Skip to main content

Advertisement

  • Review
  • Open Access

Overexpression of hypoxia-inducible factor and metabolic pathways: possible targets of cancer

  • 1,
  • 2,
  • 1,
  • 3,
  • 4 and
  • 1Email author
Cell & Bioscience20177:62

https://doi.org/10.1186/s13578-017-0190-2

©  The Author(s) 2017

  • Received: 14 July 2017
  • Accepted: 6 November 2017
  • Published:

Abstract

Cancer, the main cause of human deaths in the modern world is a group of diseases. Anticancer drug discovery is a challenge for scientists because of involvement of multiple survival pathways of cancer cells. An extensive study on the regulation of each step of these pathways may help find a potential cancer target. Up-regulated HIF-1 expression and altered metabolic pathways are two classical characteristics of cancer. Oxygen-dependent (through pVHL, PHDs, calcium-mediated) and independent (through growth factor signaling pathway, mdm2 pathway, HSP90) regulation of HIF-1α leads to angiogenesis, metastasis, and cell survival. The two subunits of HIF-1 regulates in the same fashion through different mechanisms. HIF-1α translation upregulates via mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways, whereas HIF-1β through calmodulin kinase. Further, the stabilized interactions of these two subunits are important for proper functioning. Also, metabolic pathways crucial for the formation of building blocks (pentose phosphate pathway) and energy generation (glycolysis, TCA cycle and catabolism of glutamine) are altered in cancer cells to protect them from oxidative stress and to meet the reduced oxygen and nutrient supply. Up-regulated anaerobic metabolism occurs through enhanced expression of hexokinase, phosphofructokinase, triosephosphate isomerase, glucose 6-phosphate dehydrogenase and down-regulation of aerobic metabolism via pyruvate dehydrogenase kinase and lactate dehydrogenase which compensate energy requirements along with high glucose intake. Controlled expression of these two pathways through their common intermediate may serve as potent cancer target in future.

Keywords

  • mTOR signaling pathway
  • HIF-1α
  • Hypoxia
  • Metabolic pathways
  • p53
  • Glycolysis

Background

Cancer is a known worldwide threat responsible for ~ 7.6 million deaths per year, which is expected to reach 13.1 million by 2030 [1]. Cancer, a multifactorial disease is the second main cause of human deaths after cardiovascular diseases. Biological systems have various pathways to suppress cancer propagation such as tumor suppresser genes, cell cycle check points, DNA error repair system etc. Down regulation or malfunctioning of these system results in initiation of cancer. Over expression of hypoxia inducible factor (HIF) and altered metabolic pathways are two classical features of cancer [2]. HIF-1 is a transcription factor regulating many pivotal pathways in normal as well as cancerous cells. It is over expressed in organs or tissues where oxygen level drops below threshold level [3]. High level of HIF-1 points towards angiogenesis, cell proliferation, survival and tumor progression through regulation of growth promoters, oncogenes, glycolytic pathways and pH regulation. A large number of studies support the relation of increased level of HIF-1 with aggressive tumor growth and poor patient prognosis [4–8]. Metabolic pathways are crucial for growth and survival of cells. Intensively proliferating cells (as in cancer) needs high rate of energy and thus metabolic pathways are modified to match the need. The anaerobic condition results in drastic drop of energy production as lower number of ATPs are produced. Up-regulation of glycolysis and regulated feedback systems solve this problem. These two factors (HIF-1 and metabolic pathways) help cancer cells in rapid proliferation and also for angiogenesis, metastasis and evading apoptosis. This review is thus compiled to analyze the role of HIF-1 and altered metabolic regulation in cancer.

Hypoxia-inducible factor

Structure

HIF is a heterodimer protein consisting of two subunits, HIF-α and HIF-β. There are two other substitutes of HIF-1α such as HIF-2α and HIF-3α [9, 10]. Both HIF-1α and HIF-2α have the ability to heterodimerize to HIF-1β subunit because of 85% sequence similarity in bHLH domain [11]. Expression of HIF-α subunit is oxygen dependent while HIF-β constitutively expresses independent of oxygen level. HIF-β subunit is also known as aryl hydrocarbon receptor nuclear translocator (ARNT) and binds to aryl hydrocarbon receptor (AhR) to promote its translocation to the nucleus [12]. Both HIF-α and HIF-β subunits belong to bHLH-PAS (basic helix loop helix-Per ARNT Sim) protein family found in Drosophila [13]. All three HIF-α subunits contain oxygen-dependent degradation domain (ODD) and N-terminal transactivational domain (N-TAD). In addition, HIF-1α and HIF-2α also contain a C-terminal transactivational domain (C-TAD) [14], but HIF-1β lacks all regulatory regions (Fig. 1). The ODD domain is crucial for activity and stability of HIF-α subunits as it contains proline and asparagine for hydroxylation under normoxic conditions [15]. Some co-activators such as C-TAD binding protein (CBP) and P300 bind with C-TAD and regulate HIF expression by altering local chromatin structure through lysine acetyltransferase (KAT) activity and interaction with core transcriptional machinery [16].
Fig. 1
Fig. 1

