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Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells (Review)

  • Authors:
    • Annapoorna Sreedhar
    • Yunfeng Zhao
  • View Affiliations

  • Published online on: November 21, 2017     https://doi.org/10.3892/br.2017.1022
  • Pages: 3-10
  • Copyright: © Sreedhar et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor cells carry various genetic and metabolic alterations, which directly contribute to their growth and malignancy. Links between metabolism and cancer are multifaceted. Metabolic reprogramming, such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid (TCA) cycle metabolic enzymes, and dependence on lipid and glutamine metabolism are key characteristics of cancer cells. Understanding these metabolic alterations is crucial for development of novel anti-cancer therapeutic strategies. In the present review, the broad importance of metabolism in tumor biology is discussed, and the current knowledge on dysregulated metabolic enzymes involved in the vital regulatory steps of glycolysis, the TCA cycle, the pentose phosphate pathway, and lipid, amino acid, and mitochondrial metabolism pathways are reviewed.

Introduction

Metabolic alteration is a hallmark of cancer cells (1). A growing body of evidence indicates that malignant transformation is characterized by the occurrence of multiple changes in metabolic pathways that are linked to the synthesis of macromolecules (2). Metabolism is the fundamental architecture of cellular life. Typically, every cell in the body, either directly or indirectly, undergoes metabolism. Metabolism is a sum or a collection of biochemical reactions that produce energy for vital processes and for synthesizing macromolecules. Unsurprisingly, mitochondria, the power house of cells, perform a central role in energy metabolism. Either because of a direct impact or its pivotal role in signal transduction, mitochondria are hubs for metabolic alterations and reprogramming. Furthermore, mitochondria are involved in the production of adenosine triphosphate (ATP), and exert key roles in redox regulation, calcium homeostasis, cell signaling, cell death, and production of various intermediates that are necessary for macromolecule synthesis (36).

Increasing attention has been given to the role of mitochondrial metabolism in cancer biology. The complex connection between metabolism and tumorigenesis is a promising area of cancer research. Mounting evidence has demonstrated that targeting mitochondrial metabolism in cancer cells may present as a novel strategy for anti-cancer therapy (711). As summarized from current knowledge, the process of tumorigenesis and mitochondrial biology inter-cross at multiple levels as follows: i) Direct signals from mitochondria promote tumorigenesis; ii) oncogenic signaling pathways alter mitochondrial functions; iii) perturbation of mitochondrial functions have been shown to have a major role in regulating metabolism and bioenergetics; iv) mutations in mitochondrial DNA, proteins and enzymes result in altered levels of metabolites, which support tumor development and progression. The current review focuses on the importance of various such classic alterations in cancer metabolism. Hence, by understanding this aspect of metabolism, cancer biology may be better understood and novel anti-cancer drugs may be developed.

Glycolysis

All parts of the body require energy to work and this energy is derived from consumption of food. Typically, all food is broken down into smaller parts to generate the energy source, ATP. ATP is a chemical energy generated via controlled oxidation of glucose and other molecules. The process of the breakdown of glucose, termed glycolysis, occurs in the cytoplasm of mammalian cells. Glucose from food is taken up by specific glucose transporters in the cell surface, and via a series of enzyme-catalyzed reactions, broken down to pyruvate, the end-product of glycolysis under aerobic conditions (Fig. 1). If there is a lack of oxygen supply, pyruvate is converted to lactate (anaerobic glycolysis). Theoretically, one molecule of glucose yields two molecules of pyruvate and two molecules of ATP via glycolysis.

Since the early twentieth century, abnormalities of glycolysis in cancer cells have been observed. Warburg (12), a German physiologist and a Nobel laurate, observed that tumor cells depend solely on glycolysis for energy production, even with an ample quantity of oxygen. This phenomenon is since termed the Warburg effect of cancer cells. This raises the question as to why cancer cells switch their metabolism to aerobic glycolysis, unlike normal cells, which depend on oxidative phosphorylation for energy production. While the exact reasons remain unclear, the current explanations include: i) Aerobic glycolysis, although less efficient than the classic oxidative phosphorylation, provides rapid supply of ATP; ii) glycolysis intermediates provide sufficient building blocks for macromolecule synthesis required for the enhanced cell proliferation. Due to this feature of cancer cells, studies have been focused on novel strategies to selectively inhibit glucose metabolism and/or glucose transport in cancer cells (1316).

