8/9/2019 [6] Review Mistery of Cancer 2013
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Review
Unraveling the mystery of cancer metabolism in the genesis of
tumor-initiating cells and development of cancer
Gaochuan Zhang b,1, Ping Yang a,1, Pengda Guo a,1, Lucio Miele c, Fazlul H. Sarkar d,Zhiwei Wang a,e,, Quansheng Zhou a,a Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Afliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Soochow University,
Ministry of Health, Suzhou, Jiangsu 215123, PR Chinab Department of Bioinformatics, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu 215123, PR Chinac University of Mississippi Cancer Institute, Jackson, MS 39216, USAd Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USAe Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
a b s t r a c ta r t i c l e i n f o
Article history:
Received 6 January 2013
Received in revised form 6 March 2013
Accepted 11 March 2013
Available online 21 March 2013
Keywords:
Cancer metabolism
Stem cells
Cancer therapy
Oncogenic metabolic genes
Robust anaerobic metabolism plays a causative role in the origin of cancer cells; however, the oncogenic meta-
bolic genes,factors, pathways, andnetworks in genesis of tumor-initiating cells (TICs) havenot yet been system-
atically summarized. In addition, the mechanisms of oncogenic metabolism in the genesis of TICs are enigmatic.
In this review, we discussed multiple cancer metabolism-related genes (MRGs) that are overexpressed in TICs
and are responsible for inducing pluripotent stem cells. Moreover, we summarized that oncogenic metabolic
genes and onco-metabolites induce metabolic reprogramming, which switches normal mitochondrial oxidative
phosphorylation to cancer anaerobic metabolism, triggers epigenetic, genetic, and environmental alterations,
drives the generation of TICs, and boosts the development of cancer. Importantly, cancer metabolism is con-
trolledby positive and negative metabolic regulators. Positive oncogenic metabolicregulators, including keyon-
cogenic metabolic genes, onco-metabolites, hypoxia, and an acidic environment, promote oncogenic metabolic
reprogramming and anaerobic metabolism. However, dysfunction of negative metabolic regulators, including
defects in p53, PTEN, and LKB1-AMPK-mTOR pathways, enhances cancer metabolism. Loss of the metabolic bal-anceresults in oncogenic metabolic reprogramming, genesis of TICs, and tumorigenesis.Collectively, thisreview
provides new insight intothe roleand mechanismof these oncogenic metabolisms in the genesis of TICsand tu-
morigenesis. Accordingly, targeting key oncogenic genes, onco-metabolites, pathways, networks, and the acidic
cancer microenvironment appears to be an attractive strategy for novel anti-tumor treatment.
2013 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2. Overexpression of oncogenic metabolism-related genes triggers the genesis of TICs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.1. glycine decarboxylase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.2. Pyruvate kinase M2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3. Metabolic gene mutant driver oncogenic metabolic reprogramming and genesis of TICs . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.1. Oncogenic reprogramming of glucose metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513.1.1. MYC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.1.2. RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.1.3. AKT1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.1.4. SRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3.1.5. BCR-Abl and ALDH2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Biochimica et Biophysica Acta 1836 (2013) 4959
Correspondence to: Z. Wang, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, USA. Tel.: + 1 617
735 2474; fax: +1 617 735 2480.
Correspondence to: Q. Zhou, Cyrus Tang Hematology Center, Soochow University, Room 703-3505, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, PR China.
Tel.: +86 512 65882116; fax: +86 512 65880929.
E-mail addresses:[email protected](Z. Wang), [email protected](Q. Zhou).1 These authors contributed equally to this work.
0304-419X/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.bbcan.2013.03.001
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3.2. Oncogenic metabolic reprogramming of the glutaminolytic pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3.3. Oncogenic metabolic reprogramming of glycine metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4. Onco-metabolites cause oncogenic metabolic reprogramming and tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.1. 2-hydroxyglutarate (2-HG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.2. Lactate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.3. Kynurenine (Kyn) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5. The potential role of non-coding RNA in oncogenic metabolic reprogramming and tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . 54
5.1. miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
5.2. piRNAs and Piwi proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6. Loss of the metabolic Yin
Yang balance promotes cancer initiation and progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546.1. Positive oncogenic metabolic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.1.1. Oncogenes and onco-metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.1.2. Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.1.3. Acidic microenvironment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
6.2. Negative oncogenic metabolic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6.2.1. p53 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6.2.2. PTEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
6.2.3. LKB1 and AMPK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
7. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
1. Introduction
In 1927, the biochemist Otto Warburg found that cancer tissues had
a unique metabolic pattern distinct from normal tissues, by which can-
cer cells preferred a robust anaerobic metabolism even in the presence
ofsufcient oxygen [1]. In 1956, Warburg suggested the theory that an-
aerobic metabolism played a causative role in the origin of cancer cells
[2]. Unfortunately, cancer metabolism had not been paid enough atten-
tion for decades until recently when cancermetabolism was recognized
as a hallmark of cancer [3],playing a pivotal role in cell reprogramming
and initiation of cancers[4]. In addition to the rapid progress in cancer
metabolism, another breakthrough in the cancer research eld is the
nding of tumor-initiating cells (TICs) or cancer stem cells (CSCs). In
1997, Bonnet and Dick found that a small subpopulation of CD34 +
CD38 leukemic cells displayed strong self-renewal capability and dif-ferentiation potential, and could be leukemia-initiating cells[5]. Subse-
quently, TICs were also found in several solid tumors [6]. More recently,
a pivotal role of TICs in cancer initiation, development, metastasis and
drug resistance has been demonstratedin vivo[7,8]. However, the role
and mechanism of oncogenic metabolism in the genesis of TICs remain
to be further investigated.
Accumulated data have shown thatsustained anaerobicmetabolism
not only provides energy and various biomaterials to meet the demand
of tumor growth[9,10], but also contributes to the genesis of TICs and
tumorigenesis [3,4,11]. During the initiation and development of malig-
nant tumors, cancer cells usually reprogram their metabolism need
through vigorous aerobic glycolysis to produce sufcient energy and
various biomaterials. For a long time, it was generally believed that
tumor cells underwent robust glycolysis due to a defectin mitochondri-al glucose oxidative phosphorylation [1,2]. However, recent studies
have indicated that glucose oxidative phosphorylation in mitochondria
of most cancer cells was normal, and cells preferentially underwent an-
aerobic metabolism even in the presence of abundant oxygen. Cancer
cells reprogram glucose metabolism, amino acid, lipid, and nucleic
acid metabolism [911]. Cancer metabolism undertakes a complex pro-
cess that even Warburg did not expect[4,12]and the landscape of can-
cer metabolism has recently been broadened far beyond the classic
Warburg effect in cancer metabolism.