Structure of HIF-1α and HIF-1β gene. These genes contain a common basic helix-loop-helix and PAS domain for DNA binding and dimerization. HIF-1β lacks an N-TAD, C-TAD and ODD regulatory regions

Functions

Human tissues need ample supply of oxygen to maintain constant energy level through aerobic metabolic pathways. In some disorders such as cancer, chronic obstructive pulmonary disorders, ischemia or heart diseases, the oxygen level is drained, thus leading to hypoxic condition [17]. These conditions up-regulate HIF expression and down-regulate its degradation. HIF plays an important role in various cell signaling pathways besides three major roles, to regulate angiogenesis, metabolic pathways and pH (Fig. 2). Hypoxia is mainly common in solid tumors, where cells proliferate very fast, resulting in compression of blood vessels. To compensate this problem, HIF up-regulates the angiogenic growth factors such as vascular endothelial growth factor (VEGF) [18] and epidermal growth factor (EGF) through transcriptional activation. HIF enhances endothelial cell migration towards tissues with low oxygen level. These cells aid to form new blood vessels to overcome oxygen requirement [19]. VEGF enhances the infiltration of macrophages through macrophage receptors (flt-1). These macrophages release more VEGF and tumor necrosis factor- alpha (TNF-α) indicating positive regulation. HIF-1 also regulates glycolysis which is a vital pathway for energy production. It regulates the uptake of glucose through glucose transporters, i.e. glucose transporter 1 (GLUT1) and sodium–glucose transporters (SGLT) [20]. In absence of oxygen, metabolic pathways shift from more productive oxidative phosphorylation to less efficient anaerobic metabolism for maintenance of ATP production (Warburg effect) [21]. This shift is done through up-regulation of hexokinase, aldolase, pyruvate kinase and down-regulation of pyruvate dehydrogenase which promotes the conversion of pyruvate to acetyl CoA to enter the citric acid cycle [22]. Recently, it has been observed that the embryonic stem cells go through metabolic shift during development towards glycolysis which is regulated by HIF-1 [23].
Fig. 2
Fig. 2

Major roles of HIF-1; regulation of angiogenesis through VEGF, pH through sodium hydrogen pumps and glycolysis through glycolytic enzymes as well as glucose transporters

Tumor cells have acidic extracellular pH (6.2–6.8) than normal cells (7.2–7.4) [24, 25]. More lactic acid production and poor removal, as well as the production of carbonic acid, are main reasons for this condition. Monocarboxylate transporters (MCT4) upregulates by hypoxic conditions, which secrete more lactic acid from tumor cells [26]. Also, HIF-induced ectoenzyme CA (carbonic anhydrase) IX or XII converts diffused carbon dioxide into carbonic acid to reduce extracellular pH [27]. Histochemical studies have shown that CA IX and CA XII isoforms expressed highly in tumor cells, which are thus a suggestive diagnostic marker for cancer.

Regulation of HIF-1

HIF-1α constitutively expresses independently of oxygen level through various signaling pathways in cancer [28]. Most post-translational modification accounts for HIF-1α stability and transcriptional activity via ubiquitination, acetylation, sumoylation, hydroxylation, and phosphorylation [28]. There are two types of the pathway which regulate the expression of HIF-1α, oxygen dependent and oxygen independent pathway (Fig. 3).
Fig. 3
Fig. 3

Oxygen-dependent and independent regulatory pathways of HIF-1

Oxygen-dependent regulation

pVHL dependent pathway

In normoxic conditions, level of HIF-1 is tightly regulated by von Hippel-Lindau protein (pVHL), a tumor suppressor protein through proteasomal degradation and ubiquitination [29]. Another enzyme called prolyl-4-hydroxylases (PHDs) or HIF-1 prolyl hydroxylases (HPH) also participates in the degradation of HIF-1α. Two proline residues (P402/P564) present on KXXLAP amino acid motif of ODD domain acts as a substrate for PHDs [30, 31]. This degradation requires 2-oxoglutarate (2-OG), oxygen and ascorbate [32]. An enzyme, arrest defective-1 (ARD-1) plays an important role by acetylating lysine (K532) residue in the ODD domain [33]. Hypoxic condition inhibits the activity of both the enzymes resulting in up-regulation of HIF-1α activity. Hypoxia disrupts the electron transport chain, thus accumulating reactive oxygen species (ROS), which in turn oxidizes Fe2+ to Fe3+ resulting in inhibition of PHD activity and stabilization of HIF-1α. Knockdown of transferrin receptor-1 through small hairpin RNA (shRNA) leads to decrease in iron uptake, high HIF expression and extensive angiogenesis in breast cancer cell lines [34]. Antioxidant response from junD in Ki-Ras transformed fibroblast cells have been reported to reduce HIF expression and angiogenesis by enhancing PHDs expression [35]. Both antioxidant N-acetylcysteine and ascorbate abolish HIF activation through increased hydroxylation [36]. These findings propose the involvement of hypoxia and reactive oxygen species in altering HIF expression through various mechanisms. HIF-1α promoter contains a binding site for necrosis factor-kappa B (NF-ĸB) which conveys up-regulation by oxidative stress [37]. Transcription of HIF-1β is also regulated directly by NF-ĸB [38]. So, it is concluded that PHDs, ARD and VHL all require oxygen to stabilize the HIF-1α structure.

