ONCOLOGY LETTERS 17: 4213-4221, 2019

Crucial role of the pentose phosphate pathway

in malignant tumors (Review)
LIN JIN1,2 and YANHONG ZHOU1,2

1
The Key Laboratory of Carcinogenesis of The Chinese Ministry of Health, Xiangya Hospital;
2
The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education,
Cancer Research Institute, Central South University, Changsha, Hunan 410078, P.R. China

Received May 8, 2018; Accepted January 4, 2019

DOI: 10.3892/ol.2019.10112

Abstract. Interest in cancer metabolism has increased in Contents

recent years. The pentose phosphate pathway (PPP) is a major
glucose catabolism pathway that directs glucose flux to its 1. Introduction
oxidative branch and leads to the production of a reduced form 2. Glucose in the PPP
of nicotinamide adenine dinucleotide phosphate and nucleic 3. Glucose breakdown through glycolysis in the PPP
acid. The PPP serves a vital role in regulating cancer cell 4. PPP in malignant tumors
growth and involves many enzymes. The aim of the present 5. Perspectives
review was to describe the recent discoveries associated with
the deregulatory mechanisms of the PPP and glycolysis in
malignant tumors, particularly in hepatocellular carcinoma, 1. Introduction
breast and lung cancer.
Metabolic adaptations are closely associated with alterations
in cellular behavior. In the past 20 years, there has been a
growing interest in cancer metabolism, particularly on glucose
metabolism (1). Cancer cells are able to reprogram their energy
Correspondence to: Professor Yanhong Zhou, The Key Laboratory metabolism to meet the increased biogenetic demands required
of Carcinogenesis of The Chinese Ministry of Health, Xiangya for their rapid and uncontrolled growth (2). Cells from normal
Hospital, Central South University, 110 Xiangya Road, Changsha, tissues mainly generate adenosine 5'‑triphosphate (ATP)
Hunan 410078, P.R. China through the mitochondrial oxidative phosphorylation. In these
E‑mail: [email protected] cells, glucose is transformed to pyruvate through glycolysis,
and most pyruvate enters mitochondrial oxidative metabolism
Abbreviations: 3‑PG, 3‑phosphoglycerate; 6PGD, 6‑phosphogluconate for efficient energy generation (3). However, most cancer cells
dehydrogenase; AML, acute myeloid leukemia; ATP, adenosine
consume glucose through glycolysis, even in the presence of
5'‑triphosphate; BAG, Bcl‑2‑associated athanogene; EMT,
sufficient oxygen; this phenomenon is called the Warburg
epithelial‑mesenchymal transition; F6P, fructose 6‑phosphate; G3P,
glyceraldehyde 3‑phosphate; G6PD, glucose 6‑phosphate dehydrogenase; effect, which leads to the production of pyruvate and lactate as
HCC, hepatocellular carcinoma; HIF‑1, hypoxia‑inducible factor 1; HK, final metabolites (4). This enhanced aerobic glycolysis allows
hexokinase; NADPH, nicotinamide‑adenine dinucleotide phosphate; cancer cells to better proliferate by generating sufficient
NRF2, nuclear factor, erythroid 2‑like 2; NSCLC, non‑small amounts of ATP and other biomolecules, including nucleo-
cell lung carcinoma; PFK1, phosphofructokinase‑1; PFKFB3, tides, amino acids and fatty acids (5).
6‑phosphofructo‑2‑kinase/fructose‑2,6‑bisphosphatase 3; PFKP, The pentose phosphate pathway (PPP), also known as the
PFK1, platelet isoform; PGAM1, phosphoglycerate mutase 1; phosphogluconate pathway or the hexose monophosphate shunt,
PK, pyruvate kinase; PKM2, pyruvate kinase M2 isoform; Plk1, is a metabolic pathway parallel to glycolysis, and represents the
Polo‑like kinase 1; PPP, pentose phosphate pathway; PTEN, first committed step of glucose metabolism (6). The PPP serves
phosphatase and tensin homolog; R5P, ribose‑5‑phosphate; RPE,
a pivotal role in supporting cancer cell survival and growth
ribulose‑5‑phosphate epimerase; RPI, ribose‑5‑phosphate isomerase;
by generating pentose phosphate for nucleic acid synthesis
RPIA, ribose‑5‑phosphate isomerase A; Ru5P, ribulose‑5‑phosphate;
STAT3, signal transduction and activator of transcription 3; TALDO, and providing nicotinamide‑adenine dinucleotide phosphate
transaldolase; TKT, transketolase; TKTL1, transketolase‑like 1; Xu5P, (NADPH), which is needed for fatty acid synthesis and cell
xylulose‑5‑phosphate survival under stress conditions (7). Previous studies indicate
that PPP flux can be directly or indirectly modulated in cancer
Key words: pentose phosphate pathway, glycolysis, hepatocellular cells, in order to improve cell survival and proliferation (2,7).
carcinoma, breast cancer Therefore, the regulatory network of PPP flux represents an
important metabolic adaptation in a number of environmental
contexts in human malignancies, including cancer.
4214 JIN and ZHOU: PENTOSE PHOSPHATE PATHWAY IN CANCER

