Mini-review on Glycolysis and Cancer

M. Akram

Journal of Cancer Education

ISSN 0885-8195

J Canc Educ
DOI 10.1007/s13187-013-0486-9

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 Author's personal copy
J Canc Educ
DOI 10.1007/s13187-013-0486-9
Mini-review on Glycolysis and Cancer
M. Akram
# Springer Science+Business Media New York 2013
Abstract Glycolysis is a universal pathway in the living
cells. The complete pathway of glycolysis was elucidated in
1940. This pathway is often referred to as Embden–Meyer-
hof pathway in honor of the two biochemists that made a
major contribution to the knowledge of glycolysis. The
objective of the study was to review the published literature
on glycolysis and relation to cancer. The material for this
review was taken mostly from up-to-date biochemistry text-
books and electronic journals. To collect publications,
PubMed and the Cochrane database of systematic reviews
were used. Some other relevant references were collected
from personal database of papers on glycolysis and cancer.
Several glycolytic inhibitors are currently in preclinical and
clinical development. Inhibition of glycolysis in cancer cells
is a novel strategy to overcome drug resistance associated
with mitochondrial respiratory defect and hypoxia. This
article is an important topic to be considered by cancer
researchers and those who treat cancers.
Keywords Glycolysis . Cancer . Research study . Literature
review
Introduction
Glycolysis takes place in all cells of the body. The enzymes
of this pathway are present in the cytosomal fraction of the
cell. Glycolysis occurs in the absence of oxygen (anaerobic)
or in the presence of oxygen (aerobic). Lactate is the end
M. Akram (*)
Department of Eastern Medicine and Surgery, Faculty of Medical
and Health Sciences, The University of Poonch,
Azad Jammu and Kashmir, Pakistan
e-mail: makram_0451@hotmail.com
M. Akram
e-mail: makram0451@gmail.com
product under anaerobic condition. In the aerobic condition,
pyruvate is formed, which is then oxidized to CO2 and H2O
[1]. Glycolysis is a major pathway for ATP synthesis in tissues
lacking mitochondria, e.g., erythrocytes, cornea and lens.
Glycolysis is very essential for brain which is dependent on
glucose for energy. The glucose in brain has to undergo
glycolysis before it is oxidized to CO2 and H2O. Glycolysis
is a central metabolic pathway with many of its intermediates
providing branch point to other pathways. Thus, the interme-
diates of glycolysis are useful for the synthesis of amino acids
and fat. Reversal of glycolysis along with the alternate ar-
rangements at the irreversible steps will result in the synthesis
of glucose (gluconeogenesis). Glycolysis rate is 200 times
higher in tumor cells than the normal cells. Otto Warburg
has described this phenomenon in 1930; this is why now it
is called as the Warburg effect. According to this phenome-
non, dysfunctionality in mitochondrial metabolism is primar-
ily cause of cancer, rather than because of uncontrolled growth
of cells. Warburg effect has been explained by various theo-
ries. One theory is that an increase in glycolysis rate is favor-
able to the body.
Enzymes of Glycolysis
The enzymes involved in glycolysis are hexokinase,
phosphoglucoisomerase, phosphofructokinase, aldolase, tri-
ose phosphate isomerase, glyceraldehyde-3-phosphate de-
hydrogenase, phosphoglycerate kinase, phosphoglycerate
mutase, enolase and pyruvate kinase.
Reactions of Glycolysis
The pathway can be divided into three distinct phases:
1. Energy investment phase or priming phase
 Author's personal copy
2. Splitting phase
3. Energy-generation phase
Energy Investment Phase
Glucose is phosphorylated to glucose 6-phosphate by hexo-
kinase or glucokinase. This is an irreversible reaction de-
pendent on ATP and Mg2+. The hexokinase enzyme is
present in almost all the tissues. It catalyzes phosphorylation
of various hexoses (fructose, mannose, etc.). It has low Km
for substrates (approximately 0.1 Mm) and inhibited by
glucose 6-phosphate [2].
Products of Glycolysis
Glycolysis produces a net amount of two ATPs and two
NADHs.
Splitting Phase
Six carbon fructose 1,6-diphosphate is divided into two
three-carbon compounds, glyceraldehyde-3-phosphate and
dihydroxyacetone phosphate by aldolase enzyme. The
enzyme phosphotriose isomerase catalyzes the reversible
interconversion of glyceraldehydes 3-phosphate and di-
hydroxyacetone phosphate. Thus, two molecules of
glyceraldehydes 3-phosphate are formed from one mol-
ecule of glucose
Energy-Generation Phase
Glyceraldehyde 3-phosphate dehydrogenase converts glycer-
aldehyde 3-phosphate to 1,3-bisphosphoglycerate. This step is
important, as it is involved in the formation of NADH2 and