pVHL independent pathway

Another regulatory pathway is post-translational modifications of HIF-1 in the presence of oxygen but without the involvement of pVHL protein. Binding of C-TAD and co-activators CBP/p300 are must for transcriptional activation of HIF-1α target genes. In the presence of oxygen, asparagine residue (N803) of HIF-1α C-TAD domain gets hydroxylated by factor inhibiting HIF-1 (FIH-1), an asparagine hydroxyl, hinders the interaction between two domains and results in the down-regulation of HIF-1α mediated gene transcription [39–42]. Hypoxic conditions hinder hydroxylation of asparagine and hence establish transactivation of HIF-1α [40–42]. Hence, pVHL dependent pathway stabilizes HIF-1α, while pVHL independent pathway regulates its transactivation.

Calcium-mediated regulation

Hypoxia-induced accumulation of calcium also promotes the expression of HIF-1α. Various targets of Ca2+/CAM such as CAM kinase II, actin and calcineurin increase the transcriptional expression of HIF-1α. Therefore suppression of Ca2+/CAM by CAM-dominant mutants, Ca2+ antagonists, i.e. HBC or Ca2+ chelators reduces transcriptional activity of HIF and thus angiogenesis [43, 44].

Oxygen-independent regulation

Despite the role of hydroxylases, there are some other oncogenic regulatory pathways which play an important role in oxygen independent regulation of HIF-1α activity.

Growth factor signaling pathway

Various growth factors regulate the expression of HIF-1α through a wide range of signaling cascades, i.e. PI3K/PTEN/AKT or RAS/RAF/MAPK [45]. Most of them regulate translation of HIF-1α while some also regulate transcription. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) regulates the expression of HIF-1α through its target protein kinase B (AKT) a serine/threonine kinase and further downstream mTOR. mTOR phosphorylates the eukaryotic translation initiation factor 4E (elF-4E) binding protein (4E-BP). 4E-BP disrupts cap-dependent mRNA translation. mTOR dependent phosphorylation of P70S6K (S6K) enhances the activity of its substrate ribosomal protein S6 and promotes HIF-1α translation [46]. The AKT signaling may regulate HIF-1α expression by both mTOR dependent and independent pathways [47]. This pathway is hindered by PTEN, which dephosphorylates PI3K products [47]. Certain growth factors activate RAS which further stimulates MAPK pathway [48]. This pathway involves RAS/RAF/MEK/ERK kinase cascade. An activated extracellular signal-regulated kinase (ERK) phosphorylate MAP kinase-interacting kinase (NNK) and S6K to activate them and 4E-BP1 to inactivate it. MNK phosphorylates elF4E protein to enhance HIF-1α translation [49]. ERK also stimulates transcriptional activation of HIF-1α by phosphorylating CBP/P300 co-activators for enhancing HIF-1α/co-activators complex formation [50].

Mdm2 pathway

Mouse double minute 2 homolog (Mdm2) plays an important role along with p53 in cancer. In hypoxic conditions binding of p53 with HIF-1α enhances its degradation through Mdm2 mediated ubiquitination and proteasomal degradation [50]. This degradation occurs in the cytoplasm and controlled by PTEN/PI3K/AKT pathway [51]. Undoubtedly, loss of p53 in the tumor is associated with the enhanced level of HIF-1α expression [52].

Through HSP90

Many other minor pathways play a key role in regulating HIF-1α level. Heat shock protein 90 (HSP90) is a molecular chaperone which facilitates synthesis and folding of proteins. Direct interaction of HSP90 with HIF-1α enhances its dimerization with HIF-1β through conformational changes [53]. Geldanamycin, an HSP90 inhibitor enhances HIF-1α degradation even in cells lacking pVHL [54]. Mutations in P402/P534 sites of HIF-1α do not secure it from Geldanamycin-induced degradation.

HIF induced metabolic alterations

The functional gain of oncogenes and loss of function of tumor suppressor genes are the main characteristic of cancer cells [55]. This causes uncontrolled proliferation to form a solid mass. So in order to maintain energy level for dividing cells, a continuous supply of anabolic building blocks and energy carriers are established. Alterations of metabolic pathways were added to the six cancer hallmarks by Hanahan and Weinberg [55]. These pathways contain up-regulation of glycolysis, mitochondrial biogenesis, lipid and amino acid metabolism, pentose phosphate pathway and macromolecule biosynthesis. Some of them are shown in Fig. 4.
Fig. 4
Fig. 4

Metabolic targets of HIF-1 in cancer cells. GLUT: glucose transporter; G6P: glucose 6-phosphate; G6PD: glucose 6-phosphate dehydrogenase; F6P: fructose 6-phosphate; F2,6BP: fructose 2,6-bisphosphate; PFK: phosphofructokinase; F1,6BP: fructose 2,6-bisphosphate; Gly3P: glyceraldehyde 3-phosphate; TPI1: triosphosphate isomerase1; DHAP: dihydroxyacetone phosphate; Gly3PD: glyceraldehyde 3-phosphate dehydrogenase; 1,3BPGly: 1,3-bisphosphoglycerate; PEP: phosphoenol pyruvate; PK: pyruvate kinase; LDHA: lactate dehydrogenase; PDH: pyruvate dehydrogenase; PDK1: pyruvate dehydrogenase kinase-1

