in some cases [3—5]. However, despite lactate dehydrogenase A (LDHA) [10—15] (Fig. 1). LDHA converts
production by tumor tissue, blood lactate level is often unaf- pyruvate to lactate and PDK1 inhibits pyruvate dehydro-
fected [6], suggesting that acidity is limited locally to the genase (PDH), which converts pyruvate to acetyl-CoA to
microenvironment around tumor tissue. produce ATP by mitochondrial oxidative phosphorylation
Accumulated evidence about cancer phenotypes has (OXPHOS) [11,16—18]. This pathway facilitates lactate pro-
indicated that all cancers have in common six biologi- duction rather than OXPHOS. Hypoxia also induces the
cal capabilities acquired during multistep development: expression of monocarboxylate transporter 4 (MCT4), which
sustained proliferative signaling, evasion of growth sup- functions as a proton-coupled transporter of lactate across
pressors, resistance to cell death, replicative immortality, cell membranes [19,20]. Thus, hypoxia enhances the War-
induction of angiogenesis, and activation of invasion and burg effect, which is responsible for high lactate secretion
metastasis [7]. Later research has revealed two additional by tumor cells.
hallmarks of cancer: reprogrammed energy metabolism and
evasion of immune-mediated destruction [8]. Recent studies 2.2. Histone deacetylases (HDACs)
have shown that metabolic reprogramming regulates cancer
stemness [9]. Thus, ‘‘cancer metabolism’’ has again become Sirtuins, which are mammalian homologs of the yeast his-
an important research topic. Here, we focus on glucose and tone deacetylase Sir2, are NAD+ -dependent HDACs and con-
glutamine metabolism. sist of seven isoforms (SIRT1—7). These enzymes are involved
10 Y. Kato et al.

Figure 1 Oncogene and tumor suppressor gene products regulate glucose and glutamine metabolism in cancer. Glycolysis is the
main source of ATP production rather than oxidative phosphorylation (OXPHOS) in tumor cells. Glucose transporters and glycolysis
metabolic enzymes are up-regulated by oncogene product c-Myc. It was believed that mutation of p53 causes loss of function. More
recently, p53’s mutation-based ‘‘gain of function’’ has been accepted: e.g., I␬B kinase (IKK) is inhibited by wild type p53 (wtp53) but
activated by mutant p53 (mutp53). Glucose transporter 4 (GLUT4) and phosphoglycerate mutase (PGM1) activities are also regulated
by p53 in the same way. This means reprogramming of which metabolic pathway is directed to lactate when cellular transformation
occurs. This is a significant reprogramming of metabolic pathways during carcinogenesis. Hypoxia accelerates glycolysis dependency
for energy production through activation of hypoxia-inducible transcription factor 1 (HIF1). Malate and oxaloacetate (OAA) in the
TCA cycle can be metabolized to pyruvate in cytosol. Especially, this pathway is important for metabolism of glutamine, rather than
glucose, through ␣-ketoglutarate (␣-KG) (see Fig. 6). Two isozymes of glutamine-OAA transaminase (GOT) are closely associated in
this pathway. ASCT2, neutral amino acid transporter; SIRT6, distant mammalian Sir2 homolog (sirtuin 6); NEK2, never in mitosis gene
A-related kinase 2; NF-␬B, nuclear factor-␬B; HK2, hexokinase 2, TIGAR, TP-53-induced glycolysis and apoptosis regulator; PFK1/2,
6-phosphofructo 1-kinase 1/2; AMPK, AMP-activated protein kinase; ALDA/C, aldolase A/C; TPI, triosephosphate isomerase; GAPDH,
glyceraldehyde-3-phosphate-dehydrogenase; PGK1, phosphoglycerate kinase 1; PGM1, phosphoglycerate mutase 1; ENO1, enolase
1; PKM1/M2, pyruvate kinase M1/M2; LDHA, lactate dehydrogenase A; Nrf2, NF-E2-related factor 2; PDH, pyruvate dehydrogenase;
PDK1, pyruvate dehydrogenase kinase 1; PTEN, tensin homolog on chromosome ten; PINK1, PTEN-induced putative kinase 1; SCO2,
cytochrome c oxidase assembly factor 2; GLS1/2, glutaminase 1/2; GLUD1, glutamate dehydrogenase 1; TCA cycle, tricarboxylic
acid cycle.