Marked progress has been made in understanding the molecular mechanisms leading to constitutive upregulation of glycolysis in tumor cells. Various glycolytic enzymes are multi-functional proteins whose expression levels are often increased in cancer cells. For example, hexokinase (HK), the enzyme that converts glucose to glucose 6-phosphate (G6P), the first step of glycolysis, is involved in transcription regulation, and its expression is often upregulated in tumor cells (17,18). The majority of malignant cells display enhanced expression levels of type II isoform (HK-II), which may contribute to the elevated glycolysis (19,20). Phosphofructokinase (PFK), the enzyme that catalyzes the rate limiting step of glycolysis, has been identified to be upregulated in types of breast cancer (21,22). Another critical regulator of glycolysis is the enzyme 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (Pfkfb), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate, which in turn is a powerful allosteric activator of PFK1. Two Pfkfb isoforms, type 2 and 3, are associated with cancers (2326). Subsequently, the enzyme aldolase that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate, has been demonstrated to be overexpressed in squamous cell lung carcinoma (27). The well-known classic glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH; the housekeeping gene) is also implicated in cancer. Overexpression of GAPDH is considered an important feature of numerous types of cancer (2830). GAPDH has been proposed as a promising target for the treatment of carcinomas (31). Pyruvate kinase (PK), the enzyme that catalyzes the irreversible phosphoryl group transfer from phosphoenolpyruvate to pyruvate, yielding pyruvate and ATP, appears to be involved in cancer; previous studies and our findings have demonstrated that tumor cells overexpress the type M2 isoform, PKM2 (3235). As the majority of cancer cells are dependent on aerobic glycolysis for ATP production, the enzyme, lactate dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactate, is the key to determining the glycolytic phenotype of cancer cells. Thus, LDH is a promising target for anti-cancer therapy. The inhibition of LDH suppresses tumor progression of lymphomas and pancreatic cancer xenografts (36). These results indicate that selectively targeting glycolysis and/or glycolytic enzymes in tumor cells may present as an effective approach for the treatment of different types of cancer.

Tricarboxylic acid (TCA) cycle

The Krebs cycle (the citric acid cycle or the TCA) is a series of chemical reactions that generate energy via the oxidation of pyruvate (Fig. 2). TCA cycles occur in all aerobic living organisms. It provides precursors for biosynthesis of compounds (such as amino acids), and nicotinamide adenine dinucleotide (NADH), which is later used by the electron transport chain to generate energy by converting NADH to NAD+. The TCA cycle is the central metabolic hub of the cell that occurs primarily in the mitochondria in contrast to glycolysis, which occurs in the cytosol. Even a minor alteration in these processes markedly influences mitochondrial energy production. Although mutations in mitochondrial DNA have been evaluated for over two decades (3739), much attention has been focused on the identification of mutations in various TCA cycle enzymes (40,41). The cycle consists of eight steps catalyzed by eight different enzymes. Mutations in genes that encode enzymes aconitase, isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) may lead to cancer. Aconitase catalyzes isomerization of citrate to isocitrate via cis-aconitase. Altered expression levels of aconitase are implicated in human prostate cancer, wherein the normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells, leading to abnormal citrate metabolism and prostate malignancy (42). IDH converts isocitrate to α-ketoglutarate (α-KG). Glioblastoma multiforme, one of the most common and lethal types of brain cancer, is characterized by IDH1 gene mutations (43). Similar studies discovered mutations in IDH1 and IDH2 genes in the pathogenesis of malignant gliomas (44). Mutations that occur in single amino acid residue of IDH1 active sites not only result in the novel ability for the mutant enzyme to convert α-KG to 2-hydroxyglutarate, which is proposed to contribute to the formation and malignant progression of gliomas (45). FH is the enzyme that converts fumarate to malate, and mutations in the FH gene are associated with cutaneous, uterine and aggressive forms of renal cancer (4648). Cancer cells that harbor FH mutations produce up to 100-fold more fumarate, and seven-fold more succinate, but decreased levels of citrate and malate (49). FH deficiency in tumor cells alters redox homeostasis to promote tumorigenesis (48). Mutations in the enzyme SDH, which catalyzes the oxidation of succinate to fumarate, are implicated in pheochromocytoma, paraganglioma, renal cell carcinoma and papillary thyroid cancers (5052). Reduced expression and loss of heterozygosity of the SDH gene are observed in gastric and colon carcinoma (53). SDH downregulation results in succinate accumulation leading to transmission of an oncogenic signal from mitochondria to the cytosol (54).

Pentose phosphate pathway (PPP)

