Gene 726 (2020) 144158

Contents lists available at ScienceDirect

Gene
journal homepage: www.elsevier.com/locate/gene

Review

Crucial players in glycolysis: Cancer progress T

⁎
Zaka Abbaszadeh, Selin Çeşmeli , Çığır Biray Avcı
Ege University, Medical School, Department of Medical Biology, Turkey

A R T I C LE I N FO A B S T R A C T

Keywords: Cancer is the second most important cause of death and new therapy modalities continue to be developed and
Glcolysis evolved. Cancer cells’ metabolism is far different from the normal, healthy cells; they are more metabolically
Oxidative phosphorylation (OXPHOS) active, have higher proliferation rate and could able to resist to cell death pathways like apoptosis. It is known
Cancer that in addition to increasing the expression of enzymes that are crucial in glycolysis for much more energy
Glycolytic enzymes
production, cancer cells produce energy from lactic acid fermentation after glycolysis. In 1920s, Warburg has
claimed that cancer cells are more active in glycolysis than normal cells and use much more glucose in order to
obtain more ATP for metabolic activities, then this is named as Warburg effect. After that; new methodologies
and therapeutics that target metabolism, began to be attractive subject in cancer studies. Therefore, the main
genes, enzymes and factors are begun to investigate and further studied for understanding their roles in meta-
bolism of cancer cells.

1. Introduction some cancer types (Ancey et al., 2018).

1.1. Glucose transporters
Solute carriers (SLC) which are integral membrane transport pro-
teins and responsible for carrying metabolites, include glucose trans-
porters. Glucose transporters allow glucose and other nutrient sources
to enter from the hydrophobic cell membrane, they have two families
that are secondary active Na+/glucose cotransporter (SGLT) and fa-
cilitative sugar transporter (GLUT). SGLT family has two members that
are SGLT1 and SGLT2, and their expression is found to be decreased in
There are 14 GLUT proteins and they are grouped into three classes,
these different GLUTs are responsible in development of embryo and
have different affinities for glucose, fructose and mannose. In cancer
cells, glucose uptake is higher than healthy cells and it is achieved by
the GLUTs, specially by GLUT1. Therefore, the overexpression of
GLUT1 that is maintained by growth factors, is thought to be associated
with malignancy. In addition, as the growth factor deprivation occur in
the healthy cells, GLUT1 is internalized in lysosomes and degraded;
therefore, glucose uptake and metabolism decrease, and cells die. On
the other hand, cancer cells overexpress GLUT1 and glucose

Abbreviations: Abhd5, α/β-hydrolase domain containing 5; Acetyl-CoA, acetyl coenzyme A; ADP, adenosine diphosphate; AMPK, adenosine monophosphate ac-
tivated protein kinase; ATP, adenosine triphosphate; CAV1, caveolin-1; c-Met, tyrosine-protein kinase Met or HGFR; CO2, carbon dioxide; CRC, colorectal cancer;
DERL3, derlin-3; DHAP, dihydroxyacetone phosphate; DNA, deoxyribonucleic acid; EGFR, epidermal growth factor receptor; EMT, epithelial–mesenchymal tran-
sition; ENO, enolase; FH, fumarate hydratase; F-1,6-P, fructose-1,6-biphosphate; GAPDH, glyceraldehyde phosphate dehydrogenase; GLUTs, glucose transporters;
GLUT1, glucose transporter-1; GLUT3, glucose transporter-3; GLUT4, glucose transporter-4; GRP78, glucose-regulated protein 78; GTPase, guanosine tripho-
sphatases; G3P, glyceraldehyde-3-phosphate; G6P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; HGFR, hepatocyte growth factor receptor; HIF,
hypoxia-inducible factor; HIF-1, hypoxia-inducible factor-1; HIF-1α, hypoxia-inducible factor-1α; HK, hexokinases; HMGA1, High Mobility Group AT-Hook 1; HRE,
hypoxia responsible element; HSPs, heat shock proteins; H2B, histone 2B; IDH1, isocitrate dehydrogenase 1; LDH, lactate dehydrogenase; LncRNA, long non-coding