in resistance to cellular stress, genomic stability, energy of expression of GLUT1, 6-phosphofructo 1-kinase/fructose
metabolism, aging and tumorigenesis. SIRT6, which deacety- 1,6-biphosphatase (PFK1/FBPase1), aldolase c (ALDOC),
lates histone H3K9, is significantly associated with glucose PDK1 and LDHA, whose expression can also be up-regulated
metabolism, elevating glucose up-take through induction by HIF1 as described above [21,22] (Fig. 1).
Cancer metabolism 11

SIRT2 directly binds ␤-catenin in response to oxidative

stress, inhibiting the expression of Wnt target genes such
as survivin, cyclin D1, and c-Myc [23]. Therefore, SIRT2 may
contribute to glycolysis through c-Myc.
HDAC inhibitors promote histone acetylation and stim-
ulation of gene expression in tumor cells; for example,
they increase the expression of p21waf1 and insulin-like
growth factor-I receptor, and reduce the expression of
cyclin D1, AKT, and the tensin homolog on chromo-
some ten (PTEN) [24—26]. PTEN is a phosphatase that
acts on phosphatidylinositol 3,4,5-triphosphate and antago-
nizes phosphatidylinositol 3-kinase (PI3K) function, thereby
inhibiting signaling by PI3K/AKT/the mechanistic target of
rapamycin (mTOR, formerly known as the mammalian tar-
get of rapamycin). Importantly, the complex of PTEN with
PTEN␣, an N-terminal extended isoform of PTEN, is involved
in electron transfer reactions in the respiratory-chain, pro-
ducing ATP by inducing the expression of PTEN-induced
putative kinase 1 (PINK1) followed by activation of the
cytochrome c oxidase complex [27]. The anti-tumor agents
vorinostat and romidopsin, which inhibit HDAC [28—30],
have been approved worldwide for the treatment of patients
with cutaneous T-cell lymphoma and also head and neck
carcinoma [28,31—33].