The PPP, which branches out from glycolysis at the first committed step is the major catabolic pathway of glucose for nucleotide synthesis in cancer cells (5557). The conversion of glucose to G6P, which is catalyzed by the enzyme HK, is a common precursor for various metabolic glucose-consuming routes (Fig. 3). Through this pathway, cancer cells produce large quantities of ribose-5 phosphate (a precursor for nucleotide synthesis) and NAPDH (a cofactor used in anabolic reactions). PPP runs parallel to glycolysis and activation of these signaling pathways is a common hallmark of tumor cells (58,59). As cancer cells are rapidly dividing, the cells require a constant supply of nucleotides, and the majority of the pentose phosphates are derived from the PPP. Thus, PPP may influence the glycolytic flux. Various enzymes that execute the PPP are implicated in different types of cancer. G6P dehydrogenase (G6PD or G6PDH), the enzyme that catalyzes the rate-limiting step in the PPP, and generates the first NADPH, is highly overexpressed in certain tumors (60). Elevated levels of G6PD in association with higher levels of PPP-derived metabolites are responsible for clear-cell renal carcinoma-associated metabolic alterations (61). Overexpression of G6PD in human U2OS bone osteosarcoma epithelial cells enhances the PPP-dependent production of NADPH (62). The same group also demonstrates that simultaneous inhibition of glycolysis and PPP using 2-deoxy-d-glucose and 6-aminonicotinamide, respectively, induces oxidative stress and sensitizes malignant human cancer cell lines to radiotherapy, presumably via the induction of multiple cell death modalities, including apoptosis, necrosis and mitotic catastrophe (63). The next enzyme that has a role in cancer is 6-phosphogluconate dehydrogenase (6PGDH). 6PGDH catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate with a reduction of NADP to NADPH. 6PGDH has been shown to be critical for lung carcinogenesis and its inhibition may be a novel strategy to treat glycolytic lung tumors (55). Ribulose-5 phosphate isomerase, another critical enzyme in the PPP, which catalyzes the conversion of ribulose-5 phosphate to ribose-5 phosphate and xylulose-5 phosphate (Xu5P), is also associated with cancer (55). Ribose-5 phosphate is important as it is a precursor for de novo nucleotide synthesis in rapidly proliferating cancer cells. Xu5P increases the levels of PFKFB, which activates PFK1 and increases glycolytic flux (64). Thus, all of these studies implicate that the regulation of PPP is vital for cancer cell survival and proliferation. Furthermore, increased glycolytic flux in cancer cells may be regulated directly or indirectly by PPP, and hence, this may represent a promising strategy for treatment of cancer cells.

Amino acid metabolism

Amino acids are one of the major fuels for biosynthetic reactions (Fig. 4), and therefore, are intricately involved in cellular metabolism. From the above-mentioned studies, it is evident that cancer cells are characterized by altered metabolism and/or dysregulated metabolic pathways. Amino acids are of utmost necessity for cancer cell proliferation, as they are the major source of nutrients. Even a slight alteration in the biosynthetic pathways may have an impact on amino acid synthesis. Despite glutamine being a nonessential amino acid, it is one of the major fuels for cancer cells (6567). In cancer cells, glutamine is a primary mitochondrial substrate required to maintain mitochondrial membrane potential, integrity and for NADPH production (65). Certain tumor cells are characterized by ‘glutamine addiction’, the ability of cancer cells to exhibit a high rate of glutamine uptake. Glutamine catabolism or glutaminolysis is elevated in certain types of tumor (6870). Enzyme glutaminase converts glutamine to glutamate and ammonia. Glutamate is further converted to α-KG and enters the TCA cycle. Emerging evidence indicates the role of glutamate and glutamate receptors in human rhabdomyosarcoma/medulloblastoma (TE671), neuroblastoma (SK-NA-S), thyroid carcinoma (FTC 238), lung carcinoma (SK-LU-1), astrocytoma (MOGGCCM), multiple myeloma (RPMI-8226), glioma (U87-MG and U343), lung carcinoma (A549), colon adenocarcinoma (HT 29), T cell leukemia cells (Jurkat E6.1), breast carcinoma (T47D) and colon adenocarcinoma (71). Glutamine is also involved in activating mechanistic target of rapamycin complex 1 (68,72). Glycine, another nonessential and one of the simplest amino acids, has also been implicated in cancer (73,74). Glycine is a significant constituent of proteins in the body, which build tissues and organs. It is the most abundant type of amino acid in the body and one of the most important regulators of inflammation (7577). Glycine metabolism has also been demonstrated to be upregulated in non-small cell lung cancers (74,78). Studies have demonstrated that glycine stimulates proliferation of tumor cells, and cancer cells deprived of glycine indicated a significant reduction in cell growth (74,79). Serine, another important nonessential amino acid that participates in nucleotide synthesis, has been shown to be upregulated in breast cancer (74,80). Studies using melanoma cells have demonstrated that significant portions of serine are converted to glycine (81). Serine, glycine, and folate (vitamin B9) are constitutively active in various tumor cells (74,79,82).