high-energy compound 1,3-bisphosphoglycerate.
In aerobic conditions, NADH passes through the electron
transport chain and six ATPs (2×3 ATPs) are synthesized by
oxidative phosphorylation. The enzyme phosphoglycerate
kinase acts on 1,3-bisphoglycerate resulting in the synthesis
of ATP and the formation of 3-phosphoglycerate. This step
is a good example of substrate level phosphorylation, be-
cause ATP is synthesized from the substrate without the
participation of the electron transport chain. Phosphoglyc-
erate kinase reaction is reversible, a rare example among the
kinase reaction.
3-Phosphoglycerate is converted to 2-phosphoglycerate
by phosphosphoglycerate mutase. This isomerization is a
reaction. The high-energy phosphoenol pyruvate compound
is produced by 2-phosphoglycerate by the enzyme enolase
[3]. This enzyme requires magnesium and manganese, and it
inhibited by fluoride.
For the estimation of glucose in the blood in the labora-
tory, fluoride is added to blood to prevent glycolysis by cells
J Canc Educ
so that glucose in the blood is properly assessed. The pyru-
vate kinase enzyme catalyzes the transfer of high-energy
phosphate from phosphoenol pyruvate to ADP, leading to
the formation of ATP. This step is also a substrate level
phosphorylation. This reaction is irreversible.
Conversion of Pyruvate to Lactate—Significance
The fate of pyruvate produced in glycolysis depends on the
presence or absence of oxygen to the cells. Under anaerobic
conditions (lack of O2), pyruvate is reduced by NADH to
lactate in the presence of the enzyme lactate dehydrogenase
[4]. The NADH2 used in this step is taken from the reaction
catalyzed by glyceraldehydes 3-phosphate dehydrogenase.
The formation of lactate allows the regeneration of NAD+ that
can be reused by glyceraldehyde 3-phosphate dehydrogenase,
so that glycolysis proceeds even in the absence of oxygen
supply ATP. The occurrence of uninterrupted glycolysis is
very essential in skeletal muscle during strenuous exercise
where oxygen supply is very limited. Glycolysis in the eryth-
rocytes leads to lactate production, since mitochondria—the
centers for aerobic oxidation—are absent. Brain, retina, skin,
renal medulla, and gastrointestinal tract derive most of their
energy from glycolysis [5].
Production of ATP in Glycolysis
Two ATPs are synthesized in anaerobic glycolysis, while
eight ATPs are synthesized under aerobic conditions. When
glycolysis is from glycogen, more ATPs are produced. This
is because no ATP is consumed for activation of glucose
(glycogen directly produces glucose 1-phosphate forming
glucose 6-phosphate). Thus, in anaerobic glycolysis, three
ATPs are produced from glycogen [6].
Glycolysis and Shuttle Pathway
In the presence of mitochondria and oxygen, the NADH
produced in glycolysis may be involved in the shuttle routes
for the synthesis of ATP. If cytosolic NADH use malate
aspartate shuttle, three ATPs are produced from each mole-
cule of NADH. This contrasts with glycerol phosphate
shuttle which produces only two ATPs [7].
Cancer and Glycolysis
Cancer cells display increased uptake of glucose and gly-
colysis. As the tumors grow rapidly, the blood vessels are
thus in a condition of hypoxia [8]. Due to this, anaerobic
 Author's personal copy
J Canc Educ
glycolysis predominantly occurs to supply energy. The can-
cer cells get adapted of hypoxic glycolysis through the
involvement of a transcription factor namely hypoxia-
inducible transcription factor (HIF) [9]. HIF increases the
synthesis of glycolytic enzymes and the glucose trans-
porters. However, the cancer cells cannot grow and survive
without proper vascularization. One of the modalities of
cancer treatment is to use drugs that can inhibit vasculari-
zation of tumors [10]. Sun et al. have reported that reversal
of the glycolytic phenotype by dichloroacetate inhibits met-
astatic breast cancer cell growth in vitro and in vivo [11]. Xu
et al. have reported the inhibition of glycolysis in cancer
cells that is a novel strategy to overcome drug resistance
associated with mitochondrial respiratory defect and hypox-
ia [12]. Altenberg et al. have reported that genes of glycol-
ysis are ubiquitously overexpressed in 24 cancer classes
[13]. Broadley et al. have reported that novel phloroglucinol
PMT7 kills glycolytic cancer cells by blocking autophagy
and sensitizing to nutrient stress [14]. Fantin et al. have
reported that attenuation of LDH-A expression uncovers a
link between glycolysis, mitochondrial physiology, and tu-
mor maintenance [15]. Ha et al. have reported that Caveolin-
1 increases aerobic glycolysis in colorectal cancers by stim-
ulating HMGA1-mediated GLUT3 transcription [16].
Scatena et al. have reported the glycolytic enzyme inhibitors