2.3. Tyrosine and serine/threonine kinases

PKM1 and PKM2 are enzymes that convert phospho- Figure 2 Increase in pyruvate kinase M2 (PKM2)/PKM1 ratio
enolpyruvate to pyruvate. PKM1 is constitutively active, by phosphorylation of tyrosine residue directs to glycine pro-
whereas PKM2 can be regulated by phosphorylation. Inter- duction. (A) PKM2 activity is regulated by phosphorylation in
estingly, phosphorylation at tyrosine or serine residues contrast to constitutively active PKM1. Phosphorylation of tyro-
has been found to differentially regulate PKM2 activity sine (Tyr) residue activates it whereas that of serine (Ser)
(Fig. 2). For example, fibroblast growth factor recep- residue inhibits it. (B) When PKM2/PKM1 ratio increases, the
tor 1 (FGFR1) directly phosphorylates tyrosine residues of metabolic pathway directs to pyruvate (continues glycolysis).
PKM2, inhibiting the formation of active, tetrameric PKM2 When the ratio decreases, glycolysis is prevented and metabolic
by disrupting the binding of PKM2 cofactor fructose 1,6- direction changes to serine followed by glycine. Glycine con-
biophosphate [34]. In contrast, the pp60src kinase, which densates with ␥-glutamylcysteine for glutathione synthesis (see
increases tyrosine phosphorylation of PKM2, inactivates Fig. 6).
the latter [35,36]. Thus, tyrosine kinase phosphorylation
by growth factor signaling inhibits PKM2, resulting in the
progression of anabolic metabolism in proliferating cells
2.4. Oncogenes and tumor-suppressor genes
[34,37]. Tyrosine phosphorylation-mediated inhibition of
PKM2 has been reported to result in the accumulation of 2.4.1. Ras
3-phosphoglycerate, resulting in the accumulation of serine Ras is a small G-protein that transmits signals of growth
followed by glycine. Glycine, along with cysteine and glu- factors, such as epidermal growth factor (EGF) and hepato-
tamate, are used to produce glutathione, which neutralizes cyte growth factor (HGF), and enhances glycolysis through
the effects of reactive oxygen species (ROS), as described the induction of HIF1␣ expression. K-Ras/B-raf signal
below. increases the transcription of Nrf2, which up-regulates the
In contrast to tyrosine phosphorylation, phosphorylation PKM2/PKM1 ratio and glycolytic enzymes [42] (Figs. 1 and 2).
of serine residues on PKM2 by serine/threonine kinases Nrf2 inhibits lipogenesis but increases NADPH regeneration
such as A-Raf and protein kinase ␦ (PKC␦) induces the for- and purine biosynthesis [43].
mation and stabilization of the tetrameric active form of
PKM2 [38,39]. Pim is a serine/threonine kinase that con- 2.4.2. c-Myc
sists of three isoforms (Pim-1, Pim-2 and Pim-3). Pim-2 c-Myc is a transcription factor that up-regulates the expres-
directly phosphorylates PKM2, which stimulates glycolysis sion of nucleotide metabolic enzymes [44] and cell cycle
and reduces mitochondrial respiration [40]. In addition, Pim- regulator proteins such as E2Fs and cyclins [45], and down-
2 induces the expression of genes targeted by HIF1 through regulates cyclin-dependent kinase inhibitors such as p15,
the activation of mTOR complex 1 (mTORC1) as described p21, and p27 [45]. c-Myc is one of the ‘‘Yamanaka factors’’
below [41]. in the original protocol for production of induced pluripotent
12 Y. Kato et al.