Lipid metabolism

The role of lipid metabolism in cancer cells has long been disregarded; over the past decade, the increased rate of lipid metabolism in cancer cells is being recognized as the prominent hallmark of transformed cells (8385). Lipids are a diverse group of molecules composed of fat, triglycerides, phospholipid, cholesterols and cholesterol esters (Fig. 5). Lipids form the major component of cell membranes (phospholipid bilayer), hormones (steroid hormones, such as cholesterol) and certain lipid-soluble vitamins. Hence, lipids perform various roles in the body, from providing energy to muscles to producing hormones (86). In rapidly proliferating cancer cells, there is an overwhelming requirement for macromolecule synthesis. Hence, cancer cells also demonstrate a high dependence on lipids (83). One of the enzymes involved in the synthesis of de novo fatty acids is ATP citrate lyase (ACLY). ACLY catalyzes the conversion of mitochondrial-derived citrate to oxaloacetate and cytosolic acetyl-CoA. Thus, ACLY links de novo lipogenesis to gluconeogenesis and the Krebs cycle (87). Studies have demonstrated that higher expression levels of ACLY correlated with advanced stages of cancer and lymph node metastasis in tissue samples from gastric adenocarcinoma patients (88). However, targeting ACLY by microRNA-22 (miR-22) suppresses cancer cell proliferation and invasion in osteosarcoma, prostate, cervical and lung cancer cells (89). Another study demonstrates that ACLY is required for low molecular weight isoform of cyclin E mediated transformation, migration, and invasion of breast cancer cells in vitro along with tumor growth in vivo (90). Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in fatty acid synthesis. ACC carboxylates acetyl-CoA to form malonyl-CoA. In patients with squamous cell carcinoma of the head and neck, there is an association between phosphorylated AMP-activated protein kinase and ACC expression, and the therapeutic outcome is that high phosphorylated-ACC expression is associated with a worse overall survival rate in the patients (91). Similarly, ACC1 expression is upregulated in patients with hepatocellular carcinoma (HCC), and upregulation of ACC1 is also significantly correlated with the poorer overall survival of, and disease recurrence in HCC patients (92). Fatty acid synthase (FASN), which catalyzes the final step in fatty acid synthesis, is often overexpressed in human cancers (93,94). Inhibition of FASN suppresses invasion and migration of HCC cells (95). In contrast to enhanced fatty acid synthesis, certain types of cancer rely on the mitochondrial fatty acid oxidation (FAO) for ATP production (96). Although the mechanism that upregulates FAO in cancer remains unclear, it is proposed that FAO may confer benefits beyond ATP production (96). The FAO contributes to maintenance of redox homeostasis, and cell survival in hematopoietic stem cells and leukemia cells (97). Carnitine palmitoyltransferase (CPT1), the enzyme that catalyzes the initial step of FAO, is implicated in various types of cancer (96,98,99). CPT1 upregulation increases FAO, ATP production and endows resistance to metabolic stress.

Metabolic crosstalk

Increased glycose consumption, lactate production, PPP, lipid metabolism, and amino acid synthesis are commonly observed metabolic profile in almost all types of cancer cell. This type of metabolic profiling of tumor cells has been proposed to support their rapid cell growth (100). High rates of glycolysis leading to lactate production (aerobic glycolysis or the Warburg effect) distinguish cancer cells from normal cells (12,13). Glucose is a remarkable fuel for cancer cell, and a precursor for the supply of various metabolic intermediates, which are utilized for lipid, amino acid and nucleotide synthesis. Glutamine serves as another important source of fuel in cancer cells (65). Glutamine enters the mitochondria to replenish the Krebs cycle intermediates (6669). Glutamine enters the Krebs cycle to produce α-KG, succinate, fumarate and malate. Highly proliferative cancer cells have a high demand for the rapid synthesis of lipids, amino acids and nucleotides (8387). Tumor cells also divert carbon from glycolysis into the PPP (58), by which cancer cells synthesize macromolecules, such as nucleic acids. In addition, citrate and acetyl-coA are key intermediates for lipid synthesis (8890). Since these metabolic pathways are interconnected, understanding the mechanism(s) leading to this metabolic switch in cancer cells is of utmost importance.

Central role of mitochondria

Mitochondrial metabolism has emerged as a key target for cancer therapy (8,9). Mitochondria are important bioenergetics and biosynthetic organelles, responsible for producing ATP and various intermediates required for macromolecule synthesis. In addition to participating in energy metabolism, mitochondria participate in calcium homeostasis, production of reactive oxygen species (ROS), regulation of apoptosis and cell signaling pathways (36). Cancer cells have been shown to exhibit various degrees of mitochondrial abnormalities, which render mitochondria a suitable target for anti-cancer drugs (79). Mutations in mitochondrial DNA- and nuclear DNA-encoded mitochondrial genes have been observed in various types of human cancer (101103). These mutations range from single nucleotide polymorphisms to severe insertions/deletions and even chain termination. Furthermore, as mitochondria are the primary source of ROS generation, mitochondrial DNA is continuously exposed to oxidative stress and damage. A previous study investigated the contributions of mitochondrial mutations to tumor cell proliferation and metastasis (104). With increasing mutations, mitochondrial respiratory capacity has been shown to decrease progressively (104,105). In addition, defects in the mitochondrial respiratory chain may either promote or inhibit apoptosis (106). Programmed cell death or apoptosis is a complex signaling cascade, which is tightly regulated by proteases, termed caspases. Initiation of apoptosis and ROS production are closely associated with mitochondria (107). Osellame et al (107), demonstrated that loss of mitochondrial outer membrane permeability is characteristic of intrinsic apoptosis. In addition, ROS may mediate pro- and anti-apoptotic effects (108). During the last decade, the implication of polyamines in initiation of apoptosis has been the focus of investigations (109,110). Novel interactions between polyamine and mitochondria have recently been summarized in a review by Grancara et al (111). There is increasing interest in understanding multiple facets of mitochondrial biology that contribute to cancer. Mitochondria act as a central hub for cell survival, cell metabolism and cell death pathways. Taking into consideration the multifaceted role of mitochondria in tumorigenesis, targeting mitochondria may present an effective approach to treating cancer.