2. Glucose in the PPP (6PG). 6PG is then oxidatively decarboxylated by 6PGD,

leading to the synthesis of Ru5P, CO2 and a second molecule
The PPP occurs in the cytosol and comprises two irrevers- of NADPH. Upregulation of 6PGD activity has been identi-
ible oxidative reactions followed by a series of reversible fied in various types of cancer, including breast, acute myeloid
interconversions (Fig. 1). The PPP is thus divided into two leukemia (AML), ovarian and lung cancers (21‑23).
biochemical branches: An oxidative and a non‑oxidative The enzyme 6PGD is commonly activated in human
branch. The oxidative branch converts glucose 6‑phosphate cancer cells after lysine acetylation, which promotes NADP+
(G6P) into ribulose‑5‑phosphate (Ru5P), CO2 and NADPH (8). binding to 6PGD and the formation of active dimers of
NADPH is vital to maintain the reduction‑oxidation (redox) 6PGD (24). In this pathway, activated 6PGD enhances the
balance under stress conditions and allows cells to proliferate oxidative phase of PPP, and nucleotide or RNA biosynthesis.
rapidly (9). The non‑oxidative branch yields the glycolytic This reaction serves a role in maintaining intracellular Ru5P
intermediates fructose 6‑phosphate (F6P), glyceraldehyde at a physiological level that is sufficient to fulfill the metabolic
3‑phosphate (G3P) and sedoheptulose sugars, resulting in requirements of rapidly growing cancer cells (25). In addition,
the production of sugar phosphate precursors for amino acid 3‑phosphoglycerate (3‑PG) directly binds to the active site of
synthesis and ribose‑5‑phosphate (R5P), which is essential for 6PGD and competes with its substrate, 6PG, to inhibit 6PGD.
nucleic acid synthesis (10). Furthermore, the glycolytic enzyme phosphoglycerate mutase
1 (PGAM1) controls intracellular levels of 3‑PG (26). A recent
Role of glucose 6‑phosphate dehydrogenase (G6PD) in the study reported that attenuation of PGAM1 results in abnormal
PPP. The PPP is primarily regulated during the G6PD reaction. accumulation of 3‑PG, which inhibits 6PGD and subsequently
G6PD catalyzes the irreversible oxidation of G6P into 6‑phos- suppresses the oxidative PPP and anabolic biosynthesis. Malic
phogluconolactone in a rate‑limiting step; the first molecule of enzyme forms a physiological hetero‑oligomer with 6PGD,
NADPH is generated during this reaction (11). G6PD acts as a which increases 6PGD activity (27).
‘gatekeeper’ of this pathway and is therefore the rate‑limiting
enzyme in the PPP. Subsequently, G6PD activity not only Roles of ribose‑5‑phosphate isomerase (RPI) and ribu‑
determines the flux partitioning between glycolysis and PPP, lose‑5‑phosphate epimerase (RPE) in the PPP. The enzyme
but also reflects the oxidative PPP flux (12). G6PD is overex- RPI converts Ru5P into R5P, and the enzyme RPE converts
pressed in cancer cells, and Ju et al (13) demonstrated that the Ru5P into xylulose‑5‑phosphate (Xu5P). It has been demon-
elevated expression of G6PD is predictive of poor survival of strated that ribose‑5‑phosphate isomerase A (RPIA) regulates
patients with cancer, indicating that G6PD may serve a vital cancer growth and tumorigenesis (28). In addition, RPIA is
role in tumorigenesis. There are two cellular isomers of G6PD, significantly overexpressed in colorectal cancer and hepatocel-
a dimer and a tetramer; the dimer stability has been demon- lular carcinoma (HCC) (29,30). RPIA also activates β‑catenin
strated to have an important role in vivo (14). High pH and by entering the nucleus to form a complex with adenomatous
ionic strength are beneficial for the dimer synthesis, whereas polyposis coli and β‑catenin, thus modulating cell prolifera-
low pH generates a shift toward the tetramer synthesis (15). tion and oncogenicity (29).