stem cells (iPS cells); this protocol has since been modified, above, signaling pathway of c-Met is shared with that
with c-Myc replaced by non-transforming L-Myc to prevent of erbB2 (EGF receptor): e.g., Ras/Raf signaling modu-
the risk of tumor formation by iPS-derived tissue [46,47]. lates PKM2/PKM1 ratio (Fig. 2) and PI3K-AKT-mTOR signaling
c-Myc directly induces the expression of genes encod- upregulates HK2 through HIF1 and c-Myc expression (Fig. 1,
ing glycolysis-related metabolic enzymes and transporters, see also Fig. 7). c-Met expression is induced by not only
including GLUT1, PFK2/FBPase2, PKM2, PDK1, ENO1, and HIF1 [65] but also wtp53 [66]. Interestingly, mutp53R175H ,
LDHA; and, together with HIF1, stimulates the expression of a common mutant, remains inducible function for c-Met
HK2 [10,11,13—15,48] (Fig. 1). Although c-Myc can synergis- expression but other mutants cannot [67]. In addition, c-
tically stimulate HIF1-induced HK2 expression, c-Myc alone Met is tightly associated with TIGAR expression and NADPH
has little effect on the induction of HK2 [10,12,48]. production [68]. Thus, growth factor signaling such as HGF
and EGF are strongly associated with glycolysis. Although
2.4.3. The never in mitosis gene A-related kinase 2 anti-cancer drugs targeting those receptor tyrosine kinases
(NEK2) have been developed and obtained clinical trials, and some
NEK2 is a transcription factor that promotes aerobic glycol- of them were approved in head neck cancer (e.g., cetuximab
ysis by increasing the PKM2/PKM1 ratio and by enhancing and erlotinib for EGF receptor and crizotinib for HGF recep-
the expression of GLUT4, HK2, ENO1, and LDHA [49] tor) [69], clinical efficacy of those drugs seems to include
(Figs. 1 and 2). All of these genes are also targeted by c-Myc the effect on glycolysis.
and HIF1.
3. Acidic metabolites
2.4.4. p53
The transcription factor p53 is a major product of the TP53 3.1. Lactate
tumor suppressor gene. Although wild type p53 (wtp53) sup-
presses the expression of GLUT1 and GLUT4, mutant p53 The distribution of lactate in frozen sections of clini-
(mutp53) enhances their expression which is known as the cally obtained tumor tissue has been successfully visualized
gain of function [50] (Fig. 1). Similarly, mutp53 upregulates using the induced metabolic bioluminescence imaging (imBI)
phosphoglycerate mutase 1 (PGM1) whereas wtp53 inhibits technique [70,71]. These studies showed that lactate con-
it [51]. HK2 induction has only been seen for mutp53 [52]. centrations in tumor tissue vary widely, from 10—20 to over
On the other hand, wtp53 upregulates the expression of the 30 ␮mol/g-tissue weight, corresponding approximately to
TP-53-induced glycolysis and apoptosis regulator (TIGAR), 10—20 mM and >30 mM, respectively. Moreover, assessments
which functions as PFK2 [53]. TIGAR, in turn, inhibits the of clinical biopsy samples of primary cervical and head and
production of fructose 2,6-bisphosphate, an activator of neck cancers showed that survival was significantly longer
PFK1 [54], thereby inhibiting glycolysis and directing the in patients with low than with high median lactate levels