RNA; LUAD, lung adenocarcinoma; miRNAs, MicroRNAs; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; NAD, nicotinamide adenine dinu-
cleotide; NADH, nicotinamide adenine dinucleotide–hydrogen; NSCLC, non-small cell lung cancer; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehy-
drogenase; PDK, pyruvate dehydrogenase kinase; PEP, phosphoenolpyruvate; PET, positron emission tomography; PFKFBs, phosphofructo-kinase/fructosebipho-
sphatases; PFKM, phosphofructokinase M; PFK2, phosphofructokinase 2; PGI, phosphoglucose isomerase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate
mutase; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PI3K, phosphatidyl-inositol 3-kinase; PK, pyruvate kinase; PPP, pentose phosphate pathway; PTTG, pi-
tuitary tumour-transforming gene; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; SDH, succinate dehydrogenase; SGLT, secondary active Na+/glucose
cotransporter; SGLT1, secondary active Na+/glucose cotransporter; SGLT2, secondary active Na+/glucose cotransporter; SLC, solute carriers; TCA, tricarboxylic
acid; TIGAR, TP53-induced glycolysis and apoptosis regulator; TPI, triosephosphate Isomerase; TRAP-1, TNF-receptor-associated protein-1; TSC1, TSC complex
subunit 1; TSC2, TSC complex subunit 2; VDAC, voltage-dependent anion channel; VEGF, vascular endothelial growth factor; 3′UTR, 3′-untranslated region
⁎
Corresponding author.
E-mail address: selcesmeli.sc@gmail.com (S. Çeşmeli).

https://doi.org/10.1016/j.gene.2019.144158
Received 20 May 2019; Received in revised form 3 October 2019; Accepted 4 October 2019
Available online 17 October 2019
0378-1119/ © 2019 Elsevier B.V. All rights reserved.
Z. Abbaszadeh, et al.
Fig. 1. GLUT1 glucose transportation into the cell. Figure shows the differences in glycolytic process between normal and cancer cells. In normal cells, glucose is
converted to ATP and CO2 through oxidative phosphorylation. But in cancer cells; after the conversion of glucose to pyruvate, lactate is produced.
metabolism is maintained hence the cells become resistant to apoptosis.
There is also another glucose transporter, GLUT3, which is considered
as the second most important transporter in cancer cells. GLUT1 and
GLUT3 have amino acid sequences with 64% similarity and GLUT3 is
shown to be overexpressed in bladder cancer. In general, GLUT1 and
GLUT3 express highly in most cancer types and result in poor survival
rates (Gonzalez-Menendez, 2018).
1.2. Glut1
GLUT1 is activated in response to HIF-1α (hypoxia-inducible factor-
1α), and other HIF-1α related factors such as (vascular endothelial
growth factor) VEGF receptor and calcium channel transactivation help
the synthesis of GLUT1. GLUT1 is over expressed in Burkitt’s lymphoma
as a result of MYC-originated chromosomal translocations and muta-
tions in both K-Ras and epidermal growth factor receptor (EGFR) on-
cogenes result in increased expression of GLUT1 in non-small cell lung
cancer (NSCLC). In K-Ras or BRAF mutant colorectal cancer (CRC) cells
which is advantage for these mutant cells with providing survival ca-
pacity in low glucose conditions, GLUT1 expression is higher than non-
mutant or wild type CRC cells (Fig. 1).
There are microRNAs (miRNAs) that regulate GLUT1; miR-144 and
miR-132 are two of them and they are shown to decrease GLUT1 ex-
pression in lung and prostate cancer cells, decreased expression of
GLUT1, increases glucose uptake and glycolysis. Another factor reg-
ulating GLUT1 is DNA methylation; in a study, Derlin-3 (DERL3) – a
tumour suppressor – was transcriptionally silenced by hypermethyla-
tion of its promoter CpG island. The study has shown that DERL3 hy-
permethylation and loss is associated with increase in GLUT1 expres-
sion. This shortened the relapse-free survival in CRC and Warburg effect
was seen in HCT-116 CRC cells.