Conclusion

Metabolic reprogramming of cancer cells is recognized as one of the hallmarks of cancer. In this review article, the core dysregulated metabolic pathways and enzymes contributing to cancer cell proliferation, differentiation and metastasis, as well as the central role of mitochondria in orchestrating metabolic reprogramming were summarized. The close connection between these metabolic pathways, the role of mitochondria and redox regulation of tumor cells represents a promising strategy to target cancer growth. Thus, targeting these important metabolic enzymes and/or mitochondrial metabolic pathways may offer a valid and novel anti-cancer therapeutic strategy.

References

1 

Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Dang CV: Links between metabolism and cancer. Genes Dev. 26:877–890. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Newmeyer DD and Ferguson-Miller S: Mitochondria: Releasing power for life and unleashing the machineries of death. Cell. 112:481–490. 2003. View Article : Google Scholar : PubMed/NCBI

4 

Wang X: The expanding role of mitochondria in apoptosis. Genes Dev. 15:2922–2933. 2001.PubMed/NCBI

5 

Detmer SA and Chan DC: Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol. 8:870–879. 2007. View Article : Google Scholar : PubMed/NCBI

6 

McBride HM, Neuspiel M and Wasiak S: Mitochondria: More than just a powerhouse. Curr Biol. 16:R551–R560. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Wallace DC: Mitochondria and cancer. Nat Rev Cancer. 12:685–698. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Weinberg SE and Chandel NS: Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol. 11:9–15. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Wen S, Zhu D and Huang P: Targeting cancer cell mitochondria as a therapeutic approach. Future Med Chem. 5:53–67. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Wang F, Ogasawara MA and Huang P: Small mitochondria-targeting molecules as anti-cancer agents. Mol Aspects Med. 31:75–92. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Carew JS and Huang P: Mitochondrial defects in cancer. Mol Cancer. 1:92002. View Article : Google Scholar : PubMed/NCBI

12 

Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI

13 

Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI

14 

DeBerardinis RJ: Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genet Med. 10:767–777. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Seyfried TN and Shelton LM: Cancer as a metabolic disease. Nutr Metab (Lond). 7:72010. View Article : Google Scholar : PubMed/NCBI

16 

Pelicano H, Martin DS, Xu RH and Huang P: Glycolysis inhibition for anticancer treatment. Oncogene. 25:4633–4646. 2006. View Article : Google Scholar : PubMed/NCBI

17 

Niederacher D and Entian KD: Characterization of Hex2 protein, a negative regulatory element necessary for glucose repression in yeast. FEBS J. 200:311–319. 1991.

18 

Herrero P, Galíndez J, Ruiz N, Martínez-Campa C and Moreno F: Transcriptional regulation of the Saccharomyces cerevisiae HXK1, HXK2 and GLK1 genes. Yeast. 11:137–144. 1995. View Article : Google Scholar : PubMed/NCBI

19 

Rempel A, Mathupala SP, Griffin CA, Hawkins AL and Pedersen PL: Glucose catabolism in cancer cells: Amplification of the gene encoding type II hexokinase. Cancer Res. 56:2468–2471. 1996.PubMed/NCBI

20 

Bustamante E and Pedersen PL: High aerobic glycolysis of rat hepatoma cells in culture: Role of mitochondrial hexokinase. Proc Natl Acad Sci USA. 74:pp. 3735–3739. 1977; View Article : Google Scholar : PubMed/NCBI

21 

El-Bacha T, de Freitas MS and Sola-Penna M: Cellular distribution of phosphofructokinase activity and implications to metabolic regulation in human breast cancer. Mol Genet Metab. 79:294–299. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Zancan P, Sola-Penna M, Furtado CM and Da Silva D: Differential expression of phosphofructokinase-1 isoforms correlates with the glycolytic efficiency of breast cancer cells. Mol Genet Metab. 100:372–378. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Clem BF, O'Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA II, Klarer AC, Redman R, Miller DM, Trent JO, et al: Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther. 12:1461–1470. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z, Mitchell R and Bucala R: High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res. 62:5881–5887. 2002.PubMed/NCBI

25 

Moon JS, Jin WJ, Kwak JH, Kim HJ, Yun MJ, Kim JW, Park SW and Kim KS: Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells. Biochem J. 433:225–233. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Okar DA, Manzano A, Navarro-Sabatè A, Riera L, Bartrons R and Lange AJ: PFK-2/FBPase-2: Maker and breaker of the essential biofactor fructose-2,6-bisphosphate. Trends Biochem Sci. 26:30–35. 2001. View Article : Google Scholar : PubMed/NCBI

27 

Li C, Xiao Z, Chen Z, Zhang X, Li J, Wu X, Li X, Yi H, Li M, Zhu G, et al: Proteome analysis of human lung squamous carcinoma. Proteomics. 6:547–558. 2006. View Article : Google Scholar : PubMed/NCBI

28 

Tokunaga K, Nakamura Y, Sakata K, Fujimori K, Ohkubo M, Sawada K and Sakiyama S: Enhanced expression of a glyceraldehyde-3-phosphate dehydrogenase gene in human lung cancers. Cancer Res. 47:5616–5619. 1987.PubMed/NCBI