Despite a tremendous advance in cancer metabolism recently, the
role and mechanism of cancer metabolism in the genesis of TICs and de-
velopment of cancer remain unclear. In the present article, we extensive-
ly discussed recent progress in oncogenic metabolic reprogramming
during the generation of TICsand development of cancers, and addressed
the critical role of the loss of metabolic YinYang regulatory balance in
the initiation of cancer. Finally, we proposed new strategies and ap-
proaches to further study cancer metabolism in the generation of TICs
and malignant tumors, and to target onco-metabolites, oncogenic meta-
bolic genes, pathways, networks, and the acidic tumor microenviron-
ment for novel anti-tumor drug discovery and effective anti-cancer
therapy.
2. Overexpression of oncogenic metabolism-related genes triggers
the genesis of TICs
Recently, accumulated evidence suggests that metabolism-related
genes (MRGs) including glycine decarboxylase (GLDC) and pyruvate ki-
nase M2 (PKM2) areoverexpressed in TICs [1316]. It is knownthat gen-
eration of TICs is also driven by intrinsic and extrinsic factor-inducedepigenetic alterations and genomic DNA mutations. Whereas genetic
mutations have beentraditionally considered a major driving force in tu-
morigenesis, recent studies have shown that epigenetic alteration usual-
ly precedes genetic mutations and is crucial to initiation of cancer
[13,14]. Epigenetic changes, including DNA methylation, histone modi-
cations (acetylation, phosphorylation, ubiquitination, biotinylation, and
SUMOylation), and non-coding RNA, promote overexpression of various
oncogenic metabolic genes including GLDC and PKM2, resulting in onco-
genic metabolic reprogramming, genesis of TICs and tumorigenesis.
2.1. glycine decarboxylase
It hasbeen known that GLDC expression is up-regulated by oncogen-
ic MYC, Ras, and phosphatidylinositol 3-kinase (PI3K) during the cellulartransformation process[11].Zhang et al. recently found overexpression
of GLDC in TICs of non-small cell lung cancer (NSCLC), which resulted
in an increase in pyrimidine synthesis and promoted cell proliferation,
colony formation, genesis of TICs, and initiation of NSCLC[11]. GLDC in-
duced oncogenic metabolic reprogramming through stimulation of gly-
cine metabolism and pyrimidine synthesis and promotion of glycolysis,
which effectively overcomes the crisis of nucleotide deciency and repli-
cation stress in rapidly proliferative cells during tumorigenesis. In NIH/
3T3 cells, overexpression of GLDC markedly increased malignant trans-
formation in vitro and colony formation in vivo, while knockdown of
GLDC in lung cancer spheroid cells from patients with NSCLC inhibited
cellproliferation and colony formation, and signicantly impairedthe tu-
morigenicity of the cells[11]. These data indicate that GLDC is likely an
oncogenic metabolic driver for genesis of TICs in lung cancer [11,15].
50 G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959
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2.2. Pyruvate kinase M2
PKM2 belongs to the embryonic pyruvate kinase M2 isoform and
plays an important role in glucose metabolism during embryogenesis.
PKM2 expression is diminished after birth in normal people; howev-
er, various malignant tumors have atavism to overexpress PKM2
which is essential for cancer anaerobic metabolism and tumorigene-
sis. PKM2 overexpression facilitates lactate production in cancer
cells and promotes rapid tumor growth [16]. PKM2 gene transcriptionis activated by hypoxia-inducible factor 1 (HIF-1). Interestingly,
PKM2 interacts directly with the HIF-1 subunit and enhances
transactivation of various HIF-1 target genes and participates in a
positive feedback loop that boosts HIF-1 mediated reprogramming
of glucose metabolic pathway in cancer cells [17]. In addition, the
cancer stem cell surface biomarker CD44 is closely related to PKM2
function and initiation of cancers. CD44 interacts with PKM2 and en-
hances the glycolytic phenotype of cancer cells. Silencing of CD44 by
small interfering RNA increased mitochondrial respiration and
inhibited glycolysis[18]. The impact of CD44 on oncogenic metabolic
reprogramming and genesis of TICs is worthy of further investigation.
Besides the important role of PKM2 in glycolysis, PKM2 also regulates
protein phosphorylation, transcription, and cell signal transduction.
Recently, Yang et al. reported that PKM2 bound to histone H3 and el-
evated histone H3 phospholyration upon epidermal growth factor re-
ceptor (EGFR) activation, which caused the dissociation of HDAC3
from the CCND1 and MYCpromoter regions, and caused acetylation
of histone H3 at K9 and overexpression of c-Myc and cyclin D1,
resulting in tumor cell proliferation, cell-cycle progression, and
brain tumorigenesis [19,20]. Additionally, PKM2 promotes de novo
serine synthesis to stimulate mTORC1 activity and sustain cell prolif-
eration [21]. Furthermore, activation of EGF-EGFR signal pathway
causes translocation of PKM2 into the nucleus. Nuclear PKM2 binds
to -catenin and leads to histone H3 acetylation and cyclinD1 expres-
sion; hence, PKM2-dependent -catenin transactivation is critical to
EGF-promoted tumor cell proliferation and brain tumor development
[22].
Recently, PKM2 was found to promote aerobic glycolysis in cancer
cells[23]. Interestingly, in rapidly dividing cancer cells, PKM2 expres-sion was accompanied with the decreased pyruvate kinase enzyme
activity. Notably, phosphoenolpyruvate (PEP), a substrate for pyru-
vate kinase, can act as a phosphate donor and participate in the phos-
phorylation of the glycolytic enzyme PGAM1, which imply an
alternate glycolytic pathway in the proliferating cancer cells [23].
Moreover, one study demonstrated that SAICAR, an intermediate of
thede novo purine nucleotide synthesis pathway, can specically pro-
mote PKM2 expression in cancer cells, and subsequently change cel-
lular energy, glucose uptake and lactate production, leading to
cancer cell survival [24]. Furthermore, it has been revealed that
PKM2 promotes Warburg effect due to ERK1/2 phosphorylation and
nuclear translocation of PKM2[25].
