[6] Review Mistery of Cancer 2013

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


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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.

http://localhost/var/www/apps/conversion/tmp/scratch_8/Unlabelled%20image


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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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[6] Review Mistery of Cancer 2013

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