Another way for controlling glucose uptake in cancer cells is the
regulation of the GLUT1 modifications. In cancer cells, mutated p53
causes GLUT1 translocation to the plasma membrane and provoke
Warburg effect, whereas wild type p53 inhibits GLUT1 expression.
2
Gene 726 (2020) 144158
Interleukin-3, GTPase Rab11a and phosphatidyl-inositol 3-kinase
(PI3K) are other factors that play role in modulating GLUT1 expression
by trafficking it through the cell (Gonzalez-Menendez, 2018).
1.3. Glut3
Several factors and signalling pathways are known to participate in
GLUT3 regulation. Caveolin-1 (CAV1) stimulates GLUT3 transcription
by activating nuclear localization of High Mobility Group AT-Hook 1
(HMGA1) which binds to promoter region of GLUT3 in colon cancer cell
lines. Moreover, mammalian target of rapamycin (mTOR) pathway
upregulates GLUT3 and via NF-ĸB pathway, mTOR complex 1
(mTORC1) enhances GLUT3 expression. In lung adenocarcinoma
(LUAD), it was shown that there is a link between EGFR signalling and
GLUT3 expression, mutated EGFR causes elevated glucose uptake and
glycolysis with gain-of-function property. In addition, OCT4 protein has
shown to be involved in the regulation of GLUT3 because of its co-
operating functions with HIF-1α.
As in the GLUT1, an EMT transcription factor ZEB1 is involved in
binding and activating enhancer of GLUT3, shown in hepatocellular
and NSCLC cells.
In NSCLC cell lines, GLUT3 expression is induced after treatment
with histone deacetylase inhibitors. 3′-untranslated region (3′UTR) is
targeted bymiR-195-5p in bladder cancer; glucose uptake and cell
growth are decreased.
1.4. Gluts and cancer therapies
GLUTs have essential roles in detection and diagnosis of cancer
diseases in some ways. In positron emission tomography (PET) scan,
which is one of the non-invasive techniques for examining tumours, is
based on glucose uptake and glycolysis rate in tumour cells. PET scan
uses radiotracer that is a glucose-analogue 2-deoxy-2-[fluorine-18]
fluoro-D-glucose and this radiotracer is crossed the membrane of cells
by the help of GLUTs.
Z. Abbaszadeh, et al.
Fig. 2. The genes and factors involved in glycolytic pathway in cancer cells. The role of each gene/factor is described in the related section.
Chemotherapy is principal method that has been applied for tu-
mours for many years, but cells could become resistant to this therapy
with many ways just as drug degradation, drug inhibition by several
mechanisms and alterations in cellular export. Studies showed that
GLUTs are also involved in these mechanisms; it was seen that in
bevacizumab-resistant tumours show higher glucose uptake, glycolysis
and these cells also overexpress GLUT3.
Similar results were claimed for GLUT1 in radiotherapy resistance;
this study showed that the overexpression of GLUT1 is associated with
radiation-resistance in cervical squamous cell carcinoma. These out-
comes show that the expression of glucose transporters must be ex-
amined before the therapy and the clinicians must consider their pos-
sible effects on the treatment method (Ancey et al., 2018).
2. Genes and factors in cancer glycolysis
2.1. Genes in glycolytic pathway
Glycolysis is regulated by several genes and enzymes, and many
regulatory factors are involved in this process (Fig. 2). These key factors
are known to be altered and expressed abnormally in many cancers. As
mentioned before, GLUTs are first regulator of glycolytic pathway be-
cause of its role in taking glucose into the cells and they are upregulated
by c-Myc, Ras oncoproteins and HIF-1; Ras molecule, which is an on-
cogene, provokes glycolytic pathway in mutated form (Yu et al., 2016).
2.1.1. Hexokinases (HKs)
Hexokinases (HKs) are enzymes that have role in phosphorylating
glucose and generating glucose-6-phosphate (G6P) which is the first
step of both glycolysis and pentose phosphate pathway (PPP). HK2 is a
common type of HKs and its expression is controlled by c-Myc and HIF-
1; also, in malignant tissues HK2′s activity is found to be upregulated.
The inhibition of HK2 is taken into consideration in many studies
and many agents such as 3-bromopyruvate, 2-deoxyglucose,
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Gene 726 (2020) 144158
lonidamine, astragalin, resveratrol, chrysin, GEN-27 and benserazide.