In addition to GLDC and PKM2, overexpression of 3-hydroxy-3-
methylglutaryl-CoA reductase (HMGCR) is known to dysregulate themevalonate pathwayand promotes oncogenic transformationandcolony
formation in vitroand tumor growth in vivo [26]. Elevation of PTP4A1 and
PTP4A12(protein tyrosine phosphatase typeIVA, member 1, 2) levelsin
stably transfectedcells resulted in a transformedphenotype, suggesting
that they may play some role in tumorigenesis[27,28]. Collectively,
epigenetic alteration-induced overexpression of oncogenic metabolic
genes may cause aberrant metabolic reprogramming and drive the
genesis of TICs and development of cancer.
3. Metabolic gene mutant driver oncogenic
metabolic reprogramming and genesis of TICs
Abnormal epigenetic changes may cause genomic DNA to be
more susceptible to endogenous and exogenous genotoxic attack,
resulting in chromosome translocation, gene mutagenesis and genera-
tion of oncogenic metabolic genes. Oncogenic metabolic genes induce
reprogramming of glucose, glutamine, and glycine metabolism to
form discrete oncogenic metabolic pathways and networks, driving
the genesis of TICs and development of malignant tumors.
3.1. Oncogenic reprogramming of glucose metabolism
It is well known that cancer cells undergo robust glycolysis to ob-tain sufcient energy and build biomaterials for their rapid growth.
Overexpression or re-activation of key metabolism-related onco-
genes, such as MYC, KRAS, AKT1, SRC, and BCR-ABL, promotes onco-
genic reprogramming of glucose metabolism through up-regulation of
several key glycolytic genes, favoring the genesis of TICs and develop-
ment of cancer (Table 1).
3.1.1. MYC
Overexpression of MYC enhances phosphatidylinositol (PI) metabo-
lism in human kidney cancer cells[29]. MYC up-regulates the expression
of various glucose metabolic genes, including LDHA, PKM2, HK2, PDK1,
C6orf108 (RCL), GLUT1, GPI,phosphofructokinase, GAPDH,phosphoglycerate
kinase, and enolase, and reprograms glucose metabolic pathways [3033].
MYC boosts transcription of PTB, hnRNPA1, and hnRNPA2, enhances the
PKM splicing error, and results in the overexpression of embryonic pyru-
vate kinase isoform PKM2 that promotes aerobic glycolysis in tumors
[34,35]. In addition, MYC-induced hexokinase 2 (HK2) catalyzes therst
step of glycolysis, while MYC-induced PDK1 inactivates pyruvate dehy-
drogenase and diminishes mitochondrial respiration, resulting in a strong
Warburg effect [36]. The glycolysis in hypoxia in cancers also depends on
the cooperation between MYC and HIF1[36]. Moreover, MYC-induced
overexpression of lactate dehydrogenase A (LDHA) markedly upgrades
glycolysis and leads to overproduction of lactate to form an acidic
tumor microenvironment, which is essential for lactate-driven genesis
of TICs and MYC-mediated oncogenic transformation and tumorigene-
sis[37,38].MYC also reprograms glutamine, proline, glycine, and lipid
metabolic pathways, as well as elevates the expression of genes that
are related to fatty acid and glycerophospholipid synthesis, such as
MECR,ACSL1,AACS,ACAT1,AGAPT5,DGAT2, andLYPLA1, resulting in anincrease in lipidbiosynthesis [39]. Additionally, MYC regulates the keto-
genic metabolism pathway through down-regulation ofHMGCS2gene
expression [40,41]. Furthermore, MYC promotes the nucleotide biosyn-
thetic pathwayviaup-regulation ofTYMS,IMPDH1,IMPDH2, andPRPS2
in various tumors[4244], as well as inhibits p53 function, thereby ad-
vancing tumorigenesis[45]. Consistent with the pivotal role of MYC in
oncogenic metabolic reprogramming, our recent bioinformatic analysis
indicated that MYC was overexpressed in various human cancer stem
cells andmalignanttumor tissues [13]. Together, MYC could bea master
oncogenic metabolic driver for metabolic reprogramming, genesis of
TICs, and tumorigenesis.
3.1.2. RAS
Overexpression of RAS family oncogenes (KRAS,HRAS, and NRAS) in-duces oncogenic metabolic reprogramming, stimulates glycolysis to pro-
duce lactate and alpha-ketoglutarate (-KG), and enhances synthesis of
nucleic acids and lipids [4648].Activation of KRAS (G12V) decreases
mitochondrial glucose oxidative phosphorylation, but increases glycoly-
sis in cells[49].Additionally, RAS stimulates phospholipid metabolism
via up-regulation of either phospholipase C or phospholipase A2 activity
in the inositol phospholipid signaling pathway [5052]. Thus, RAS-
mediated oncogenic metabolic reprogramming, including glycolysis
and lipid metabolism, is vital to support cancer cell growth[53].
3.1.3. AKT1
Frequent dysregulation of AKT1 has been observed in various human
cancers. AKT1, a serine/threonine kinase, has been found to promote cell
survival and suppress apoptosis through multiple mechanisms including
51G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 49 59
8/9/2019 [6] Review Mistery of Cancer 2013
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the regulation of glucose metabolism. AKT1 can increase mitochondria-
associated hexokinase (hexokinase I and II) activity and inhibit
cytochrome c release and apoptosis in cancer cells. Similar to MYC,
the activation of AKT1 can also lead to the Warburg effect through in-
creased cellular glucose uptake, glycolysis, and lactate generation.Once inhibiting glycolysis, AKT1-activated cells are susceptible to apo-
ptosis which is different from MYC-activated cells that are sensitive to
the inhibition of mitochondrial function[54]. Therefore, it is required
to further investigate the molecular mechanism of AKT1-regulated can-
cer metabolism.