In comparison with normal cells, cancer cells prioritize lactic acid production (anaerobic glycolysis) instead oxidative phosphorylation even in normoxic conditions also known as Warburg effect [56]. In later studies, it was observed that the dividing lymphocytes also use 90% of their glucose carbon to form lactate, which rules out the probability that anaerobic glycolysis is only associated with cancer cells [57]. HIF-1 and c-Myc are two major regulators of glycolytic enzymes such as hexokinase (HK2), phosphofructokinase (PFK1), triosephosphate isomerase (TPI1) and lactate dehydrogenase (LDHA) [20, 58–60]. At a low level of HIF-1, the end product of glycolysis is converted to acetyl-CoA, which enters into the citric acid cycle. In TCA cycle, high-energy molecules, i.e. FAD and NADH are generated, which further produce a high number of ATPs through electron transport chain in mitochondria. Normal cells prefer anaerobic glycolysis only in the absence of oxygen. In comparison, cancer cells use only anaerobic glycolysis even in abundance of oxygen [58, 61, 62]. As per the research findings, if glucose influx is high enough, only then the percentage of ATP generated from glycolysis goes above that produced from oxidative phosphorylation [63]. Pyruvate kinase an enzyme which converts phosphoenolpyruvate to pyruvate was recently reported as a regulator of Warburg effect [64].

Another glycolytic enzyme responsible for regulatory metabolic pathways at enhanced HIF-1α expression is pyruvate kinase (PK). It encodes by two genes, PKLR and PKM2. PKM2 gene codes for two alternatively spliced transcripts, PKM1 and PKM2. PKM1 is primarily restricted to brain and muscles while PKM2 to fast proliferating cells like cancer [65, 66]. Some glucose depleted cell cultures have been shown to stabilize HIF-1α by inhibiting PHDs through Pyruvate formed from lactate by lactate dehydrogenase [67]. Accumulation of lactate (10 mM) in cancer has been suggested to activate HIF-1 and VEGF [68]. Pyruvate and oxaloacetate inactivate the PHDs, reversal of which requires ascorbate [69]. Thus there are at least two mechanisms to inactivate HIF hydroxylases, one is competition with 2-OG and second by oxidation.

TCA cycle is the second pathway after glycolysis in the metabolism of glucose. Pyruvate, the end product of glycolysis enter TCA cycle only via production of acetyl-CoA. HIF-1α mediated upregulation of pyruvate dehydrogenase kinase reduce acetyl-CoA production through inactivation of pyruvate dehydrogenase enzyme by phosphorylation [70]. Production of NADH by conversion of lactate from pyruvate with the help of lactate dehydrogenase accelerates glycolysis [71]. Another benefit taken by cancer cells from enhanced production of lactate is that they secrete it in tumor microenvironment through MCT4 transporters to other cancer cells, who have not sufficient fuel supply, so to feed them energy.

Pentose phosphate pathway (PPP) is a major pathway for nucleotide biosynthesis through ribose 5-phosphate (R5P) intermediate. p53 plays a major role in controlling both the oxidative and non-oxidative arms of PPP pathway. TP53-induced glycolysis and apoptosis regulator (TIGAR), a target of p53 regulate glycolysis by suppressing the expression of phosphofructokinase-1 and by increasing substrate delivery to citric acid pathway [72]. Cancer cells lacking or mutated p53 lose their control to regulate PPP pathway and hence increases in glycolytic efflux. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays a major role in the regulation of this pathway. Suppressive oxidative phosphorylation reduces NAD+/NADH ratio and hence GAPDH activity. Hence down-regulated GAPDH expression creates a boundary for lower glycolytic pathways, creating a high pressure of upper glycolytic substrates, which then enhance reversible non-oxidative PPP pathway for nucleotide biosynthesis [73]. Glucose 6-phosphate dehydrogenase (G6PD) is another important enzyme of PPP pathway which promotes cancer formation by providing NADH [74]. P53 tightly regulate this enzyme by preventing its active dimerization [75]. G6PD is a direct target of HIF-1 to transactivate it [76]. Surprisingly, G6PD and VEGF crosstalk in cancer cells and are highly associated with angiogenesis [77, 78].