3-bromopyruvate is also able to decrease ATP level and activate cell
death; for example, in breast cancer it promotes apoptosis (Akins et al.,
2018).
Except glycolysis, hexokinases also have other functions; for anti-
apoptotic activity they translocate to mitochondrial outer membrane
and by interacting Bax protein and voltage- dependent anion channel
(VDAC), inhibit cytochrome c releasing and caspase-9-dependent
apoptosis. In addition, glioma studies showed that in the absence of
HK2, cell proliferation and angiogenesis decrease; cell death is in-
creased (Pastorino et al., 2002; Wolf et al., 2011; Bayley and Devilee,
2012).
2.1.2. Phosphoglucose isomerase (PGI)
On the other hand, another enzyme takes place in the glycolytic
mechanism which is phosphoglucose isomerase (PGI) and it converts
G6P to fructose-6-phosphate (Akins et al., 2018).
2.1.3. Phosphofructo-kinase/fructose biphosphatases (PFKFBs)
Fructose-1,6-biphosphate (F-1,6-P) formation is carried out by
PFKFBs and this enzyme is found to be overexpressed in many cancer
cells. The overexpression of PFKBs are depend on not only HIF-1α, Ras,
c-Myc or p53; also, microenvironment, ATP and reactive oxygen species
(ROS) levels and pH could control the PFKBs’ expression.
2.1.4. Aldolase (ALDO)
Then fructose-bisphosphate is converted into glyceraldehyde 3-
phosphate by the enzyme, ALDO and it is proved that a form of ALDO
enzymes, ALDO B is overexpressed in cancer cells (Zhang et al., 2017).
2.1.5. Glyceraldehyde phosphate dehydrogenase (GAPDH)
Next, 1,3-bisphosphoglycerate is formed by dehydrogenation by the
help of GAPDH which is upregulated in the breast and colorectal can-
cers (Dai et al., 2015; Du et al., 2016). GAPDH is also able to translocate
Z. Abbaszadeh, et al.
for DNA replication, in oxidative stress conditions.
2.1.6. Phosphoglycerate kinase (PGK)
PGKtransfers one phosphate group from 1,3-bisphosphoglycerate to
ADP and result in the production of ATP and 3-phosphoglycerate. With
increasing rate of glycolysis and tumour invasion in pancreatic and
gastric adenocarcinoma, increased PGK1 expression has been thought
(Xu et al., 2005; Xu et al., 2017).
2.1.7. Phosphoglycerate mutase (PGM) and Enolase (ENO)
Then, 3-phosphoglycerate is converted to 2-phosphoglycerate by
PGM enzyme and ENO transform 2-phosphoglycerate to phosphoe-
nolpyruvate (PEP). These two enzymes are also upregulated in cancer
cells such as melanoma and breast cancer.
2.1.8. Pyruvate kinase (PK)
By transferring phosphate group from PEP to ADP, PK enzyme
generates pyruvate and an ATP molecule. PKL and PKM genes code four
PKs consisting of L, R, M1 and M2 iso enzymes and it is known that c-
Myc and HIF-1 upregulate the expression of PKM2 that is overexpressed
in cancer cells.
P53 gene, which is a tumour suppressor, represses PGM’s activity
and this results in senescence and limitless proliferation. A substrate of
PK, PEP phosphorylates proteins for example PGM and when PKM2 is
absent it generates pyruvate. Thus, PKM2 overexpression is thought to
plays role in other functions in tumour cells (Hu et al., 2014). The
identification of hypoxia responsible element (HRE) within the PKM2′s
intron showed that activity of PKM2 is regulated by HIF-1 (Courtnay
et al., 2015). Reduction of PKM2 shown in mice, increases the tumour
formation and thus it was understood that PKM2 is not required for cell
proliferation in cancers (Israelsen et al., 2013). According to the stu-
dies, PKM2 switches to PKM1 to reverse Warburg effect and this
showed that aerobic glycolysis is depend on PKM2 (Courtnay et al.,
2015).
2.1.9. Lactate dehydrogenase (LDH)
In addition to these enzymes, cancer cells use LDHsfor reducing
pyruvate to lactate.