3.1.4. SRC
The tyrosine kinase SRC is overexpressed in several cancer cells, and
differentiated cells rely mainly on oxidative phosphorylation to gener-
ate ATP. It has been demonstrated that the activation of SRC regulates
phosphoinositide metabolism through stimulating the expression of
basal phospholipase A2 (PLA2), and induces the remodeling of energet-
ic metabolism through the stabilization of HIF1A and increased activi-
ties of several glycolytic enzymes including HK1 and HK2 [55]. Theactivationof SRC canpromote themetabolic reprogramming and subse-
quently elevate aerobic glycolysis in cancer cells. Moreover, SRC kinase
sustains mitochondrial respiration by phosphorylating the NDUFB10
subunit of complex I in human cancer cells[56]. Without a doubt, the
exact molecular mechanism by which SRC promotes reprogramming
of glucose metabolism needs to be further elucidated.
3.1.5. BCR-Abl and ALDH2
The well-known fusion protein BCR-Abl induces metabolic
reprogramming and generation of TICs in chronic myeloid leukemia
(CML), a myeloproliferative disorder of pluripotent stem cells [57].
Barger et al. found that BCR-Abl potently activates the protein kinase
S6K1 that drives glycolysis in leukemia cells. BCR-Abl-activated S6K1
stimulates transcription of metabolic genes, such as HIF1A, sterol
regulatory element-binding protein genes (SREBP1and SREBP2), and
many other cancer metabolic genes, promoting oncogenic metabolic
reprogramming and leukemogenesis[58,59]. Moreover, overexpression
of BCR-Abl activates multiple cancer metabolism signal pathways [60].
In addition, the defect in aldehyde metabolism due to mutations in theALDH2 gene increases the acetaldehyde-mediated DNA damage that con-
tributes to cancerous predisposition in patients with Fanconi's anemia, a
pre-leukemic condition[61], in which approximately 5% of the patients
develop leukemia subsequently.
3.2. Oncogenic metabolic reprogramming of the glutaminolytic pathway
The other oncogenic metabolic reprogramming involves gluta-
minolysis. When tumor cells undergo robust glycolysis, glucose cannot
effectively enter the tricarboxylic acid (TCA) cycle to produce suf-
cient adenosine-5-triphosphate (ATP) and biomaterials required for
rapid tumor growth; alternatively, tumor cells manage to reprogram
glutaminolytic and biosynthetic pathways. Increased glutaminolysisis now recognized as a key feature of the cancer metabolism and
contributes to the core metabolism of proliferating cells by supporting
energy production and biosynthesis[62]. Oncogenic MYC plays a pivotal
role in metabolic reprogramming of the glutaminolytic pathway. MYC
stimulates mitochondrial glutamine uptake and catabolism to meet the
cellular requirement for protein and nucleotide biosynthesis through
up-regulation of glutaminolytic genes, such as genes encoding the gluta-
mine importers ASCT2 andSN2[63]. MYC also enhances the expression of
mitochondrial glutaminase, which stimulates glutamine metabolism and
converts glutamine to glutamate, as well as increases mitochondrial pro-
ductionof acetyl-CoAfor fatty acid biosynthesis [6466]. In addition, MYC
also promotes proline anabolism by inhibiting proline oxidase and en-
hancing the enzyme activity of proline biosynthesis from glutamine
[64]. Obviously, tumor cells reprogram the metabolic pathway to obtain
Table 1
Oncogenic metabolic reprogramming drives the genesis of tumor-initiating cells and tumorigenesis.
Gene name Role in cancer metabolism Genesis of tumor-initiating cells (TICs) and
tumorigenesis
Reference
MYC Promotes g lycolysis and g lutamine, proline, glycine,
lipid metabolisms; nucleotide biosynthesis.
Triggers oncogenic metabolic reprogramming,
increment of stemness, genesis of TICs, and
tumorigenesis.
[2945,6466]
RAS (KRAS, HRAS, NRAS) Activate glycolysis as well as glutamine,
phospholipid, polyamine, and nucleic acid
metabolism.
Induce metabolic reprogramming that is essential
for RAS-mediated tumorigenesis.
[4653]
AKT1 Enhances glycolysis. Abnormal AKT1 activation promotes glycolysis and
cancer cell survival.
[54]
SRC Stimulates glycolysis as well as energy and
phosphoinositide metabolism.
Induces remodeling of energetic metabolism in
cancer cells and increases cell proliferation.
[55,56]
BCR-AB L Increas es glycolysis and RAC-mediated superoxide
production.
Induces metabolic reprogramming and generation
of TICs in chronic myeloid leukemia.
[57,60]
CD44 Interacts with PKM2 to enhance glycolysis. As a cancer stem cell marker, CD44 is implicated in
the genesis of TICs and initiation of cancers.
[18]
GLDC Triggers glycine and pyrimidine metabolism as well
as glycolysis.
Drives the genesis of TICs in non-small cell lung
cancer.
[11,71]
IDH1, IDH2 Catalyze NADPH-dependent reduction of KG to
2-hydroxyglutarate (2-HG).
Mutation in IDH1 and IDH2 contributes to initiation
and progression of gliomas and leukemia.
[7388]
PTP4A1, PTP4A2 Stimulate protein tyrosine phosphorylation. Result in a transformed phenotype and may play
some role in tumorigenesis.
[26,27]
ALDH2 Causes defective aldehyde metabolism Mutations in ALDH2 increase DNA damage and
contribute to cancer predisposition in Fanconi
anemia patients.
[28]
2-Hydroxyglutarate (2-HG) Inhibits histone demethylation, leading to
genome-wide histone and DNA methylation
alterations.
Causes epigenetic alteration and promotes
transformation and tumorigenesis.
[7388]
Lactate Promotes tumor growth and causes oncogenic
metabolic reprogramming.
Increases cell stemness and promotes stem cell
growth, genesis of TICs, and oncogenesis.
[8991]
Kynurenine (Kyn) Functions as an endogenous ligand of the human
aryl hydrocarbon receptor (AHR).
Contributes to malignant progression and poor
survival in human brain tumors.
[9396]
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sufcient energy and bio-materials through glutaminolysis for their
sturdy growth[64,6770].
3.3. Oncogenic metabolic reprogramming of glycine metabolism
In addition to the reprogramming of glycolysis and the glutaminolytic
pathway in tumor cells, oncogenic metabolic reprogramming of glycine
metabolism emerges as another critical process in cancer metabo-
lism and a driving force for tumor initiation. As stated previously,overexpression of GLDC triggers the genesis of TICs in lung cancer
through its catalytical activity in glycine metabolism, pyrimidine
synthesis, and glycolysis [11]. More recently, Jain et al. used mass
spectrometry to measure the metabolic prole of the NCI-60 cancer
cell lines and revealed robust glycine metabolism which was closely
correlated with proliferation of cancer cells, and further documented
overexpression of genes in the glycine metabolic pathway that was
associated with poor prognosis in breast cancer patients. Whereas
inhibition of glycine uptake and its mitochondrial biosynthesis pref-
erentially impaired rapidly proliferating cells [71], suggesting that
glycine metabolism plays an important role in cancer development.