in cancer treatment [17]. Fang et al. have reported that
MicroRNA-143 (miR-143) regulates cancer glycolysis via
targeting hexokinase 2 gene [18]. Granchi et al. have report-
ed the anticancer agents that counteract tumor glycolysis
[19]. Sukhatme et al. have reported that glycolytic cancer
cells lacking 6-phosphogluconate dehydrogenase metabo-
lize glucose to induce senescence [20]. Wang and his col-
leagues stated that IDH1 affinity for ICT is reduced by
mutations at sites A132Arg, A109Arg, and B212Lys IDH1
affinity for ICT is increased by mutation at sites A77Thr,
A94Ser, and A275Asp, that enhances IDN1 catalytic activ-
ity. Mutant IDH1 proteins with higher catalytic activity is a
novel therapy useful for glioblastoma multiforme [21]. We
are discussing about anaerobic glycolysis and its effect on
cancer. In case of anaerobic glycolysis, lactic acid is pro-
duced. Alternate source of energy are lipids and proteins but
their oxidation occurs in mitochondria that is totally oxida-
tive pathway. Therefore, in case of anaerobic conditions,
TCA does not work properly for oxidation of lipids and
proteins. Cancer cells mostly depend on glycolysis for ATP
production due to mitochondrial injury and hypoxia. Inhi-
bition of glycolysis severely depletes ATP production in
cancer cell with mitochondrial respiration defects. As a
result, there will be dephosphorylation of glycolysis–apo-
ptosis integrating molecule BAD at Ser(112), relocalization
of BAX to mitochondria, and massive cell death. Xu and his
colleagues stated that glycolysis inhibition kills colon cancer
cells and lymphoma cells in anaerobic conditions. ATP
depletion via glycolysis pathway inhibits potently induced
apoptosis in multidrug-resistant cells which indicates that
depletion of cellular energy is an effective way to treat
multidrug resistance. The study of Xu and his colleagues
indicated that glycolysis inhibition is useful in cancer ther-
apy and also overcome the drug resistance [12].
Irreversible Steps in Glycolysis
Most of the reactions of glycolysis are reversible. However,
the three steps catalyzed by the enzymes hexokinase (or
glucokinase), phosphofructokinase, and pyruvate kinase
are irreversible. These three stages mainly regulate glycoly-
sis. The reversal of glycolysis, with alternate arrangements
made at the three irreversible stages, leads to the synthesis of
glucose from pyruvate (gluconeogenesis) [22].
Regulation of Glycolysis
Enzyme Activator
The three enzymes, namely hexokinase (and glucokinase),
phosphofructokinase, and pyruvate kinase, catalyze the ir-
reversible reaction regulate glycolysis. Hexokinase is acti-
vated by AMP/ADP. Phosphofructokinase is activated by
AMP/ADP and fructose-2,6-bisphosphate. Pyruvate kinase
is activated by AMP/ADP and fructose-1,6-bisphosphate
[23, 24].
Enzyme Inhibitor
Hexokinase is inhibited by glucose-6-phosphate. Phospho-
fructokinase is inhibited by ATP and citrate. Pyruvate kinase
is inhibited by ATP, acetyl CoA, and alanine.
Significance of 2,3-BPG
Production of 2,3-bisphosphoglycerate (BPG) allows the
glycolysis to proceed without the synthesis of ATP. This is
advantageous to erythrocytes since glycolysis occurs when
the need for ATP is minimal. Rapoport–Leubering cycle is,
therefore, regarded as a shunt pathway of glycolysis to
dissipate or waste the energy not needed by erythrocytes.
2,3-BPG, however, is not a waste molecule in RBC. It
combines with hemoglobin (Hb) and reduced Hb affinity
with oxygen. Therefore, in the presence of 2,3-BPG, oxy-
hemoglobin unloads more oxygen to the tissues. Increase in
erythrocyte 2,3-BPG is observed in hypoxic condition, high
altitude, fetal tissues, anemic conditions, etc. In all these
cases, 2,3-BPG will enhance the supply of oxygen to the
tissues. Glycolysis in the erythrocytes is linked with 2,3-
 Author's personal copy
BPG production and oxygen transport. In the deficiency of
the enzyme hexokinase, glucose is not phosphorylated,
hence the synthesis and concentration of 2,3-BPG are low
in RBC. The hemoglobin exhibits high oxygen affinity in
hexokinase-defective patients. On the other hand, the level
of 2,3-BPG in erythrocytes is high in patients with pyruvate
kinase deficiency, resulting in low oxygen affinity [25].
Conclusion
Glycolysis is a universal pathway in the living cells. The
complete pathway of glycolysis was elucidated in 1940.
This pathway is often referred to as Embden–Meyerhof
pathway in honor of the two biochemists that made a major
contribution to the knowledge of glycolysis. This article is
an important topic to be considered by cancer researchers
and those who treat cancers. This is a very important subject
that has been addressed.
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