The tumor suppressor p53 binds to G6PD and inhibits the
formation of the active dimer and suppresses NADPH produc- Roles of transketolase (TKT) and transaldolase (TALDO) in
tion, glucose consumption and biosynthesis, which results in the PPP. TKT and TALDO are two enzymes that convert R5P
inhibition of the PPP (16). Polo‑like kinase 1 (Plk1) is a key and Xu5P, and the gluconeogenetic intermediates G3P and F6P.
regulator of cell mitosis and enhances PPP flux and macro- TKT and TALDO are responsible for complex interconversion
molecule biosynthesis through the direct phosphorylation of reactions within the non‑oxidative PPP (10). TKT converts
G6PD to promote the formation of G6PD active dimer. This excess R5P into G3P and F6P through a number of reactions,
is an essential feature of Plk1 as a promoter of cancer cell G3P is metabolized alongside further steps of glycolysis, and
cycle progression and growth (17). In addition, glycosylation F6P is converted into G6P that re‑enters the oxidative PPP to
activates G6PD activity, and modification of G6PD with an generate additional NADPH (31). Elevated TKT expression
O‑linked β‑N‑acetylglucosamine sugar increases the glucose levels were reported in lung cancer cells, breast cancer cells
flux to the PPP (18). Mammalian target of rapamycin complex and prostate cancer cells (21,22).
1 upregulates the transcriptional and the post‑transcriptional TKT expression is closely regulated by the nuclear factor,
expression of G6PD to activate PPP (19). p21‑activated kinase erythroid 2‑like 2 (NRF2)/Kelch‑like ECH‑associated protein
4 increases G6PD activity by enhancing Mdm2‑mediated p53 1/BTB and CNC homolog 1 oxidative stress sensor pathway in
ubiquitination and degradation (20). Furthermore, suppression various types of cancer (32). For example, exposure to ultraviolet
of G6PD lowers glutathione levels, decreases NADPH produc- A increases cancer proliferation by upregulating intracellular
tion, reduces the capacity to scavenge reactive oxygen species concentrations of TKT in melanoma (33). In addition, fructose
(ROS) and enhances the oxaliplatin‑induced apoptosis through stimulates TKT activity and is preferentially used over glucose
ROS‑mediated damage in vitro (13). These results indicate that to generate nucleic acids via the non‑oxidative PPP (34). Higher
G6PD may be a potential prognostic biomarker and represent a vertebrates obtain transketolase‑like 1 (TKTL1) by genome
promising target in cancer therapy. duplication and exon skipping (35,36). TKTL1 upregulation
is a general phenomenon in epithelial malignancies, ocular
Role of 6‑phosphogluconate dehydrogenase (6PGD) in the adnexal tumors, malignant pleural effusion and other types of
PPP. The 6‑phosphogluconolactone hydrolase irreversibly cancer (37‑39). TKTL1 is therefore considered a novel tumor
hydrolyzes 6‑phosphogluconolactone into 6‑phosphogluconate marker and a potential good target in cancer treatment (40).
 ONCOLOGY LETTERS 17: 4213-4221, 2019 4215

Figure 1. PPP. G6PD converts glucose‑6‑phosphate into 6‑phosphogluconolactone. 6‑Phosphogluconolactone then converted to Ru5P by 6PGD. Ru5P
undergoes isomerization by RPI or RPE to generate ribose‑5‑phosphate or xylulose‑5‑phosphate, respectively. In the non‑oxidative reactions of PPP, TKT
and TALDO are responsible for relatively complex interconversion reactions. Curved arrows indicate that G6PD, 6PGD, RPI, TKT and TALDO are over-
expressed in cancer cells. 6PGD, 6‑phosphogluconate dehydrogenase; G6PD, glucose 6‑phosphate dehydrogenase; PPP, pentose phosphate pathway; RPE,
ribulose‑5‑phosphate epimerase; RPI, ribose 5‑phosphate isomerase; Ru5P, ribulose‑5‑phosphate; TALDO, transaldolase; TKT, transketolase.