Together, overexpression or activation of oncogenes, such as MYC,
KRAS,AKT1, SRC, and GLDC, drives oncogenic reprogramming of glu-
cose, glutamine, and glycine metabolic pathways, resulting in the
genesis of TICs and initiation of malignant tumors.
4. Onco-metabolites cause oncogenic metabolic reprogramming
and tumorigenesis
It has been well established that tumor cells produce more lactate
and other metabolic materials than normal cells (14); however, the
associated metabolites have not been recognized as a driving force in
tumorigenesis until the last 5 years. Emerging evidence has shown
that several metabolites, such as 2-hydroxyglutarate (2-HG), lactate,
and kynurenine, may cause several epigenetic and genetic alterations,
resulting in the genesis of TICs and oncogenesis; hence, these onco-
genic metabolites have recently been called onco-metabolites[72].
4.1. 2-hydroxyglutarate (2-HG)
Cytosolic isocitrate dehydrogenase 1 (IDH1) or its mitochondrial ho-
molog IDH2 could sustain mutations, such as IDH1-R132, IDH2-R172,
and IDH2-R140, that cancause a defect in theconversion from isocitrate
to alpha-ketoglutarate (-KG).However, IDH mutantsstrongly catalyze
2-HG production and, consequently, 2-HG accumulates in various can-
cer patients[7376], including those with glioma[76], acute myeloid
leukemia (AML)[77,78],thyroid carcinoma[79], and chondrosarcoma
[80]. For example, Luchman et al. found that a glioma tumor stem cell
line (BT142) with an endogenous IDH1-R132H mutation produced
high 2-HG levels and demonstrated aggressive tumor-initiating capaci-
tyin vitroand in vivo; additionally, the glioma stem cells were readily
propagated in orthotopic xenografts of NOD/SCID mice [81].Condition-
al IDH1 mutation (R132H) knock-in mice also showed increased 2-HGproduction and early hematopoietic progenitors, as well as developed
anemia with extramedullary hematopoiesis[82]. Mutation of IDH1 or
IDH2 causes high 2-HG levels in some cancer patients, and the amount
of onco-metabolite 2-HGin cancerpatients canbe up to 100-fold higher
thanthat in normal individuals [83]. Overproduction of 2-HG is respon-
sible for the oncogenic feature in IDH1 and IDH2 mutations, implying
that 2-HG could be a key player in the initiation of cancer in patients
with IDH mutations[84]. Mechanistic studies have shown that 2-HG
competitively inhibited -KG-dependent enzymes, such as histone
demethylases and DNA hydroxylases, leading to profound epigenetical-
terations and tumorigenesis. Xu et al. demonstrated that2-HG occupied
the same space as-KG in the active site of histone demethylases and
inhibited histone demethylation and 5-methylcytosine hydroxylation,
as well as caused an increase in histone methylation, but a decrease in
5-hydroxylmethylcytosine, resulting in genome-wide histone and
DNA methylation alterations[85]. 2-HG signicantly increased his-
tone H3K9 methylation and elevated repressive histone methyla-
tion marks; notably, it effectively repressed the expression of various
lineage differentiation-specic genes and caused blockage of cell differ-
entiation, thereby increasing the cancer stem/progenitor population
[86]. Consistent with these ndings, cells derived from IDH1-mutant
(R132H) knock-in mice have hypermethylated histones and abnormal
DNA methylation, similar to those observed in human IDH1-mutantAML[87]. Particularly, R-2HG, but not S-2HG, enhances proliferation
and soft agar growth of human astrocytes[88]. Collectively, the onco-
metabolite 2-HG inhibits histone demethylation, increases DNA and
histone methylation, causes abnormal genome-wide histone and DNA
methylation, and stimulates overexpression of oncogenic genes,
resulting in cell reprogramming, expansion of stem/progenitor cells,
blockage of cell differentiation, and tumorigenesis[85].
4.2. Lactate
Traditionally, lactate from glycolysis has been considered a high-
energy metabolic fuel for tumor cells. Emerging evidence has shown
that lactate in tumor tissues also plays a pivotal role in metabolic
reprogramming, which is an early event in the development of malignant
tumors; additionally, high lactate levels in cancer patients have been
identied as a prognostic parameter for metastasis and poor overall sur-
vival of cancer patients[89].Ubaldo et al. recently reported that lactate
not only promoted stem cell growth, but also increased cell stemness.
Mechanistic studies revealed that lactate caused cell reprogramming
through overexpression of genes associated with stemness, including
genes that encode several stem cell-associated transcription factors
(SP1,MAZ,MEIS1,MLLT7, LEF1,TCF3,ELK1, SREBF1,PAX4, andESRRA); ad-
ditionally, lactate elevated nuclear histone acetylation and epigenetic al-
teration in MCF7 cancer cells and promoted dissociation of histones
from DNA, as well as enhanced gene transcription[89]. Lactate also pro-
motes the production and secretion of VEGF, a potent tumor angiogenic
driver, and induces the formation of tumor new vasculature and growth
[90]. In addition to tumor cell production of lactate, cancer-associated-broblasts undergo strong aerobic glycolysis and secrete lactate to feed
adjacent cancer cells, promoting cell reprogramming and increasing cell
stemness [91]. In addition, lactate recruits human MSCs towards
tumor cells to enhance stem cell migration[92]. Furthermore, L-lactate
stimulates cancer metastasis in the lung by 10-fold[92]. Collectively, the
onco-metabolite lactate causes oncogenic metabolic reprogramming
and enhances cell stemness, genesis of TICs, and tumor growth; and accu-
mulation of lactate in solid tumors is an important early event in the de-
velopment of cancer.
4.3. Kynurenine (Kyn)
Indoleamine 2, 3-dioxygenase catalyzes tryptophan metabolismto produce kynurenine. Various human tumor cells constitutively
generate a high level of kynurenine, which functions as an en-
dogenous ligand of the human aryl hydrocarbon receptor [93].