metabolism of glucose to the pentose phosphate pathway. [72,73]. These studies also showed a positive correlation
This results in the production of NADPH, which protects cells between lactate concentration and the incidence of both
against ROS-associated apoptosis [53]. TIGAR knockdown recurrence and metastasis, suggesting that lactate not only
has been shown to radiosensitize glioma cells by inhibiting fuels tumor growth but survival and metastasis after uptake
the nuclear translocation of thioredoxin-1, a redox-sensitive into the cytoplasm through MCT1/SLC16A1.
oxidoreductase [55]. Nucleoredoxin, a thioredoxin-related Lactate is produced not only by tumor cells but by fibrob-
oxidoreductase, has been reported to inhibit PFK1 activity, lasts in tumor tissue [74] (Fig. 3). These fibroblasts are
suggesting that nucleoredoxin is a regulator of the bal- ‘‘educated’’ by tumor cells, such that their properties differ
ance between glycolysis and the pentose phosphate pathway from those of ‘‘normal’’ fibroblasts. These educated fibrob-
[56]. In mitochondria, wtp53/mutp53 induces expression of lasts are also called cancer-associated fibroblasts (CAFs).
cytochrome c oxidase assembly factor 2 (SCO2), which reg- Because tumor cells can take up lactate through MCT1, CAFs
ulates the cytochrome c oxidase complex associated with supply energy to tumor cells via lactate and stroma-derived
oxidative phosphorylation [57,58]. Regulation of redox state lactate sustains tumor progression [75,76].
by wtp53/mutp53 has also been found to induce expression Lactate also functions as a ligand that binds to G-protein-
of glutaminase 2 (GLS2), which contributes to glutathione coupled receptor 81 (GPR81/HCAR1) [77] (Fig. 3). GPR81
production [59]. Loss of wtp53 activates nuclear factor ␬B expression is high in several tumor types and promotes the
(NF-␬B), thereby increasing GLUT3 expression and enhanc- malignant phenotype of breast cancers [78]. Silencing of
ing glycolysis [60]. Interestingly, insulin-dependent GLUT4 GPR81 was found to inhibit tumor growth and metasta-
expression has been observed in gastric [61] and lung [62] sis in vivo by downregulating the expression of MCT1, a
cancers. GLUT4 expression can be increased by loss of wtp53 receptor essential for lactate up-take [79]. GPR81 signal-
function [50]. Because expression of insulin receptor is ing induced angiogenesis in breast cancers by activating
higher in cancer cells than in normal cells [63,64], GLUT4 the PI3K/AKT pathway, thereby inducing the expression
is thought to be associated with tumor development and of several genes, including those encoding amphiregulin,
progression. platelet-derived growth factor-BB (PDGF-BB), urokinase
type plasminogen activator (uPA) and vascular endothelial
2.4.5. c-Met and ErbB2 growth factor (VEGF); whereas GPR81 knockdown impaired
The Met and ERBB2, which are proto-oncogene, encode cell proliferation and increased apoptosis [78]. Thus, lactate
receptor tyrosine kinases knowing as HGF receptor (c- supports survival, growth, and metastatic behavior through
Met) and EGF receptor (ErbB2), respectively. As mentioned GPR81 signaling.
Cancer metabolism 13