29 

Schek N, Hall BL and Finn OJ: Increased glyceraldehyde-3-phosphate dehydrogenase gene expression in human pancreatic adenocarcinoma. Cancer Res. 48:6354–6359. 1988.PubMed/NCBI

30 

Epner DE, Partin AW, Schalken JA, Isaacs JT and Coffey DS: Association of glyceraldehyde-3-phosphate dehydrogenase expression with cell motility and metastatic potential of rat prostatic adenocarcinoma. Cancer Res. 53:1995–1997. 1993.PubMed/NCBI

31 

Krasnov GS, Dmitriev AA, Snezhkina AV and Kudryavtseva AV: Deregulation of glycolysis in cancer: Glyceraldehyde-3-phosphate dehydrogenase as a therapeutic target. Expert Opin Ther Targets. 17:681–693. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Feng C, Gao Y, Wang C, Yu X, Zhang W, Guan H, Shan Z and Teng W: Aberrant overexpression of pyruvate kinase M2 is associated with aggressive tumor features and the BRAF mutation in papillary thyroid cancer. J Clin Endocrinol Metab. 98:E1524–E1533. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, Simmet T and Seufferlein T: PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation. Mol Cancer. 15:32016. View Article : Google Scholar : PubMed/NCBI

34 

Lu W, Cao Y, Zhang Y, Li S, Gao J, Wang XA, Mu J, Hu YP, Jiang L, Dong P, et al: Up-regulation of PKM2 promote malignancy and related to adverse prognostic risk factor in human gallbladder cancer. Sci Rep. 6:263512016. View Article : Google Scholar : PubMed/NCBI

35 

Wittwer JA, Robbins D, Wang F, Codarin S, Shen X, Kevil CG, Huang TT, Van Remmen H, Richardson A and Zhao Y: Enhancing mitochondrial respiration suppresses tumor promoter TPA-induced PKM2 expression and cell transformation in skin epidermal JB6 cells. Cancer Prev Res (Phila). 4:1476–1484. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL and Dang CV: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA. 107:pp. 2037–2042. 2010; View Article : Google Scholar : PubMed/NCBI

37 

Linnane AW, Marzuki S, Ozawa T and Tanaka M: Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1:642–645. 1989. View Article : Google Scholar : PubMed/NCBI

38 

Taylor RW and Turnbull DM: Mitochondrial DNA mutations in human disease. Nat Rev Genet. 6:389–402. 2005. View Article : Google Scholar : PubMed/NCBI

39 

Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, Jen J and Sidransky D: Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science. 287:2017–2019. 2000. View Article : Google Scholar : PubMed/NCBI

40 

Cardaci S and Ciriolo MR: TCA cycle defects and cancer: When metabolism tunes redox state. Int J Cell Biol. 2012:1618372012. View Article : Google Scholar : PubMed/NCBI

41 

Rustin P, Bourgeron T, Parfait B, Chretien D, Munnich A and Rötig A: Inborn errors of the Krebs cycle: A group of unusual mitochondrial diseases in human. Biochim Biophys Acta. 1361:185–197. 1997. View Article : Google Scholar : PubMed/NCBI

42 

Singh KK, Desouki MM, Franklin RB and Costello LC: Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues. Mol Cancer. 5:142006. View Article : Google Scholar : PubMed/NCBI

43 

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI

44 

Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, et al: IDH1 and IDH2 mutations in gliomas. N Engl J Med. 360:765–773. 2009. View Article : Google Scholar : PubMed/NCBI

45 

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 462:739–744. 2009. View Article : Google Scholar : PubMed/NCBI

46 

Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, et al: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 73:95–106. 2003. View Article : Google Scholar : PubMed/NCBI

47 

Chen YB, Brannon AR, Toubaji A, Dudas ME, Won HH, Al-Ahmadie HA, Fine SW, Gopalan A, Frizzell N, Voss MH, et al: Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: Recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 38:627–637. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A, et al: Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature. 477:225–228. 2011. View Article : Google Scholar : PubMed/NCBI

49 

Gaude E and Frezza C: Defects in mitochondrial metabolism and cancer. Cancer Metab. 2:102014. View Article : Google Scholar : PubMed/NCBI

50 

Neumann HP, Pawlu C, Pęczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, et al: European-American Paraganglioma Study Group: Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 292:943–951. 2004. View Article : Google Scholar : PubMed/NCBI

51 

Pollard PJ, Wortham NC and Tomlinson IP: The TCA cycle and tumorigenesis: The examples of fumarate hydratase and succinate dehydrogenase. Ann Med. 35:632–639. 2003. View Article : Google Scholar : PubMed/NCBI

52 

Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, et al: Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 14:2231–2239. 2005. View Article : Google Scholar : PubMed/NCBI

53 

Habano W, Sugai T, Nakamura S, Uesugi N, Higuchi T, Terashima M and Horiuchi S: Reduced expression and loss of heterozygosity of the SDHD gene in colorectal and gastric cancer. Oncol Rep. 10:1375–1380. 2003.PubMed/NCBI