Kynurenine suppresses endogenous antitumor immunity and pro-
motes tumor cell survival and tumorigenesis [93,94]. Patients with
endometrial, ovarian, and vulvar cancer have high levels of serum
kynurenine and a high Kyn/Trp ratio compared with controls,
suggesting that kynurenine may contribute to these gynecologic
cancers[95]. Interestingly, a pilot study showed that an increase in
tryptophan degradation and a high level of kynurenine were ob-
served in early-stage breast cancer [96].Together, these data suggest
that kynurenine may be a novel onco-metabolite to promote tumor-
igenesis and further investigation is warranted especially in brain
tumors.
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5. The potential role of non-coding RNA in oncogenic metabolic
reprogramming and tumorigenesis
In addition to glycolysis, abnormal nucleic acid metabolismemerges
as a new player in oncogenic metabolic reprogramming in cells. Nota-
bly, aberrant microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs)
have been found in TICs and have been implicated in oncogenic meta-
bolic reprogramming and tumorigenesis[97].
5.1. miRNAs
Epigenetic alterations may cause an abnormal miRNA expression pro-
le and produce onco-miRNAs, such as miR-302s, miR-21, miR-27a,
miR-96, and miR-182, whichinduceoncogenic metabolic reprogramming
and tumorigenesis [98101]. For example, miR-23b stimulates glutamine
catabolism in human kidney tumors[64]. Additionally, miR-122 inhibits
mitochondrial metabolic function and is involved in the regulation of
fatty acid and cholesterol metabolism in hepatocellular carcinoma
[102,103]. Conversely, certain miRNAs have been implicated to have an
inhibitory effect on oncogenic metabolic reprogramming, including
let-7, miR-133a/b, miR-143, miR-145, miR-181a, miR-22, miR-23a/b,
miR-29b, miR-326, miR-34a, and miR-502 [104114]. For instance,
miR-326 inhibits embryonic and tumor-dominant PKM2 and induces ap-
optosis in glioma and glioma stem cells [109]. The miR-133a suppresses
glutathione S-transferase P1 and exerts a tumor suppressive effect in
head and neck squamous cell carcinoma[111]. The miR-143 impedes
glycolysis, cancer cell proliferation, and tumor formation through inhi-
bition of HK2expression in cancer cells [104,112,113]. ThemiR-34a par-
ticipates in multiple tumor suppressive pathways by suppressing
inosine 5-monophosphate dehydrogenase, a rate-limiting enzyme of
de novoguanosine-5-triphosphate biosynthesis[107,114]in addition
to many direct targets of miR-34a. However, the mechanisms of
miRNA-dominant oncogenic metabolic reprogramming remain to be
further investigated.
5.2. piRNAs and Piwi proteins
Dysfunction of piRNAs and their partner Piwi proteins is associatedwith the genesis of TICsand tumorigenesis. The piRNA 651 is aberrantly
overexpressed in multiple cancers, including gastric, colon, lung, and
breast cancer [115]. ThepiRNAs interact with thePiwi familyof proteins
to regulate the stem-likeepigenetic state of cancer and cell stemness.
For example, both mouse Piwil2 and the human Piwi ortholog Hiwi
have been found to be aberrantly expressed in various human cancers,
and abnormal expression of Piwil2 and Hiwi has been found to be asso-
ciated with the development of TICs and tumorigenesis, and it was
further correlated with poor clinical prognosis of cancer patients
[116]. We have recently reported that tumor cells overexpressed sever-
al N-ternimal truncated Piwil2 variants, called Piwil2-like proteins,
which are implicated in tumorigenesis[117]. More recently, Siddiqi et
al. demonstrated that overexpression of Hiwi in mesenchymal stem
cells inhibited cell differentiation in vitroand promoted the generationof sarcomasin vivo; in addition, Hiwi enhanced DNA methylation, act-
ing as a tumor suppressor gene [118]. The piRNAs play important
roles in maintaining genome integrity by epigenetic silencing of trans-
posons in the genome via DNA methylation. In addition to DNA methyl-
ation, Piwil2 enhances histone H3 acetylation and chromatin relaxation
[119]. Thus, piRNAs control cellular DNA methylation and histone H3
acetylation, and defects in piRNAs and Piwil2/Hiwi proteins contribute
to the genesis of TICs and oncogenesis.
6. Loss of the metabolicYinYang balance promotes cancer initiation
and progression
In healthy individuals, metabolism is tightly controlled by a positive
regulatory force (Yang) and negative regulatory force (Yin) to achieve
a YinYang balance. Intrinsic and extrinsic oncogenic factors may cause
loss of this metabolicYinYang balance,resulting in oncogenic metabolic
reprogramming and tumorigenesis. Accumulated data have shown that
positive oncogenic metabolic regulatory factors, such as oncogenes and
onco-metabolites, hypoxia, and an acidic environment, drive oncogenic
metabolic reprogramming and tumorigenesis; conversely, inactivation
of negative metabolic regulatory factors (Yin) also triggers oncogenic
metabolic reprogramming and cancer initiation. Thus, loss of the meta-
bolic Yin
Yang balance is critical to the initiation of TICs and develop-ment of malignant tumors (Fig. 1).
6.1. Positive oncogenic metabolic regulation
6.1.1. Oncogenes and onco-metabolites
As mentioned above, intrinsic and extrinsic oncogenic factors, such
as metabolism-related oncogenes, onco-metabolites, hypoxia, and an
acidic environment, act as positive oncgenic metabolic regulators to
promote oncogenic metabolic reprogramming and initiation of cancer.
Thus, the key oncogenes includeMYC,MYCN,FOS,RAF,MOS,RAS,SRC,
MET, TRK, GLDC, IDH1, IDH2, Piwil2, HMGCR, PTP4A1, PTP4A2, and
ALDH2, whereas the key onco-metabolites include 2-HG, lactate, and
kynurenine (Fig. 1).
6.1.2. Hypoxia
The key extracellular positive oncogenic regulators are hypoxia and
an acidic microenvironment. When a tumor expands to larger than
2 mm in diameter, the central part of the tumor lacks oxygen; thus, the
tumor cells in a large tumor survive under hypoxic conditions. Hypoxia
induces overexpression of HIF1A, which functions as a master trans-
cription factor to activate transcription of several hundred genes, includ-
ing various metabolic, angiogenic, proliferative, and metastatic genes.