LDH regulates histone 2B (H2B) and cell cycle by binding to Oct-1
trans activator in normal conditions; but when the NAD+/NADH level
becomes low, lactate production is started by LDH (19). Reversely, high
ratio of NAD+/NADH causes movement of LDH to the nucleus and
progression in cell cycle by the help of transcription factors (Sun et al.,
2011).
LDHA-encoded M subunit of LDH is found abundantly in tumours.
Inhibition of LDH’s activity causes the translocation of it to the nucleus,
cell proliferation increases. On the other hand, as LDH activity increases
lactate production increases too and cancer cells are killed due to
acidosis. LDH is also used in diagnosis by using as a biomarker in some
diseases like cancer (Hardie et al., 2012).
In addition, 14-3-3ζ-mediated upregulation of LDHA in breast cells
showed to increase glycolysis rate and therefore is thought to cause
breast cancer formation (Chang et al., 2016).
In addition to the enzymes take place in glycolytic pathway and at
the end of glycolysis, pyruvate dehydrogenase (PDH) is inactivated by
pyruvate dehydrogenase kinase (PDK), which is upregulated by HIF and
c-Myc. Also, acetyl coenzyme A (acetyl-CoA) formation is inhibited by
blocking pyruvate import into the mitochondrial matrix (Bayley and
Devilee, 2012).
2.2. Other genes and factors in glycolysis
2.2.1. c-Myc oncogene
c-Myc gene, which is activated by many pathways in cancer cells, is
the master regulatory element in metabolism and cell proliferation;
also, it causes malignancy with changes in metabolism. When c-Myc is
4
Gene 726 (2020) 144158
activated, cell division speed increases due to the inhibition of genes
that are antiproliferative functions (Miller et al., 2012). In addition, c-
Myc can promote apoptotic pathway.
The expression of c-Myc is regulated by some signals. When positive
signals are present which is observed especially in tumour cells, c-Myc
transcription and protein levels increase, then proliferation is induced.
In addition to the positive signals, post-translational modifications,
including mutations, stimulate overexpression of c-Myc. On the other
hand, miRNAs regulate c-Myc expression and, they are also targeted by
c-Myc.
C-Myc targets many genes involved in cellular functions. These
genes include cyclins A2, D2, E1 and ENO, LDHA, serine hydro-
xymethyl transferase, cadherin, integrin and others that have role in
metabolism, translation, transformation and proliferation.
One of the most important duties of c-Myc is in glycolysis, LDHA is
targeting. In several studies, LDHA is showed to be downstream target
that stimulates Warburg effect. Human pituitary tumour-transforming
gene (PTTG) represses c-Myc, PKM2, GLUT1 and LDHA. However,
overexpressed c-Myc can inhibit PTTG and this proves that PTTG is able
to modulate the metabolism in c-Myc-dependent manner (Yu et al.,
2016).
In the absence of c-Myc expression, it downregulates LDHA and
lactate production decreases. Also; GLUT1, HK2, ENO and phospho-
fructokinase M (PFKM) are other targets that result in Warburg effect.
Under hypoxic conditions, ENO1 causes the generation of MBP-1 that is
a translation initiation product and negative regulator of c-Myc and
therefore this results in negative feedback loop (Miller et al., 2012). c-
Myc also controls the expression of phosphofructokinase 2 (PFK2), PK
and glucokinase that are involved in carbohydrate metabolism (Yu
et al., 2016). Because of its roles in essential functions of cells, c-Myc is
considered in developing new cancer therapies.
2.2.2. HIF
HIF is the regulator of cell proliferation and it is involved in tran-
scriptional regulation. As is evident from its name, HIF is stimulated in
hypoxia. When oxygen is present, HIF degradation occurs by ubiquiti-
nation (Jun et al., 2017). But in hypoxic conditions, HIF-α and HIF-β
subunits are form dimer and result in HIF-1 product. After the activa-
tion of HIF-1, oxygen levels increase and angiogenesis is induced thus
the tumour cells take much more nutrient. On the other hand, HIF-1
regulates the GLUTs activity and increase the expression of HK, PDH
and LDH. PDH is responsible for converting pyruvate to acetyl-CoA for
tricarboxylic acid (TCA) cycle and PDK-1 inhibits the activity of PDH by
phosphorylating then prevents pyruvate to enter TCA cycle (Yu et al.,
2016). Therefore, PDK-1 inhibitors are thought to be efficient in cancer
therapies.