Among the CAs, CAIX has been well studied in cancers.

CAIX, a CA9 gene product, has been categorized as an ␣
class CA and exists as a homodimer. This enzyme consists
of a unique extracellular proteoglycan domain, a trans-
membrane domain and an intracellular catalytic domain,
whereas CA II exists in cytosol [93,94]. The promoter region
of CA9 contains a hypoxia-responsive element, with CA9
mRNA expression upregulated by HIF1 [95]. CAIX is highly
expressed in tumors and is thought to be tightly associated
with primary cancer development, progression and metas-
tasis [96—100].
TACE/ADAM17 has been found to induce the shedding of
the extracellular domain of CAIX, also called soluble CAIX
[101]. This molecule has been detected in the sera of cancer
patients and has been shown diagnostic and/or prognostic
in several cancers, including head and neck cancer [102],
breast cancer, prostate cancer [103], renal cell carcinoma
[104—106], ovarian cancer [107], gastric cancer [108], rectal
cancer [109], and non-small cell lung cancer [103,110].

Figure 3 Cell to cell communication by proton and acidic 3.3. Ketone bodies
metabolites (lactate and ␤-hydroxybutyrate). Carbonic anhy-
drase (CA) catalyzes H2 O and CO2 yielding H2 CO3 followed by H+ Ketone bodies consist of acetoacetate, ␤-hydroxybutyrate,
and HCO3 − . CA II and CA IX are located on the cytosol and plasma and acetone, although ␤-hydroxybutyrate is not a ketone
membrane, respectively. Intracellular H+ is secreted by vacuolar compound. Ketone bodies are abundant in the liver and are
type-ATPase (v-ATPase), Na+ /H+ exchanger 1 (NHE1). Mono- observed during diabetic ketoacidosis in children with type
carboxylate transporter (MCT) functions as the lactate/H+ or 1 diabetes mellitus [111]. Although lipolysis is increased in
␤-hydroxybutyrate (␤OHB)/H+ co-transporter. MCT1 and MCT4 adipocytes of tumor patients, due to the high consumption
are associated with their up-take and secretion, respectively. of blood glucose by tumor cells, the blood levels of ketone
Intracellular HCO3 − can be secreted by Cl− /HCO3 − exchanger, bodies from the liver are not obviously enhanced [6]. Ketone
which is not shown in this figure. Upper cell: tumor cells in nor- bodies, however, may be secreted by CAFs and utilized
moxia and sufficient nutrition due to proximity to blood vessels. by tumor cells, suggesting that ketone bodies are impor-
Lower cell: cancer-associated fibroblasts (CAFs) or tumor cells tant in the microenvironment of tumor cells [74,112,113].
in hypoxic and inadequate nutrition due to distance from blood Moreover, similar to lactate, ketone bodies function as lig-
vessels. ands of GPR41/FFAR3, GPR43/FFAR2, GPR81/HCAR1, and
GPR109a/HCAR2 [77,114] (Fig. 3).
Although lactate enhances the malignant behavior of
3.2. Carbon dioxide and carbonic anhydrases (CAs)
tumor cells, ketone bodies have the opposite clinical effect,
with a ketogenic diet prolonging the overall survival rate of
Once incorporated into cells, glucose is converted to glu-
patients with glioma [115—118]. Administration of a keto-
cose 6-phosphate, which is metabolized by the glycolytic
genic diet has been thought to reduce the consumption of
and pentose phosphate pathways; the latter, called the
glucose, as ketone bodies supply an abundant amount of
secondary pathway of glycolysis, results in the produc-
acetyl-CoA. Furthermore, ␤-hydroxybutyrate functions as
tion of ribose 5-phosphate and NADPH [80]. This pathway
an endogenous and specific inhibitor of HDACs when incor-
results in the production of one molecule of CO2 from one
porated into its transporter, such as MCT1/SLC16A1 and
molecule of glucose 6-phosphate, whereas glycolysis of glu-
sodium-coupled MCT1 (SMCT1/SLC5A8) [119].
cose 6-phosphate does not produce CO2 . Tumors express high
A study using a mouse glioma model found that a keto-
amounts of CAs, which catalyze the reaction of CO2 with
genic diet reduced the expression of the HIF-1A and CA9
H2 O to produce H2 CO3 , which dissociates to H+ and HCO3 − .
genes and the activation of NF-␬B, as well as suppressing
Experiments in glycolysis-impaired mice showed that CO2
angiogenesis, invasive potential and vascular permeability
derived from the pentose phosphate pathway was a main
[120]. These findings suggested that, in contrast to lactate,
cause of extracellular acidity in tumors [81]. The intracel-
ketone bodies have anti-tumor activity.
lularly yielded H+ from the dissociation of H2 CO3 secretes
into extracellular space through a proton pump/vacuolar-
type ATPase (v-ATPase) [82—84] or an Na+ /H+ exchanger 4. Acidic pHe signaling and metastasis
[85,86], whereas the HCO3 2− is secreted through a chlo-
ride exchanger coupled with an Na+ /H+ exchanger [87,88] Hyaluronidases and cathepsins have optimal activity at
(Fig. 3). Interestingly, glucose stimulates the assembly of acidic pH, allowing their efficient digestion of extracellu-
the V0 and V1 domains of v-ATPase through PI3K, result- lar matrices in an acidic pHe microenvironment [121—123].
ing in its activation [89]. Na+ /H+ exchangers localize to the Acidic pHe also affects cellular activity through an as yet
invadopodia (invasion front) [90], resulting in the front cell incompletely identified intracellular signaling cascade. Acid
surface being more acidic than the rear [91,92]. sensing ion channel 1a (ASIC1a) is an H+ gated cation chan-
14 Y. Kato et al.