Catabolism of glutamine is another key metabolic pathway for cancer cells. End products of glutaminolysis serve as intermediates for TCA cycle. Like glycolysis, glutaminolysis provides not only ATP but also some crucial precursors for cell proliferation [79–81]. C-Myc transactivates alanine–serine–cysteine (ASCT2) and system N (SN2) transporters for glutamine and up-regulates glutaminase (GLS1) expression [82]. The high rate of lactate and alanine excretion per mole of glutamine, like the evident insufficiency of Warburg effect, has been seen in proliferating cells [78, 83]. Rather than regular discernment that normal cells use glutamine as a nitrogen source, glutamine digestion in tumor cells bring high intracellular nitrogen that must be discharged as alanine or ammonia. Glutaminase enzyme removes its amido group as ammonia. In glioblastoma cells, a large part of glutamine’s amino groups was likewise lost in α-ketoglutarate (α-KG) producing reactions (glutamate dehydrogenase and alanine aminotransferase) [84]. In this way, usage of glutamine as an anaplerotic precursor and source of NADPH results in the discharge of large fraction of glutamine-derived carbon and nitrogen. A portion of secreted molecules may, therefore, be utilized as precursors for hepatic gluconeogenesis, hence giving more fuel for tumor digestion. At first look, these seem, by all accounts, to be side effects of metabolic inefficiency. However, they may actually give a logical and specialized metabolism that empower cell growth and metabolism. In this way, HIF-1α alter a number of metabolic pathways that play their role in cancer by providing energy to the cell for proliferation, growth, and survival. Targeting specific substrates of these pathways may help to control cancer progression.

Conclusions

Both HIF-1 and metabolic pathways participate in cancer progression by giving an enhanced supply of energy (metabolic pathways) and sufficient oxygen (HIF-1). A sequence of signaling cascades is involved by these two factors to survive cancer cells through the harsh environment and immune surveillance. Both the pathways are up-regulated in cancer. Warburg effect, which is a characteristic of altered glycolytic pathways in cancer, is also seen in dividing lymphocytes and embryonic stem cells. HIF-1, a mark of the hypoxic condition is also seemed to be regulated in an oxygen-independent manner. This complex regulation contributes to the propagation of cancer through multiple pathways.

Future perspectives

The involvement of HIF in cancer progression directs our intention to discover anticancer drugs which inhibit HIF-1 expression directly or indirectly by regulating HIF-1α mRNA, HIF-1 α protein translation, HIF-1α protein degradation, HIF-1α and HIF-1β subunit interactions and HIF-1α DNA binding activity. Numerous studies focused on cancer, entail discovery of drugs which are synthetic in nature. A number of studies are reported to compile mode of action of these anticancer drugs in contrast with the HIF-1 regulation [20, 85–91]. However, even after extensive research, there is a gap to target cancer with a single molecule because of multiple survival pathways, different infected organs and huge side effects of synthetic drugs. From last decade, researchers have identified some natural plant compounds, i.e. vinca alkaloids, taxanes, camptothecins [92] which have fewer side effects than synthetic ones. Recently, a new natural compound sulforaphane was identified, which eliminates cancer stem cells in many cancer types [93–95]. Multiple survival pathways make trouble for anticancer drug discovery. Some substrates which are common for multiple responsible pathways for cancer may help to target it with a novel universal drug in future. This requires extensive study of signaling cascades and its regulation on each step.

Abbreviations

HIF-1: 

hypoxia-inducible factor

ROS: 

reactive oxygen species

ARNT: 

aryl hydrocarbon receptor nuclear translocator

AhR: 

aryl hydrocarbon receptor

bHLH: 

basic helix loop helix

PAS: 

Per ARNT Sim

ODD: 

oxygen-dependent domain

N-TAD: 

N-terminal transactivational domain

C-TAD: 

C-terminal transactivational domain

CBP: 

C-TAD binding protein

KAT: 

lycin acetyl transferase

DNA: 

deoxyribonucleic acid

VEGF: 

vascular endothelial growth factor

EGF: 

epidermal growth factor

TNF-α: 

tumor necrosis factor-α

GLUT1: 

glucose transporter 1

SGLT: 

sodium–glucose transporter

ATP: 

adenosine triphosphate

MCT-4: 

monocarboxylate transporter-4

CA: 

carbonic anhydrase

VHL: 

von Hippel-Lindau

PHDs: 

prolyl-4-hydroxylases

HPH: 

HIF-1 prolyl hydroxylase

2-OG: 

2-oxoglutarate

ARD-1: 

arrest defective-1

shRNA: 

small hairpin ribonucleic acid

NF-ĸB: 

necrosis factor-kappa B

FIH-1: 

factor inhibiting HIF-1

PI3K: 

phosphatidyl inositol-4,5-bisphosphate 3-kinase

m-TOR: 

mammalian target of rapamycin

elF-4E: 

eukaryotic translation initiation factor-4E

4EBP: 

elF-4E binding protein

PTEN: 

phosphatase and tensin homolog

MAPK: 

mitogen-activated protein kinase

ERK: 

extracellular signal-regulated kinase

MNK: 

MAP kinase-interacting kinase

Mdm2: 

mouse double minute 2 homolog

HSP90: 

heat shock protein 90

CAM: 

calmodulin-dependent kinase

HK2: 

hexokinase 2

PFK1: 

phosphofructokinase 1

TPI1: 

triphosphate isomerase 1

LDHA: 

lactate dehydrogenase

TCA: 

tricarboxylic acid

FAD: 

flavin adenine dinucleotide

NADH: 

nicotinamide adenine dinucleotide

PPP: 

pentose phosphate pathway

R5P: 

ribose 5-phosphate

TIGAR: 

TP-53-induced glycolysis and apoptosis regulator

GAPD: 

glyceraldehyde-phosphate dehydrogenase

G6PD: 

glucose 6-phosphate dehydrogenase

PK: 

pyruvate kinase

ASCT: 

alanine, serine, cysteine transporter 2

SN2: 

system n-2 transporter

GLS1: 

glutaminase 1

αKG: 

α-ketoglutarate

mRNA: 

messenger ribonucleic acid

Declarations

Authors’ contributions

DS, RA, and PK collected the data and wrote the manuscript. BS and RM helped in the correction of the manuscript. Corresponding author SA conceived the idea, analyzed the data and helped in the correction of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

All data are fully available without restrictions.