TALDO catalyzes the reversible transfer of a three‑carbon HK activity. Therefore, the induction of HK2 expression is
unit between various sugar phosphates (from ketose to aldose required. Overall, HK2 is elevated in cancer cells, promotes
sugar phosphates) (10). A previous study has revealed that glycolysis and inhibits mitochondrial‑mediated apoptosis (47).
TALDO is significantly overexpressed in gastric adenocar- The induction of HK2 expression by oncogenic Ras is crucial
cinoma (41). Furthermore, its expression is associated with for accelerated ribonucleotide synthesis (48). Bcl‑2‑associated
metastatic behavior in HCC (42). In addition, a combination athanogene (BAG)‑3, a member of the BAG cochaperone family
of arginine and ascorbic acid decreases intracellular NADPH that comprises six BAGs (BAG1‑BAG6), increases HK2 expres-
levels by reducing TALDO activity in the PPP (43). sion by interacting with HK2 mRNA (49). Hypoxia‑inducible
factor (HIF)‑1α induces the expression of the glycolytic enzyme
3. Glucose breakdown through glycolysis influencing PPP HK2. The sustained expression of the oncogene forms of the
human papillomavirus E6 and E7 is vital to maintain HK2
Numerous regulatory pathways for tumor cells exist within the expression levels by upregulating the pro‑oncogene MYC and
PPP, and most reactions in glycolysis are crucial to maintain downregulating microRNA (miR)‑143‑3p (50). In AML, an
tumor cell function. Since PPP and glycolysis are metabolically internal tandem duplication mutation in the Fms‑like tyrosine
linked for sharing the common intermediate G6P, the increased kinase 3 gene upregulates the level of mitochondrial HK2, causing
glycolysis during reperfusion concomitantly led to decreased a significant increase in aerobic glycolysis; therefore, leukemic
PPP rate (44). The conversion of glucose to pyruvate occurs in cells become highly dependent on glycolysis, which increases
two stages (Fig. 2). In the first stage, phosphorylated forms of their sensitivity to the pharmacological inhibition of glycolytic
pyruvate intermediates are synthesized, leading to ATP synthesis. activity (51). In addition, the histone‑lysine N‑methyltransferase
Hexokinase (HK) phosphorylates glucose into G6P, and phospho- NSD2 is recruited to and methylates HK2 promoters (52).
fructokinase‑1 (PFK1) catalyzes the conversion of F6P to fructose NSD2‑driven tamoxifen‑resistant cancers exhibit an enhanced
1,6‑bisphosphate. In the subsequent stage, ATP is generated by PPP activity, elevated NADPH production and reduced ROS
substrate‑level phosphorylation and metabolism of glucose. The levels. For example, treatment of ovarian cancer xenografted
final step of glycolysis is catalyzed by the pyruvate kinase (PK) mice with the HK2 inhibitor 3‑bromopyruvate attenuates tumor
enzyme that leads to the synthesis of pyruvate and ATP. In cancer growth and confers a survival advantage (53).
cells, the glycolytic reaction generates a ‘bottleneck’ effect by
increasing the upstream part of the glycolytic flux up to PK and Role of phosphofructokinase in the conversion of glucose by
decreasing the glycolytic flux from PK downward (45). glycolysis in the PPP. PFK1 irreversibly phosphorylates F6P
into fructose‑1,6‑bisphosphate. This reaction is a crucial and a
Role of HK in the conversion of glucose by glycolysis in the rate‑limiting step in glycolysis. It has been demonstrated that
PPP. HK catalyzes glucose phosphorylation, which is one PFK1 activity is increased in cancer cell lines, and expression
of the regulatory reactions of glycolysis. To maintain the of PFK1 is upregulated in breast and liver cancers (54,55). In
Warburg effect, cancer cells upregulate HK. Four isoforms addition, PFK1 is regulated by ATP and F6P substrates (56).
of HK exist (HK1‑HK4). HK2, which may be in a soluble In response to hypoxia, O‑GlcNAcylation suppresses PFK1
form in the cytoplasm or bound to the mitochondrial outer activity and redirects glucose towards the PPP, which provides
membrane, has a glucose affinity 100‑fold higher than HK1, an advantage for cancer cell growth (57). A Krüppel‑associated
HK3 and HK4 (46). In addition, the expression of HK1 may be box‑type zinc‑finger protein named p53 inhibitor of TIGAR
sufficient for normal cell metabolism. However, the acceler- activation (PITA) is a selective regulator of p53, and PITA
ated anabolic metabolism in cancer cells demands a robust transgenic mice exhibit increased PFK1 activity and elevated
4216 JIN and ZHOU: PENTOSE PHOSPHATE PATHWAY IN CANCER