(p38 and ERK1/2) and NF-␬B is common in mice and humans

[130,131]. Moreover, acidic pHe also stimulated acidic sphin-
gomyelinase activity, the activation of which is independent
of intracellular Ca2+ , as well as contributing to NF-␬B acti-
vation [132]. Acidic pHe signaling was recently shown to
upregulate the expression of PLD isozyme type 1 (PLD1),
but not type 2 (PLD2) via activation of rhoA [133]. Phos-
phatidate, which is a PLD product, was reported to show
survival signaling by activating mTOR and inhibiting MDM2,
the ubiquitin ligase of p53 [134,135].
We found that acidic pHe changes the morphology of
cancer cells to fibroblastic, as shown by the induction of
matrigel invasion; up-regulation of MMP-9, vimentin, MMP-3,
and MMP-13 gene expression; and down-regulation of E-
cadherin expression [127,136]. These findings indicated that
acidic pHe induces epithelial mesenchymal transition (EMT),
an important event in the development of a metastatic phe-
notype [136]. Similar, others have also reported that acidic
pHe induced EMT-like changes [130,137].
Acidic pHe may contribute to drug resistance through
Figure 4 Acidic pHe signaling. In acidic pHe signaling, Ca2+ ASIC1a/Ca2+ /PI3K/AKT/mTOR signaling. Moreover, drugs
influx may be common in various tumor cells. Increase in that inhibit this signaling may have efficacy in suppress-
intracellular Ca2+ causes activation of phospholipase D and ing acidic pHe −mediated malignant phenotype. Antitumor
two mitogen-activated protein kinases (MAPKs) (extracellular drugs that inhibit the PI3K/AKT/mTOR pathway are cur-
signal-regulated kinase (ERK) 1/2 and p38) followed by nuclear rently being tested in clinical trials, with some, such as
factor-␬B (NF-␬B) activation. NF-␬B is also activated by acidic BEZ235, approved for treatment [138]. These drugs are
sphingomyelinase (aSMase) independent of Ca2+ influx. expected to effectively suppress the acidic pHe -associated
malignant phenotype of human cancer cells.
nel. Its activation by acidic pHe results in Ca2+ influx, thereby
activating calmodulin-dependent protein kinase II [124].
Ca2+ influx through ASIC1a also activates PI3K/AKT signal- 5. Amino acid usage in cancer
ing, which has been associated with resistant to anticancer
drugs [125]. PI3K/AKT signaling, in turn, activates mTOR, 5.1. Glutamine
which has been associated with various diseases, including
cancers [126]. Glutamine is most abundant amino acid in the blood, with a
We have reported that acidic pHe -triggered Ca2+ influx concentration of about 0.57 mM [139]. Following its uptake
activates phospholipase D (PLD); two mitogen activated by cells, glutamine is metabolized to the non-essential
kinases (MAPKs), p38 and extracellular signal-regulated amino acid glutamate by the cytoplasmic enzyme glutam-
kinase 1/2 (ERK1/2); and the NF-␬B pathway, resulting in inase [140]. There are two isozymes of glutaminase, namely
the induction of matrix metalloproteinase-9 (MMP-9) expres- kidney type (mitochondrial enzyme) encoded by GLS1, and
sion [127—129] (Fig. 4). The MMP-9 induction rate was found liver type (cytoplasmic enzyme) encoded by GLS2 [141].
to correlate with cellular metastatic activity in mouse B16 Glutamine metabolism is regulated by oncogene and tumor
melanoma cells. Acidic pHe -induced activation of MAPKs suppressor gene products dependent on cell cycle status

Figure 5 Cell cycle dependent glutamine metabolism. Glutamine to ␣-ketoglutarate is metabolized by different enzymes depend-
ing on cell cycle status. (A) Oncogenic molecules such as c-Myc and K-ras activate glutaminase 1 (GLS1) and glutamine-oxaloacetate
transaminase 2 (GOT2) in proliferating cells. K-ras inhibits glutamate dehydrogenase 1 (GLUD1). Thus, GLS1 and GOT2 are major
metabolic enzymes in proliferating cells. (B) Wild type p53 (wtp53) not only increase in the cyclin-dependent kinase inhibitor p21
but also glutaminase 2 (GLS2). GLUD1 is not inhibited by K-ras in quiescent cells, thereby metabolizing by GLS2 and GLUD1.
Cancer metabolism 15