Consent for publication

All authors reviewed the manuscript and consent for publication.

Ethics approval and consent to participate

Not applicable.

Funding

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, 143005, India
(2)
Department of Biochemistry, Sri Guru Ram Das University of Health Sciences, Amritsar, 143001, India
(3)
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
(4)
Department of Pathology, Sri Guru Ram Das University of Health Sciences, Amritsar, 143001, India

References

  1. World Health Organization. Fact sheet no 297. 2017. http://www.who.int/mediacentre/factsheets/fs297/en/index.html. Accessed 19 Jun 2017.
  2. Masson N, Ratcliffe PJ. Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways. Cancer Metab. 2014;2:1–3.View ArticleGoogle Scholar
  3. Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–76.View ArticlePubMedGoogle Scholar
  4. Chen L, Shi Y, Yuan J, Han Y, Qin R, Wu Q, et al. HIF-1 alpha overexpression correlates with poor overall survival and disease-free survival in gastric cancer patients post-gastrectomy. PLoS ONE. 2014;9:e90678.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, et al. HIF-1α overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol. 2010;176:2292–301.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Investig. 2013;123:3664–71.View ArticlePubMedPubMed CentralGoogle Scholar
  7. Kurokawa T, Miyamoto M, Kato K, Cho Y, Kawarada Y, Hida Y, et al. Overexpression of hypoxia-inducible-factor 1α (HIF-1α) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Br J Cancer. 2003;89:1042–7.View ArticlePubMedPubMed CentralGoogle Scholar
  8. Zhou J, Huang S, Wang L, Yuan X, Dong Q, Zhang D, et al. Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis. World J Surg Oncol. 2017;15:104.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci. 1997;94:4273–8.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA. Molecular characterization and chromosomal localization of a third α-class hypoxia inducible factor subunit, HIF-3α. Gene Expr. 1998;7:205–13.PubMedGoogle Scholar
  11. Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 1997;11:72–82.View ArticlePubMedGoogle Scholar
  12. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci. 1995;92:5510–4.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem. 1996;271:17771–8.View ArticlePubMedGoogle Scholar
  14. Pugh CW, O’Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. Activation of hypoxia-inducible factor-1; definition of regulatory domains within the α subunit. J Biol Chem. 1997;272:11205–14.View ArticlePubMedGoogle Scholar
  15. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.View ArticlePubMedGoogle Scholar
  16. Bedford DC, Kasper LH, Fukuyama T, Brindle PK. Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases. Epigenetics. 2010;5:9–15.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev. 2000;14:1983–91.PubMedGoogle Scholar
  18. Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80:51–60.PubMedPubMed CentralGoogle Scholar
  19. Richard DE, Berra E, Pouysségur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1α in vascular smooth muscle cells. J Biol Chem. 2000;275:26765–71.PubMedGoogle Scholar
  20. Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer. 2008;8:705–13.View ArticlePubMedGoogle Scholar
  21. Burk D, Schade AL. On respiratory impairment in cancer cells. Science (New York, NY). 1956;124:270.Google Scholar
  22. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269:23757–63.PubMedGoogle Scholar
  23. Zhou W, Choi M, Margineantu D, Margaretha L, Hesson J, Cavanaugh C, et al. HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO J. 2012;31:2103–16.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Harguindey S, Orive G, Pedraz JL, Paradiso A, Reshkin SJ. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin—one single nature. Biochimica et Biophysica Acta (BBA) Rev Cancer. 2005;1756:1–24.View ArticleGoogle Scholar
  25. Gerweck LE, Vijayappa S, Kozin S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther. 2006;5:1275–9.View ArticlePubMedGoogle Scholar
  26. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J Biol Chem. 2006;281:9030–7.View ArticlePubMedGoogle Scholar
  27. Švastová E, Hulı́ková A, Rafajová M, Zat’ovičová M, Gibadulinová A, Casini A, et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 2004;577:439–45.View ArticlePubMedGoogle Scholar
  28. Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L. Activation of hypoxia-inducible factor 1α: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci. 1997;94:5667–72.View ArticlePubMedPubMed CentralGoogle Scholar
  29. Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, et al. Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci. 1999;96:12436–41.View ArticlePubMedPubMed CentralGoogle Scholar
  30. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–40.View ArticlePubMedGoogle Scholar
  31. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43–54.View ArticlePubMedGoogle Scholar
  32. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72.View ArticlePubMedGoogle Scholar