Figure 2. Glycolysis. Glycolysis consists of two stages, the first stage consuming ATP and the second stage generating ATP. There are three crucial reactions in
tumor cells. First, HK catalyzes the conversion of glucose to glucose‑6‑phosphate. Second, fructose‑6‑phosphate is converted into fructose 1,6‑bisphosphate
by PFK1, and fructose 1,6‑bisphosphate is converted into fructose 2,6‑bisphosphate by PFK2. Third, phosphoenolpyruvate is converted into pyruvate by PK.
Curved arrows indicate that HK, PFK1 and PK are overexpressed in cancer cells. HK, hexokinase; PK, pyruvate kinase; PFK, phosphofructokinase.

glycolytic rate (58). The PFK1 platelet isoform (PFKP), the Upon glucose starvation, cellular levels of succinylamino-
predominant PFK1 isoform, is overexpressed in human imidazole‑carboxamide riboside, an intermediate of the de novo
glioblastoma cells and promotes aerobic glycolysis and brain purine nucleotide synthesis pathway, are increased. This leads
cancer cell proliferation (59). In addition, the loss of phospha- to the stimulation of PKM2 activity in cancer cells, which alters
tase and tensin homolog (PTEN) and activation of epidermal cellular energy level, glucose uptake and lactate generation (66).
growth factor receptor (EGFR)‑dependent phosphoinositide Following EGFR activation, PKM2 binds and phosphorylates
3‑kinase cause AKT activation, which in turn increases PFKP histone H3 at T11. PKM2‑dependent histone H3 modification
stability (59). In leukemic cells, the cyclin D3‑cyclin depen- contributes to EGF‑induced cyclin D1 and c‑MYC expression,
dent kinase 6 (CDK6) phosphorylates PFKP and suppresses tumor cell proliferation, cell cycle progression and brain tumori-
its activity (60), thus shifting the glucose‑derived carbon into genesis (67). In human lung cancer cells, the marked increase
the PPP. Through this mechanism, cyclin D3‑CDK6 enhances in intracellular ROS leads to the inhibition of the glycolytic
NADPH production to neutralize ROS. Snail1, which is a key enzyme PKM2 by oxidation of Cys358, which requires the
transcriptional repressor of epithelial‑mesenchymal transition transfer of glucose flux into the PPP, stimulating redox potential
(EMT), represses PFKP, leading to the glucose flux switch and ROS detoxification (68). In addition, PKM2 gene transcrip-
to PPP and the generation of NADPH (61). In addition, heme tion is activated by HIF‑1 by direct interaction with the HIF‑1α
oxygenase‑1/carbon monoxide reduces methylation of 6‑phos- subunit (69). Serine binds to and activates human PKM2, and the
phofructo‑2‑kinase/fructose‑2,6‑bisphosphatase 3 (PFKFB3) PKM2 activity in cells after depletion of serine is reduced. This
in cancer cells, thus redirecting glucose from the glycolysis reduction in PKM2 activity switches the cells into a fuel‑saving
pathway to the PPP, ensuring cancer cell resistance against mode in which more pyruvate is transferred to mitochondria to
oxidative stress (62). The dynamic regulation of PFKP enhances support cell proliferation (70).
the survival of cancer cells undergoing metabolic stress and
therefore increases their ability to metastasize in vivo. 4. PPP in malignant tumors