54 

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB and Gottlieb E: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell. 7:77–85. 2005. View Article : Google Scholar : PubMed/NCBI

55 

Patra KC and Hay N: The pentose phosphate pathway and cancer. Trends Biochem Sci. 39:347–354. 2014. View Article : Google Scholar : PubMed/NCBI

56 

Deberardinis RJ, Sayed N, Ditsworth D and Thompson CB: Brick by brick: Metabolism and tumor cell growth. Curr Opin Genet Dev. 18:54–61. 2008. View Article : Google Scholar : PubMed/NCBI

57 

Riganti C, Gazzano E, Polimeni M, Aldieri E and Ghigo D: The pentose phosphate pathway: An antioxidant defense and a crossroad in tumor cell fate. Free Radic Biol Med. 53:421–436. 2012. View Article : Google Scholar : PubMed/NCBI

58 

Jiang P, Du W and Wu M: Regulation of the pentose phosphate pathway in cancer. Protein Cell. 5:592–602. 2014. View Article : Google Scholar : PubMed/NCBI

59 

Cairns RA, Harris IS and Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 11:85–95. 2011. View Article : Google Scholar : PubMed/NCBI

60 

Jonas SK, Benedetto C, Flatman A, Hammond RH, Micheletti L, Riley C, Riley PA, Spargo DJ, Zonca M and Slater TF: Increased activity of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase in purified cell suspensions and single cells from the uterine cervix in cervical intraepithelial neoplasia. Br J Cancer. 66:185–191. 1992. View Article : Google Scholar : PubMed/NCBI

61 

Lucarelli G, Galleggiante V, Rutigliano M, Sanguedolce F, Cagiano S, Bufo P, Lastilla G, Maiorano E, Ribatti D, Giglio A, et al: Metabolomic profile of glycolysis and the pentose phosphate pathway identifies the central role of glucose-6-phosphate dehydrogenase in clear cell-renal cell carcinoma. Oncotarget. 6:13371–13386. 2015. View Article : Google Scholar : PubMed/NCBI

62 

D'Alessandro A, Amelio I, Berkers CR, Antonov A, Vousden KH, Melino G and Zolla L: Metabolic effect of TAp63α: Enhanced glycolysis and pentose phosphate pathway, resulting in increased antioxidant defense. Oncotarget. 5:7722–7733. 2014. View Article : Google Scholar : PubMed/NCBI

63 

Sukhatme VP and Chan B: Glycolytic cancer cells lacking 6-phosphogluconate dehydrogenase metabolize glucose to induce senescence. FEBS Lett. 586:2389–2395. 2012. View Article : Google Scholar : PubMed/NCBI

64 

Nishimura M and Uyeda K: Purification and characterization of a novel xylulose 5-phosphate-activated protein phosphatase catalyzing dephosphorylation of fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase. J Biol Chem. 270:26341–26346. 1995. View Article : Google Scholar : PubMed/NCBI

65 

Wise DR and Thompson CB: Glutamine addiction: A new therapeutic target in cancer. Trends Biochem Sci. 35:427–433. 2010. View Article : Google Scholar : PubMed/NCBI

66 

DeBerardinis RJ and Cheng T: Q's next: The diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 29:313–324. 2010. View Article : Google Scholar : PubMed/NCBI

67 

Dang CV: Glutaminolysis: Supplying carbon or nitrogen or both for cancer cells? Cell Cycle. 9:3884–3886. 2010. View Article : Google Scholar : PubMed/NCBI

68 

Altman BJ, Stine ZE and Dang CV: From Krebs to clinic: Glutamine metabolism to cancer therapy. Nat Rev Cancer. 16:619–634. 2016. View Article : Google Scholar : PubMed/NCBI

69 

Hensley CT, Wasti AT and DeBerardinis RJ: Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J Clin Invest. 123:3678–3684. 2013. View Article : Google Scholar : PubMed/NCBI

70 

Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, et al: Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 105:pp. 18782–18787. 2008; View Article : Google Scholar : PubMed/NCBI

71 

Stepulak A, Luksch H, Gebhardt C, Uckermann O, Marzahn J, Sifringer M, Rzeski W, Staufner C, Brocke KS, Turski L, et al: Expression of glutamate receptor subunits in human cancers. Histochem Cell Biol. 132:435–445. 2009. View Article : Google Scholar : PubMed/NCBI

72 

Durán RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E and Hall MN: Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell. 47:349–358. 2012. View Article : Google Scholar : PubMed/NCBI

73 

Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB and Mootha VK: Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 336:1040–1044. 2012. View Article : Google Scholar : PubMed/NCBI

74 

Amelio I, Cutruzzolá F, Antonov A, Agostini M and Melino G: Serine and glycine metabolism in cancer. Trends Biochem Sci. 39:191–198. 2014. View Article : Google Scholar : PubMed/NCBI