De-functioning of long non-coding RNAs (lncRNAs) and miRNAs
may also control HIF-1α and stimulate aerobic glycolysis. In addition,
hypoxic conditions and ROS is other parameter that regulates HIF-1α
expression (Yu et al., 2017).
HIF-1α is the main factor in activating Warburg effect and it is
stimulated by other mutated factors, then GLUTs and enzymes parti-
cipate in glycolysis. During this process, tumour development begins by
regulating the PI3K-Akt-mTOR pathway and its elements. PI3K and Akt
have essential role in glucose metabolism. PI3K can be activated by
several factors like receptor tyrosine kinases (RTKs), platelet-derived
growth factor receptor (PDGFR), insulin-like growth factor receptor and
EGFR; it is deregulated by Pten phosphatase and Pten therefore inhibits
glycolysis. Akt, which is a serine/threonine kinase, regulates HK2,
GLUT1 and PFK2 and provides the activation of aerobic glycolysis and
growth of cancer cells. mTOR, that is a serine/threonine kinase just like
Akt and involved in tumorigenesis (Yu et al., 2016). In consideration of
these factors, many researchers has focused on metabolism in cancer
studies. In this year; William Kaelin Jr., Sir Peter Ratcliffe and Gregg
Semenza, who are proffessors from different universities currently,
have been awarded Nobel Prize in Medicine for their discoveries of how
Z. Abbaszadeh, et al.
cells sense and adapt to oxygen availability. The idea of cells’ need for
energy is a crystal-clear fact, however the way they use it and effect in
changes in the oxygen levels on the cells were not known until the
argument of this precious scientists. While Ratcliffe were investigating
the effect of oxygen on the regulation of EPO which is a gene normally
expressed in kidneys, Gregg Semenza has studied the EPO gene and its
regulatory ways in different oxygen levels. In Semenza’s Specific DNA
segments are located the region near to EPO gene, which claimed the
response to hypoxic conditions. These studies has shown that the ex-
istence of oxygen sensing mechanisms in all tissues (Semenza, 1991).
After that Semenza identified a complex called hypoxia- inducible
factor (HIF) that binds to specific DNA by depending on oxygen
(Semenza, 1995). In the light of latter studies, they began to search for
the answer about the binding of ubiquitin to HIF -1α, and Kaelin come
to the help. Because he showed that VHL, that is amutated gene in von
Hippel-Lindau’s disease, is able to prevent to onset of cancer by en-
coding a protein. In addition, Kaelin proved that hypoxia regulated
genes are highly found in cancer cells that lacks of functional VHL gene.
This showed that VHL involve in the controlling the responses to hy-
poxic conditions. Then Ratcliff and his friends claimed that VHL can
interact with HIF-1α and also in normal oxygen levels, it is essential for
the degradation (Ratcliffe, 1999). In 2001, they revealed that hydroxyl
groups are added to HIF-1α at specific positions under normal oxygen
conditions and this modiciation is named as prolyl hydroxylation which
allows recognition and binding of HIF-1α by VHL. More research
showed that oxygen-dependent hydroxylation controls the gene acti-
vation carried out by HIF-1 (Kaelin, 2001; Ratcliffe, 2001). The studies
of these three nobel laureates have marked an era for upcoming studies
to fight with diseases like cancer, anemia with these pioneer dis-
coveries.