Role of PK in the conversion of glucose by glycolysis in the HCC is one of the most common cancers worldwide (71). Breast
PPP. PK converts phosphoenolpyruvate into pyruvate during cancer is the second most common cancer in the world, with 1.7
the third irreversible reaction of glycolysis; thus, PK serves an million new cases diagnosed annually (72). Lung cancer is the
important role in the control of metabolism in cancer cells. The leading cause of cancer‑associated mortality worldwide (73).
ratio between the active and inactive forms of PK in cancer One of the main features of these three malignancies is the
cells determines whether glucose is used for OXPHOS or for alteration of glucose metabolism. Improved understanding of
PPP to support cell growth (63). Low pyruvate kinase activity this metabolic alteration may therefore serve to optimize strat-
increases glucose influx into PPP for biosynthesis while high egies for the prevention, early diagnosis and treatment of HCC,
pyruvate kinase activity increases OXPHOS and decreases breast and lung cancer. In addition, a thorough understanding
glucose influx into PPP (64). PK possesses two isoforms of cancer cell metabolism may provide potential novel thera-
generated by alternative splicing of PK named M1 and M2, of peutic strategies for various types of cancer.
which expressions are location and time dependent: The pyru-
vate kinase M2 isoform (PKM2) is preferentially expressed PPP in HCC. Elevated expression of G6PD is associated with
in cancer cells, where complex regulation of its activity is HCC metastases and poor prognosis of patients with HCC,
essential for the control of cellular metabolism (65). and G6PD knockdown inhibits the proliferation, migration
 ONCOLOGY LETTERS 17: 4213-4221, 2019 4217