  33. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, et al. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell. 2002;111:709–20.View ArticlePubMedGoogle Scholar
  34. Eckard J, Dai J, Wu J, Jian J, Yang Q, Chen H, et al. Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Cancer Cell Int. 2010;10:28.View ArticlePubMedPubMed CentralGoogle Scholar
  35. Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D, et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell. 2004;118:781–94.View ArticlePubMedGoogle Scholar
  36. Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell. 2007;12:230–8.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Bonello S, Zähringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, et al. Reactive oxygen species activate the HIF-1α promoter via a functional NFκB site. Arterioscler Thromb Vasc Biol. 2007;27:755–61.View ArticlePubMedGoogle Scholar
  38. Van Uden P, Kenneth NS, Webster R, Müller HA, Mudie S, Rocha S. Evolutionary conserved regulation of HIF-1β by NF-κB. PLoS Genet. 2011;7:e1001285.View ArticlePubMedPubMed CentralGoogle Scholar
  39. Block KM, Wang H, Szabó LZ, Polaske NW, Henchey LK, Dubey R, et al. Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine. J Am Chem Soc. 2009;131:18078–88.View ArticlePubMedPubMed CentralGoogle Scholar
  40. Dann CE, Bruick RK, Deisenhofer J. Structure of factor-inhibiting hypoxia-inducible factor 1: an asparaginyl hydroxylase involved in the hypoxic response pathway. Proc Natl Acad Sci. 2002;99:15351–6.View ArticlePubMedPubMed CentralGoogle Scholar
  41. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16:1466–71.View ArticlePubMedPubMed CentralGoogle Scholar
  42. McNeill LA, Hewitson KS, Claridge TD, Seibel JF, Horsfall LE, Schofield CJ. Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the β-carbon of asparagine-803. Biochem J. 2002;367:571–5.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Kwon HJ. Discovery of new small molecules and targets towards angiogenesis via chemical genomics approach. Curr Drug Targets. 2006;7:397–405.View ArticlePubMedGoogle Scholar
  44. Jung HJ, Kim JH, Shim JS, Kwon HJ. A novel Ca2+/calmodulin antagonist HBC inhibits angiogenesis and down-regulates hypoxia-inducible factor. J Biol Chem. 2010;285:25867–74.View ArticlePubMedPubMed CentralGoogle Scholar
  45. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441:437–43.View ArticlePubMedGoogle Scholar
  46. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 2001;15:807–26.View ArticlePubMedGoogle Scholar
  47. Pore N, Jiang Z, Shu HK, Bernhard E, Kao GD, Maity A. Akt1 Activation can augment hypoxia-inducible factor-1α expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res. 2006;4:471–9.View ArticlePubMedGoogle Scholar
  48. Semenza GL. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64:993–8.View ArticlePubMedGoogle Scholar
  49. Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem. 2003;278:14013–9.View ArticlePubMedPubMed CentralGoogle Scholar
  50. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 2000;14:34–44.PubMedPubMed CentralGoogle Scholar
  51. Joshi S, Singh AR, Durden DL. MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J Biol Chem. 2014;289:22785–97.View ArticlePubMedPubMed CentralGoogle Scholar
  52. Bae MK, Ahn MY, Jeong JW, Bae MH, Lee YM, Bae SK, et al. Jab1 interacts directly with HIF-1α and regulates its stability. J Biol Chem. 2002;277:9–12.View ArticlePubMedGoogle Scholar
  53. Gradin K, McGuire J, Wenger RH, Kvietikova I, Toftgård R, Tora L, et al. Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor. Mol Cell Biol. 1996;16:5221–31.View ArticlePubMedPubMed CentralGoogle Scholar
  54. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem. 2002;277:29936–44.View ArticlePubMedGoogle Scholar
  55. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.View ArticlePubMedGoogle Scholar
  56. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.View ArticlePubMedGoogle Scholar
  57. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–70.PubMedGoogle Scholar
  58. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.View ArticlePubMedGoogle Scholar
  59. DeBerardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18:54–61.View ArticlePubMedPubMed CentralGoogle Scholar
  60. Dang CV, Lewis BC, Dolde C, Dang G, Shim H. Oncogenes in tumor metabolism, tumorigenesis, and apoptosis. J Bioenergy Biomembr. 1997;29:345–54.View ArticleGoogle Scholar
  61. Yeung SJ, Pan J, Lee MH. Roles of p53, MYC and HIF-1 in regulating glycolysis—the seventh hallmark of cancer. Cell Mol Life Sci. 2008;65:3981–99.View ArticlePubMedGoogle Scholar
  62. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.View ArticlePubMedPubMed CentralGoogle Scholar
  63. Guppy M, Greiner E, Brand K. The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. Eur J Biochem. 1993;212:95–9.View ArticlePubMedGoogle Scholar
  64. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.View ArticlePubMedGoogle Scholar