2.2.3. PI3K/Akt/mTOR
PI3K molecule includes lipid enzymes that are able to phosphorylate
–OH groups on the plasma membrane. Several studies have showed the
roles of PI3K in metabolism, survival and cancer progression because of
regulating glucose uptake and PI3K via Akt moderate the expression of
GLUT1. PI3K classified in several categories and class I subclass 1A is
one of them, which is activated by RTKs. PI3K helps phosphoinositide-
dependent kinase-1 (PDK1) and protein kinase b (Akt) for binding to
phosphatidylinositol (3,4,5)-trisphosphate (PIP3) molecule, results in
uncovering the phosphorylation sites of Akt and then the first phos-
phorylation of it. mTOR, which is activated by PI3K allows the second
phosphorylation of Akt and its complete activation process. Active Akt
is involved in cell cycle progression, growth, cell death and GLUT1-
mediated glucose uptake regulation (Courtnay et al., 2015). mTOR
regulates the expression of c-Myc, NF-ĸB and HIF-1α and it also pro-
mote PKM2 which is critical in growth and aerobic glycolysis. PKM2
disruption occurs by the help of c-Mycand inhibits tumorigenesis that is
mediated by mTOR. In addition, tumour suppressor TSC complex sub-
unit 1 (TSC1) and TSC complex subunit 2 (TSC2) gene complex reg-
ulates GLUT3 expression and upregulation of GLUT3 is achieved with
the help of mTORC1 and by NF-ĸB signalling (Yu et al., 2016).
Moreover; Ras, isocitrate dehydrogenase 1 (IDH1), fumarate hy-
dratase (FH) and succinate dehydrogenase (SDH) are linked to glyco-
lysis with the HIF-1 activation. The activation of these, result in in-
creased expression of genes involved in glycolysis (Miller et al., 2012).
K-Ras activation results in dysfunctional mitochondria and thereby
switch to glycolysis. When K-Ras is mutated, GLUT1 expression in-
creases and so glycolysis and lactate production (Yu et al., 2016).
2.2.4. p53
p53 is a tumour suppressor gene that is involved in both tran-
scription and regulation of cellular processes, importantly cell death. It
causes the initiation of cellular cell death pathways or DNA repair after
binding to DNA (Ozaki and Nakagawara, 2011).
p53 is an essential for functions of cell and when DNA is damaged, it
5
Gene 726 (2020) 144158
helps the cells in both death and repair decisions. However, mutated
p53 could not bind DNA and therefore the cell division occur in un-
desirable way and resulting in tumorigenic cells with damaged DNA
(Courtnay et al., 2015). Moreover, glucose metabolism that is regulated
by p53 could be depend on the NF-ĸB transcription factor. GLUT1,
GLUT3 and GLUT4′s expression is downregulated depend on p53 and
PGM degradation and TP53-induced glycolysis and apoptosis regulator
(TIGAR) is regulated by p53. p53 inhibits glucose-6-phosphate dehy-
drogenase (G6PD) and this way regulates metabolism. Furthermore;
activation of certain genes such as Pten, adenosine monophosphate
activated protein kinase (AMPK) by p53, causes negative regulation of
PI3K/Akt/mTOR signalling. Pten leads to PI3K/Akt signal inhibition,
whereas AMPK causes mTOR downregulation (Yu et al., 2016).
AMPK regulates metabolism between anabolic and catabolic pro-
cesses; when it is activated anabolism is turned off and protein pro-
duction is repressed by inhibiting translation that is depend on mTOR.
These proteins include HIF-1α, therefore the enzymes involved in gly-
colysis is downregulated and oxidative phosphorylation (OXPHOS) is
preferred by the cell (Yu et al., 2016).
2.2.5. TIGAr
Another factor that is involved in regulation of glycolytic pathway is
TIGAR, which also controls oxidative stress and glycolysis in a cell.
TIGAR is translated from the TIGAR gene which is located on chro-
mosome 12p13-3. Apoptotic signals that are associated to ROS are
decreased because of lowering in ROS levels by TIGAR, thus it is con-
sidered as a mediator of the tumour suppression by p53. In addition to
decreasing ROS levels and controlling survival, TIGAR plays role in
DNA repair (Bensaad et al., 2006).
TIGAR, as a tumour suppressor, degrades fructose-2,6-bisphosphate
and block glycolysis and causes the G6P precursor accumulation, hence
glucose catabolism turns into PPP. When TIGAR is in an oncogene role,
for the protection the carcinoma cells from the apoptosis; this process is
stimulated by c-Met (Hu et al., 2014). However, whether presence or
the level of TIGAR expression affects tumour formation is not fully
known yet and upcoming studies is necessary.