and invasion of HCC cell lines in vitro (74). In addition, G6PD inhibition of hexokinase using 2‑deoxyglucose induces chloro-
promotes HCC cell migration and invasion by activating the quine‑resistance in breast cancer (89). In addition, metformin
signal transduction and activator of transcription 3 (STAT3) stimulates the glycolytic flux caused by starvation by interfering
pathway to induce EMT (74). The transcription factor NRF2 with HK2 activity (90). Furthermore, the AMPK‑dependent
is required for G6PD induction, and miR‑1 is involved in its phosphorylation of PFKFB3 substitutes oxidative respiration
activation (75). BAG directly interacts with G6PD to suppress by glycolysis, which causes inhibition of cell death and of
the PPP flux, DNA synthesis and HCC cell growth (76). antitumor efficiency of the microtubule toxin in breast cancer
Furthermore, PTEN binds to G6PD to prevent formation of cells (91). Sonic hedgehog phosphorylates PFKFB3 to promote
the active G6PD dimer, which subsequently inhibits the PPP. glycolysis and proliferation of breast cancer cells, which
However, the AKT coactivator T cel1 leukemia/lymphoma is mediated by smoothened and p38/MK2 (92). In addition,
protein IA promotes G6PD activity and increases G6PD the 6‑phosphofructo‑2‑kinase/fructose‑2,6‑bisphosphatase 4
pre‑mRNA splicing and protein expression (77). Inhibitor of (PFKFB4) in breast cancer cells can phosphorylate the onco-
differentiation and DNA binding‑1 (ID1), regulates c‑MYC genic steroid receptor coactivator‑3, which rapidly increases
through Wnt/β‑catenin pathway activation to promote G6PD its transcriptional activity and promotes the glucose flux
promoter transcription and activate the PPP (78), which confers switch towards purine synthesis (93). Furthermore, PKM2 is
to HCC cells an oxaliplatin chemoresistance (79). In addition, phosphorylated at tyrosine 105 and forms oncogenic dimers
ID1 activates the PPP to increase NADPH production and in breast cancer cells, whereas PKM2 is largely unphosphory-
reduce intracellular ROS levels, thus promoting chemotherapy lated and forms non‑tumorigenic tetramers in non‑transformed
resistance in HCC. MCF10A cells (94). Moreover, the intragenic DNA methyla-
Numerous key enzymes from the glycolysis pathway are tion‑mediated binding of the protein brother of regulator of
involved in the carcinogenesis of HCC. The major distinction imprinted sites on the replacement exon of PK is associated
between HCC cells and normal hepatocytes is the difference with cancer‑specific splicing that promotes the Warburg effect
in enzymes that catalyze the first step of glucose metabolism. and thus breast cancer progression (95).
In normal hepatocytes, this step is catalyzed by glucokinase,
whereas this enzyme is lacking in HCC cells and is replaced PPP in lung cancer. G6PD is overexpressed in non‑small
by HK2 (80). The long non‑coding RNA taurine upregulated cell lung carcinoma (NSCLC) (96), and the survival rate of
gene 1 (TUG1) controls cell migration and glycolysis by regu- patients with overexpressed G6PD protein is significantly
lating the p21/miR‑455‑3p axis, which affects HK2 stability poorer compared with those of patients with no G6PD
during translation but not transcription (81). In addition, overexpression (97). In addition, G6PD inhibition enhances
miR‑125a overexpression significantly decreases HK2 protein lung cancer cell sensitivity to cisplatin by inducing oxidative
level in HCC cells, which indicates that miR‑125a directly stress (98). In addition, 6PGD promotes cisplatin resistance
targets HK2 (82). In addition, overexpression of STAT3 in lung cancer, through the decreased expression of miR‑206
upregulates HK2 mRNA and HK2 protein expression (83). and miR‑613 (23). G6PD and 6PGD may therefore represent
Furthermore, hypomethylation in the HK2 promoter CpG potential novel targets to overcome cisplatin resistance.
island (CGI) N‑shore region increases HK2 expression, and Furthermore, 6PGD is required for lung tumor cell migration
hypermethylation in the HK2‑CGI suppresses HK2 expres- in vitro through the promotion of c‑Met phosphorylation at
sion by inhibiting the interaction between a hypoxia response tyrosine residues (99). TKTL1 overexpression is an indepen-
element and HIF‑1α (84). dent predictor of survival in NSCLC (100). Small interfering
RNA‑mediated silencing of 6PGD has been demonstrated to
PPP in breast cancer. G6PD is closely associated with downregulate essential metabolic enzymes, including TKT,
molecular subtypes of breast cancer, and its upregulation is a which leads to inhibition of lung cancer cell migration (101).
negative prognostic factor in breast cancer (85,86). It has been HK2 is essential for lung cancer cell growth in vitro and
demonstrated that G6PD silencing increases the glycolytic lung cancer tumorigenesis in vivo (102). It has been reported
flux, reduces lipid synthesis and increases glutamine uptake in that EGFR signaling inhibition in NSCLC cells induces
breast cancer cells, whereas TKT silencing reduces glycolysis dramatic decrease in HK2 and PKM2 levels (103,104). In
flux (31). Overexpression of NSD2 in breast cancer induces addition, miR‑214 downregulation inhibits HK2 expression
cancer resistance to tamoxifen by upregulating G6PD and and NSCLC cell proliferation (105). NAD(P)H:quinone oxido-
HK2 expression, which enhances PPP flux (52). In addition, reductase 1 increases HK2 gene expression, which enhances
G6PD expression and activity are continuously unregulated cellular glycometabolism and stimulates NSCLC cell prolif-
in breast cancer cells, and it has been reported that G6PD eration (106). PFKFB1, 2, 3 and 4 mRNAs are overexpressed
inhibition leads to an increase in 5'‑AMP‑activated protein in human lung cancers compared with corresponding normal
kinase (AMPK) signaling, a decrease in lipid biosynthesis and tissues (107). It has been demonstrated that miR‑128 directly
the inhibition of breast cancer cell growth and survival (21). targets PFK liver type at the mRNA and protein levels in
Furthermore, TKT expression is associated with tumor size lung cancer cells by AKT phosphorylation inhibition (108).
in the 4T1/BALB/c syngeneic model, and high TKT levels are An increase in intracellular ROS leads to inhibition of the
associated with poor survival (87). glycolytic enzyme PKM2 through oxidation of cysteine 358,
The YAP/TEAD/p65 axis upregulates HK2 transcription, which requires glucose transfer into the PPP; this phenomenon
which promotes breast cancer cell migration. This axis may then stimulates ROS detoxification (68). All these enzymes
therefore represent a potential therapeutic target for treatment may represent potential targets to develop novel strategies for
of metastatic breast cancer (88). It has been reported that diagnosis and treatment of lung cancer.
4218 JIN and ZHOU: PENTOSE PHOSPHATE PATHWAY IN CANCER

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