HIF1A induces the expression of glucose transporters GLUT1 and
GLUT3, glycolytic enzymes HK1 and HK2, phosphoglycerate kinase 1,
and LDHA, promoting glycolysis to produce lactate. In addition, HIF1A in-
duces a switch from mitochondrial oxidative phosphorylation to aerobic
glycolysis under hypoxic conditions through reduction of oxygen con-
sumption in mitochondria and activation of LDHA. HIF1-induced meta-bolic reprogramming is not onlylimitedto carbohydrate metabolism, but
also lipid metabolism[120]. HIF1 induced-glycolysis is essential for the
generation of stem cells and maintenance of the stemness of hematopoi-
etic stem cells, and HIF1 plays a crucial role in the survival and mainte-
nance of leukemic stem cells in CML [121]. Under hypoxia, prostate
cancer cells express higher HIF1and HIF-2 levels, and gain stem-like
cell properties, including overexpression of Oct3/4, Nanog, CD44, and
ABCG2, formation of additional colonies and spheres, and production of
an increased side population [122]. Similarly, under hypoxia,ovariancan-
cer cell lines ES-2 and OVCAR-3 overexpress Oct3/4, Sox2, and the cancer
stemcell marker CD133, as well as become putativecancerstem-like cells
[123]; additionally, nuclear HIF1A is closely related to overexpression of
CD133 in renal cell carcinoma [124]. Thus, hypoxia-induced HIF1A
plays an important role in metabolic reprogramming and genesis of TICs.
6.1.3. Acidic microenvironment
Tumor cell mediated oncogenic metabolism generates abundant
lactic acid and protons, leading to the reduction in the extracellular
pH values to as low as 6.0 (the usual range is 6.57.0) in tumor tissues
[125]. As mentioned above, the onco-metabolite lactate induces on-
cogenic metabolic reprogramming and boosts cell stemness. Acidic
pH activates mTOR and its downstream target (Eif4ebp1), insulin
modulators (Trib3 and Fetub) and facilitates anaerobic metabolism,
but diminishes catabolic processes; and these effects were indepen-
dent of changes in oxygen concentration or glucose supply [126].
The tumor acidic microenvironment fosters initiation of TICs, tumor
progression, and metastasis [89]. Because hypoxia and low pH are
usually coupled in tumor tissues, the net impact of low pH on
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oncogenic metabolic reprogramming and genesis of TICs need to be
claried.
6.2. Negative oncogenic metabolic regulation
Increasing data have shown that p53, PTEN, LKB1, and AMPK are mas-
ter genes responsible for the negative regulation of cancer metabolism.
6.2.1. p53
The tumor suppressor p53 is a master transcription factor that con-
trols normal metabolism in cells through multiple metabolicand signal-
ing pathways (Fig. 1). First, p53 inhibits the transcription of the
transporters GLUT 1 and 4, impeding cellular glucose uptake. Second,p53 induces the expression of the TIGARgene, which lowers the intra-
cellular concentrations of fructose 2,6 bisphosphatase and decreases
glycolysis. Third, p53 increases ubiquitination of phosphoglycerate
mutase and reduces the activity of this glycolytic enzyme. Fourth, p53
enhances the expression ofcytochromec oxidase2 (SCO2) andglutaminase
2 genes and increases the rate of the TCA cycle and oxidative phosphory-
lation. Cells with mutant p53 have a low efcacy of oxidative phos-
phorylation, but a robust glycolysis. Furthermore, p53 regulates the
transcription of the genes PTEN, IGF-binding protein-3, tuberous
sclerosis protein 2, as well as the gene encoding the beta subunit of
AMPK, all of which negatively regulate the AKT-mTOR signaling path-
way[127,128].Thus, p53 favors glucose oxidative phosphorylation and
impedes the Warburg effect, exerting an anti-tumor metabolic effect
along with tumor suppressive function [129]. The p53 mutation or
silencing of p53 expression leads to metabolic reprogramming and
tumorigenesis. Strikingly, mutation in the p53 gene occurs in ap-
proximately 50% of human cancers, and p53 knockout mice easily
grow various tumors; therefore, deciency in the anti-cancer meta-
bolic function of p53 will facilitate metabolic reprogramming and
cause stem-like phenotypes in p53 mutant cells.
6.2.2. PTEN
The tumor suppressor genePTENencodes a lipid phosphatase that
degrades phosphatidylinositol-3,4,5-triphosphate and inhibits the
PI3K-Akt-mTOR pathway. PTEN governs cellular energy metabolism
and many other activities[130]. PTEN transgenic mice show increasedenergy expenditure and reduced body fat accumulation. Cells derived
from these mice show reduced glycolysis and glucose but increased mi-
tochondrial oxidative phosphorylation, and the cells are resistant to on-
cogenic transformation. Elevation of the PTEN level and activity inhibits
PI3K-Akt-mTOR-dependent and -independent pathways and reverses
cancer metabolism from glycolysis to oxidative phosphorylation. Thus,
PTEN acts as an inhibitor of oncogenic metabolism [131,132]. PTEN
loss leads to the activation of the PI3K/AKT signaling pathway and
switch to cancer metabolism, which correlates with human cancer ini-
tiation, progression,and metastasis [133]. In addition,PTENlossin pros-
tate cancer causes signicant enhancement in the RAS/MAPK pathway
and increases stem/progenitor subpopulation, causing epithelial-to-
mesenchymal transition (EMT) and macrometastasis [134]. Together,
PTEN is an important negative oncogenic metabolic regulator.
Fig. 1.Loss of metabolic YinYang balance causes the initiation of TICs and development of malignant tumors. An increase in key oncogenic metabolic drivers and decrease in on-
cogenic metabolic inhibitors result in loss of the balance of metabolic-regulation and cause metabolic reprogramming, genesis of TICs, and tumorigenesis. Legends: activation,
inactivation.