2.2.6. Triosephosphate isomerase (TPI)
Triosephosphate isomerase, also known as TPI, is a homodimeric
enzyme that is translated from TPI gene and it participates in invasion
and migration. TPI is abundantly expressed in many cancer cells in-
cluding urinary cancer, lung cancer and squamous cell lung carcinoma,
and it is located on 12p13, near to TIGAR (Lincet and Icard, 2015). In
addition to glycolytic activity by conversion of dihydroxyacetone
phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P) or vice versa,
TPI plays role in cell growth (Chen et al., 2017). Activation of TPI en-
zyme results in ATP production and inhibition of the enzyme result in
the orientation dihydroxyacetone to PPP. Transcription of gene ex-
pression under stress conditions is achieved by ribose that is produced
by PPP and this is the regulation of metabolic pathway controlled by
TPI. When phosphoenolpyruvate accumulation TPI supresses activity
thus promotes PPP pathway and protect cells from ROS. In addition, TPI
upregulation can be involved in reversing multidrug-resistance pheno-
type and therefore it is thought to be an anti-drug-resistant enzyme in
some cancers such as gastric cancer (Lincet and Icard, 2015; Chen et al.,
2017).
3. Other regulators of glycolysis
In addition to the genes, enzymes and several factors; there are
other regulators involved in glycolytic pathway (Neugent et al., 2018).
Wnt signalling is one of them and it interacts PDK-1 in controlling
glycolysis. When Wnt is repressed, overexpressed PDK-1 recovers the
cell in both glycolysis and growth of vessels. There is also focal adhe-
sion kinase (FAK) which helps glycolysis by inhibiting ENO, LDH,
PKM2 and other proteins. An ATP-gated channel, P2X7 receptor is
Z. Abbaszadeh, et al.
responsible in aerobic glycolysis and regulates many glycolytic enzymes
(Chatterjee and Burns, 2017). In addition, HSP40 and TNF-receptor-
associated protein-1 (TRAP-1) that are members of heat shock proteins
(HSPs), participate in switching OXPHOS to aerobic glycolysis and vice
versa. Moreover; glucose-regulated protein 78 (GRP78), ZBTB7A, sur-
vivin, KLF4, α/β-hydrolase domain containing 5 (Abhd5) and GRIM-19
gene are involved in the regulation of glycolysis with various ways (Yu
et al., 2016).
4. Conclusion
As the incidence of cancer patients has increased and no exact cure
has found; studies have focussed on different hallmarks of cancer. One
and the most important characteristics of cancer is hidden in cell me-
tabolism. After Warburg’s hypothesis, cancer researches in worldwide
has been focussed on glucose metabolism and scientists have begun to
investigate the reason behind the choosing aerobic glycolysis by the
cancer cells. In the light of these studies, many oncogenes and tumour
suppressor, signalling pathways and factors involved in these pathways
have been discovered. Therefore, these genes are targeted in many re-
searches and various molecules, chemical, nanomedicines, inhibitors,
their analogues and also miRNAs are developed against them. However,
mechanism behind the glycolytic switch and the role of the main player
should be determined in addition to the consideration of specificity of
this player and the agent toxicity before approval. As the 2019 Nobel
Prize in physiology or medicine has awarded to Kaelin, Ratcliffe and
Semenza for their studies on cell metabolism and oxygen sensation and
adaptation to oxygen level alterations. They studied on the ways to
sense oxygen by the cell and cell’s adaptation to alterions in oxygen
levels. And they described a machinery that regulates the genes’ activity
in the case of changes in oxygen level. They drawn the attention of
other scientists who are studying various fields of health and studies
especially in cancer research concentrate on the metabolism. Further
studies justify the hope that immunotherapy may be a key point in
future cancer treatments. Although the progressions in researches, there
are still dark areas in Warburg effect and thus still needed to further
studies. But it is known that conventional chemotherapy with glycolytic
inhibitors is much more efficient in the both beginning and progression
of tumours and surpassing the drug resistance. Therefore, knowledge of
glycolytic players and inhibition of these elements will continue to be
essential in cancer therapies.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
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