  65. Netzker R, Greiner E, Eigenbrodt E, Noguchi T, Tanaka T, Brand K. Cell cycle-associated expression of M2-type isozyme of pyruvate kinase in proliferating rat thymocytes. J Biol Chem. 1992;267:6421–4.PubMedGoogle Scholar
  66. Altenberg BA, Greulich KO. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics. 2004;84:1014–20.View ArticlePubMedGoogle Scholar
  67. Sonveaux P, Copetti T, De Saedeleer CJ, Végran F, Verrax J, Kennedy KM, et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE. 2012;7:e33418.View ArticlePubMedPubMed CentralGoogle Scholar
  68. Hunt TK, Aslam RS, Beckert S, Wagner S, Ghani QP, Hussain MZ, et al. Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal. 2007;9:1115–24.View ArticlePubMedPubMed CentralGoogle Scholar
  69. Lu H, Dalgard CL, Mohyeldin A, McFate T, Tait AS, Verma A. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem. 2005;280:41928–39.View ArticlePubMedGoogle Scholar
  70. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL, Tumor and Angiogenesis Research Group. Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. Neoplasia. 2005;7:1–6.View ArticlePubMedPubMed CentralGoogle Scholar
  71. Dang CV, Lewis BC, Dolde C, Dang G, Shim H. Oncogenes in tumor metabolism, tumorigenesis, and apoptosis. J Bioenerg Biomembr. 1997;29:345–54.View ArticlePubMedGoogle Scholar
  72. Bensaad K, Tsuruta A, Selak MA, Vidal MNC, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126:107–20.View ArticlePubMedGoogle Scholar
  73. Dong W, Keibler MA, Stephanopoulos G. Review of metabolic pathways activated in cancer cells as determined through isotopic labeling and network analysis. Metab Eng. 2017. https://doi.org/10.1016/j.ymben.2017.02.002.Google Scholar
  74. Riganti C, Gazzano E, Polimeni M, Aldieri E, Ghigo D. The pentose phosphate pathway: an antioxidant defense and a crossroad in tumor cell fate. Free Radic Biol Med. 2012;53:421–36.View ArticlePubMedGoogle Scholar
  75. Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 2011;13:310.View ArticlePubMedPubMed CentralGoogle Scholar
  76. Gao L, Mejı́as R, Echevarrı́a M, López-Barneo J. Induction of the glucose-6-phosphate dehydrogenase gene expression by chronic hypoxia in PC12 cells. FEBS Lett. 2004;569:256–60.View ArticlePubMedGoogle Scholar
  77. Pan S, Kovacs CJ, Berk BC. Glucose 6-phosphate dehydrogenase is regulated through c-Src–mediated tyrosine phosphorylation in endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29:895–901.View ArticlePubMedGoogle Scholar
  78. Brand K. Glutamine and glucose metabolism during thymocyte proliferation. Pathways of glutamine and glutamate metabolism. Biochem J. 1985;228:353–61.View ArticlePubMedPubMed CentralGoogle Scholar
  79. Dang CV. Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? Cell Cycle. 2010;9:3884–6.View ArticlePubMedGoogle Scholar
  80. Dang CV, Semenza GL. Oncogenic alterations of metabolism. Trends Biochem Sci. 1999;24:68–72.View ArticlePubMedGoogle Scholar
  81. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15:6479–83.View ArticlePubMedPubMed CentralGoogle Scholar
  82. Gangrade A, Calin GA. MicroRNAs and cancer hallmarks. Cancer Hallm. 2013;1:50–7.View ArticleGoogle Scholar
  83. Reitzer LJ, Wice BM, Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem. 1979;254:2669–76.PubMedGoogle Scholar
  84. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci. 2007;104:19345–50.View ArticlePubMedPubMed CentralGoogle Scholar
  85. Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov. 2003;2:803–11.View ArticlePubMedGoogle Scholar
  86. Melillo G. Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 2007;26:341–52.View ArticlePubMedGoogle Scholar
  87. Ban HS, Uto Y, Nakamura H. Hypoxia-inducible factor inhibitors: a survey of recent patented compounds (2004–2010). Expert Opin Ther Pat. 2011;21:131–46.View ArticlePubMedGoogle Scholar
  88. Onnis B, Rapisarda A, Melillo G. Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med. 2009;13:2780–6.View ArticlePubMedPubMed CentralGoogle Scholar
  89. Wang RB, Zhou SS, Li SS. Cancer therapeutic agents targeting hypoxia-inducible factor-1. Curr Med Chem. 2011;18:3168–89.View ArticlePubMedGoogle Scholar
  90. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.View ArticlePubMedGoogle Scholar
  91. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.View ArticlePubMedGoogle Scholar
  92. Kinghorn AD, Chin YW, Swanson SM. Discovery of natural product anticancer agents from biodiverse organisms. Curr Opin Drug Discov Devel. 2009;12:189.PubMedPubMed CentralGoogle Scholar
  93. Li Y, Zhang T. Targeting cancer stem cells with sulforaphane, a dietary component from broccoli and broccoli sprouts. Future Oncol. 2013;9:1097–103.View ArticlePubMedGoogle Scholar
  94. Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010;16:2580–90.View ArticlePubMedPubMed CentralGoogle Scholar
  95. Sun L, Burnett J, Gasparyan M, Xu F, Jiang H, Lin CC, et al. Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer. Oncotarget. 2016;7:51408–22.View ArticlePubMedPubMed CentralGoogle Scholar

Copyright

© The Author(s) 2017

Advertisement

Cell & Bioscience

ISSN: 2045-3701

Contact us