Figure 7 Regulation of mTORC1. mTORC1 comprises five

molecules: mTOR; the regulatory associated protein of mTOR
Figure 6 Glucose and glutamine metabolism in redox pre- (RAPTOR); the DEP domain containing mTOR interacting protein
vention. Production of NADPH is mainly obtained from glucose (DEPTOR); the proline-rich Akt substrate of 40-kDa (PRAS40);
metabolism (the pentose phosphate pathway) and glutamine and the mammalian lethal with SEC13 protein 8 (mLST8). Glu-
metabolism (pathway from malate to pyruvate) through part tamine activates mTORC1 through ADP-ribosylation factor 1
of the TCA cycle. Glutathione is a tripeptide comprising gluta- (ARF1) but leucine and arginine does through Rag small G pro-
mate, cysteine, and glycine. OAA, oxaloacetate; Asp, aspartate; teins. mTORC1 promotes mRNA translation and protein synthesis
␣-KG, ␣-ketoglutarate. through inhibition of the eukaryotic translation initiation fac-
tor 4E-binding protein (4E-BP1) and activation of the ribosomal
(Fig. 5). Glutamate is subsequently metabolized by gluta- protein S6 kinase (S6 K). It also inhibits ULK1 and HIF1␣ which
mate dehydrogenases (GLUDs) to ␣-ketoglutarate, which induce autophagy and glycolysis, respectively. mTORC1 induces
enters the tricarboxylic acid (TCA) cycle and can be metab- inflammation and lipid synthesis through NF-␬B and the sterol
olized to aspartate and malate (Fig. 6). Glutamine can also regulatory element binding protein 1 (SREBP1), respectively.
be used as an energy source by OXPHOS through NADH and
FADH2 . Glutamine and aspartate are nitrogen donors in the family kinases, thereby increasing metastatic activity
synthesis of purine and pyrimidine bases and aspartate also [131,153,154]. Although glutathione-mediated antioxidant-
provides the carbon skeleton for pyrimidine bases [142]. The targeting therapy was expected to be useful in treating
survival of some types of cancer cells depends on glutamine, cancer patients, recent studies showed that antioxidants
a phenomenon known as glutamine addiction that is driven accelerate tumor malignant phenotypes, including those
by redox balance [143]. c-Myc activation induces the expres- associated with metastasis [155—158]. These findings sug-
sion of the glutamine transporter ASCT2, glutaminase, and gest that intracellular redox status is critical for tumor
several glycolytic enzymes, as described above, thereby pro- survival and malignant phenotype [159].
moting glutaminolysis and triggering cellular addiction to
glutamine as a bioenergetic substrate [144] (see Fig. 1).
5.3. Activation of mTORC1

5.2. Redox regulation PI3K/AKT signaling activates mTOR, resulting in cell survival
and growth [160]. mTORC1 comprises five molecules; mTOR;
Glutathione is a tripeptide consisting of cysteine, gluta- the regulatory associated protein of mTOR (RAPTOR); the
mate, and glycine. Glutathione S-transferase contributes DEP domain containing mTOR interacting protein (DEPTOR);
to drug resistance [145]. Glutathione peroxidase oxidizes the proline-rich AKT substrate of 40-kDa (PRAS40); and the
glutathione in the presence of NADPH, with the resulting mammalian lethal with SEC13 protein 8 (mLST8) [161,162].
oxidized glutathione being a substrate of the enzyme glu- PI3K/AKT/mTOR signaling also induces expression of HIF1␣
tathione reductase to neutralize H2 O2 . Thus, glutathione and c-Myc [163—166], the activities of which are associated
plays major role in scavenging ROS [146—150]. Thioredoxin with glycolysis, as described above. Aberrant amino acid
reductase is another NADPH dependent enzyme that neu- signaling promotes growth and metastasis through Rab1A-
tralizes free radicals [151]. NADPH can be supplied by the dependent activation of mTORC1 [167].
pentose phosphate pathway and by the metabolic path- Glutamine, leucine, and arginine are the most potent
way synthesizing pyruvate from malate (Fig. 6). Glutamine stimuli of mTORC1 activation, resulting in autophagy [168].
can be metabolized to malate through ␣-ketoglutarate and Glutamine up-regulates the small G-protein ADP ribosyla-
aspartate [140]. tion factor 1 (ARF1), thereby activating mTOR (Fig. 7).
Increased glutathione concentrations contribute to the Unlike glutamine, leucine and arginine stimulate the recruit-
absorption of free radicals and are associated with tumorige- ment of mTORC1 to the surface of lysosomes, with the
nesis, angiogenesis, and drug resistance [146—148,150,152]. small G-proteins RagA/B affecting kinase activation. The
Acidic pHe enhances the formation of ROS by a path- GTP-binding protein RheB increases mTOR kinase activ-
way independent of MAPKs (p38 and ERK1/2) and Src ity [162,169]. In contrast, wtp53 activates AMP-activated
16 Y. Kato et al.

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