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6.2.3. LKB1 and AMPK
Malignanttumor tissuesusually consume more ATPthan normaltis-
sues, and thus the tumor is often under metabolic stress; however, the
tumor undergoes oncogenic metabolic reprogramming to adapt to the
stress through altering the LKB1-AMPK pathway[135]. Both LKB1 and
AMPK are tumor suppressors and participate in an energy-sensing cas-
cade that responds to the depletionof ATP, acting as a master metabolic
regulator. LKB1 activates its downstream signaling protein AMPK. The
LKB1-AMPK pathway inhibits anabolic processes but stimulates cata-bolic processes, and plays a critical role in the inhibition of oncogenic
metabolism[136]. Recent studies have revealed the serine/threonine
kinase LKB1 to be at the crossroads linking energy metabolism and he-
matopoietic stem cell maintenance, and deletion of LKB1 has been
shown to promote tumorigenesis and metastasis[137139]. Germline
mutations inLKB1lead to cancer-susceptible PeutzJeghers Syndrome
(PJS), EMT, and defects in cell differentiation. Multiple LKB1mutations
have been identied in variousmalignant tumors, such as sporadic can-
cers and epithelial cancers[140147].
AMPK is a metabolic master switch that senses intracellular energy
status, and it is activated in the presence of decreased levels of ATP
and increased levels of AMP or ADP[148150]. AMPK is activated by
phosphorylation of the activation loop within the kinase domain by
the upstream kinase LKB1; once activated, AMPK phosphorylates a
broad range of downstream targets, in particular, mTOR, a central con-
troller of energy metabolism, cell growth, and proliferation[151153].
Activation of AMPK with metformin inhibits the reprogramming of
mouse embryonic and human diploid broblasts into iPS cells, and
AMPK activators hinder oncogenic metabolic reprogramming even
with a deciency in p53[154]. AMPK activation results in enhanced
ATP-producing pathways, but reduces ATP-consuming pathways, and
switches cancerous glycolysis to normal oxidative phosphorylation.
These data indicate that AMPK activation exerts an anti-cancer meta-
bolic reprogramming effect and activation of AMPK could be a new
strategy for metabolictargeting of TICs and cancercells [155157]. Clin-
ical studies have shown that AMPK activation is associated with an in-
crease in life span [158] and prolongation of survival of patients
diagnosed with lung cancer and many other malignant tumors[159].
In contrast,AMPKgene mutation has been found to be closely associat-ed with various cancers and thatthe down-regulation ofAMPKgene ex-
pression has been found in various cancers, including hepatic [160],
colonal[161], gastric[162], kidney[163], ovarian[164], and various
other malignant tumors[165167].
In summary, the LKB1-AMPK-mTOR pathway is a key metabolic
switch between normal and malignant cells. Activation of the
LKB1-AMPK-mTOR pathway suppresses malignant metabolic re-
programming, transformation, and tumor cell proliferation, whereas
defects in the LKB1-AMPK-mTOR pathway enhance cancer metabolism
and tumorigenesis. Thus, the LKB1-AMPK-mTOR pathwayappears to be
an attractive target for anti-cancer metabolic agent and antineoplastic
drug discovery.
7. Conclusions and perspectives
In conclusion, emerging evidence hasindicated that an excess of pos-
itive (Yang) oncogenic metabolic regulators, including metabolism-
related oncogenes, onco-metabolites, hypoxia, and an acidic environ-
ment, and deciency of negative (Yin) metabolic regulators, such as
p53, PTEN, LKB1, and AMPK could switch aerobic metabolism to anaero-
bic metabolism in cells through re-engineering of metabolic pathways
andnetworks. Therefore, theloss of metabolic YinYang balance triggers
cell reprogramming, genesis of TICs, and the development of cancer. Al-
though cancer metabolism is regardedas the seventh hallmarkof cancer,
the mechanisms of oncogenic metabolic reprogramming in the genesis
of TICs are still incomplete. We still face with many challenges, including
(1) identifying specic cancer metabolic drivers and metabolic regula-
tors during cancer initiation and development, (2) deciphering the key
knots of oncogenic metabolic pathways and networks, (3) studying the
dynamics of oncogenic metabolism in driving the genesis of TICs, and
(4) nding specic biomarkers and targets of cancer metabolism for
novel anti-cancer drug discovery.
Oncogenic metabolic reprogramming is necessary for the genesis of
TICs and development of cancer, and the acidic microenvironment
caused by aerobic glycolysis nurtures the generation and maintenance
of TICs. Thus, cancer metabolism is an attractive target for cancer ther-
apy. The anti-diabetic drug metformin has demonstrated anti-tumorproperties, and is increasingly being considered a drug to prevent and
treat obesity-related cancers. Metformin induces phosphorylation of
acetyl-CoA carboxylase alpha, inhibits the expression of lipogenic tran-
scription factor SREBP1c, and blocks the formation of malonyl-CoA.
Metformin-induced activation of AMPK can reduce stemness of cancer
cells and inhibit tumor cell proliferation of breast cancer cells in vitro
andin vivo[168]. Interestingly, metformin also suppresses the growth
of TICs and various tumor cells[169,170]. However, the effects of met-
formin in anti-tumor therapies are not satisfactory by its low tumor
specicity and moderate anti-cancer efcacy, which have prevented
successful and wide clinical use in anti-cancer therapy. Thus, it is neces-
sary to use a new strategy to identify highlyspecic oncogenic metabol-
ic targets and to discover novel effective anti-cancer metabolic drugs.
Targeting key knots of cancer metabolism, including (1) inhibition of
specic oncogenic metabolic genes and key regulators, (2) blockage of
oncogenic metabolic pathways and disruption of cancer metabolic net-
works, (3) elimination of onco-metabolites, and (4) normalization of
the acidic tumor environment, may efciently suppress the genesis of
TICs and progression of cancer, and thus the future appears to be
brighter in the development of new therapeutics to balance the Yin
Yang phenomenon toward cancer therapy.
Conict of interest
The authors declare that they have no conict of interest.
Acknowledgements
This study was supported by grants from the National Natural Sci-
ence Foundation of China (grant nos. 30971138 and 81172087), the
Chinese Academy of Science Special National Strategic Leader Project
(no. XDA01040200), the Suzhou City Scientic Research Funds (nos.
SWG0904, SS201004, and SS201138), and a project funded by the Pri-
ority Academic Program Development of Jiangsu Higher Education In-
stitutions (PAPD), Cultivation Base of State Key Laboratory of Stem
Cell and Biomaterials built together by the Ministry of Science and
Technology and Jiangsu Province, and Jiangsu Province's Key Disci-
pline of Medicine (XK201118).
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