75 

Hasegawa S, Ichiyama T, Sonaka I, Ohsaki A, Okada S, Wakiguchi H, Kudo K, Kittaka S, Hara M and Furukawa S: Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells. Clin Exp Immunol. 167:269–274. 2012. View Article : Google Scholar : PubMed/NCBI

76 

Alarcon-Aguilar FJ, Almanza-Perez J, Blancas G, Angeles S, Garcia-Macedo R, Roman R and Cruz M: Glycine regulates the production of pro-inflammatory cytokines in lean and monosodium glutamate-obese mice. Eur J Pharmacol. 599:152–158. 2008. View Article : Google Scholar : PubMed/NCBI

77 

Cruz M, Maldonado-Bernal C, Mondragón-Gonzalez R, Sanchez-Barrera R, Wacher NH, Carvajal-Sandoval G and Kumate J: Glycine treatment decreases proinflammatory cytokines and increases interferon-γ in patients with type 2 diabetes. J Endocrinol Invest. 31:694–699. 2008. View Article : Google Scholar : PubMed/NCBI

78 

Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, Soh BS, Sun LL, Tai BC, Nga ME, et al: Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 148:259–272. 2012. View Article : Google Scholar : PubMed/NCBI

79 

Locasale JW: Serine, glycine and one-carbon units: Cancer metabolism in full circle. Nat Rev Cancer. 13:572–583. 2013. View Article : Google Scholar : PubMed/NCBI

80 

Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, et al: Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 476:346–350. 2011. View Article : Google Scholar : PubMed/NCBI

81 

Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, et al: Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 43:869–874. 2011. View Article : Google Scholar : PubMed/NCBI

82 

Mattaini KR, Sullivan MR and Vander Heiden MG: The importance of serine metabolism in cancer. J Cell Biol. 214:249–257. 2016. View Article : Google Scholar : PubMed/NCBI

83 

Baenke F, Peck B, Miess H and Schulze A: Hooked on fat: The role of lipid synthesis in cancer metabolism and tumour development. Dis Model Mech. 6:1353–1363. 2013. View Article : Google Scholar : PubMed/NCBI

84 

Santos CR and Schulze A: Lipid metabolism in cancer. FEBS J. 279:2610–2623. 2012. View Article : Google Scholar : PubMed/NCBI

85 

Currie E, Schulze A, Zechner R, Walther TC and Farese RV Jr: Cellular fatty acid metabolism and cancer. Cell Metab. 18:153–161. 2013. View Article : Google Scholar : PubMed/NCBI

86 

Vance JE and Vance DE: Biochemistry of lipids, lipoproteins and membranes. Elsevier; Amsterdam: 2002, View Article : Google Scholar

87 

Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C and Thompson CB: ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 24:6314–6322. 2005. View Article : Google Scholar : PubMed/NCBI

88 

Qian X, Hu J, Zhao J and Chen H: ATP citrate lyase expression is associated with advanced stage and prognosis in gastric adenocarcinoma. Int J Clin Exp Med. 8:7855–7860. 2015.PubMed/NCBI

89 

Xin M, Qiao Z, Li J, Liu J, Song S, Zhao X, Miao P, Tang T, Wang L, Liu W, et al: miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: Evidence in osteosarcoma, prostate cancer, cervical cancer and lung cancer. Oncotarget. 7:44252–44265. 2016. View Article : Google Scholar : PubMed/NCBI

90 

Lucenay KS, Doostan I, Karakas C, Bui T, Ding Z, Mills GB, Hunt KK and Keyomarsi K: Cyclin E associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells. Cancer Res. 76:2406–2418. 2016. View Article : Google Scholar : PubMed/NCBI

91 

Su YW, Lin YH, Pai MH, Lo AC, Lee YC, Fang IC, Lin J, Hsieh RK, Chang YF and Chen CL: Association between phosphorylated AMP-activated protein kinase and acetyl-CoA carboxylase expression and outcome in patients with squamous cell carcinoma of the head and neck. PLoS One. 9:e961832014. View Article : Google Scholar : PubMed/NCBI

92 

Wang MD, Wu H, Fu GB, Zhang HL, Zhou X, Tang L, Dong LW, Qin CJ, Huang S, Zhao LH, et al: Acetyl-coenzyme A carboxylase alpha promotion of glucose-mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients. Hepatology. 63:1272–1286. 2016. View Article : Google Scholar : PubMed/NCBI

93 

Bauerschlag DO, Maass N, Leonhardt P, Verburg FA, Pecks U, Zeppernick F, Morgenroth A, Mottaghy FM, Tolba R, Meinhold-Heerlein I, et al: Fatty acid synthase overexpression: Target for therapy and reversal of chemoresistance in ovarian cancer. J Transl Med. 13:1462015. View Article : Google Scholar : PubMed/NCBI

94 

Ogino S, Kawasaki T, Ogawa A, Kirkner GJ, Loda M and Fuchs CS: Fatty acid synthase overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype. Hum Pathol. 38:842–849. 2007. View Article : Google Scholar : PubMed/NCBI

95 

Gong J, Shen S, Yang Y, Qin S, Huang L, Zhang H, Chen L, Chen Y, Li S, She S, et al: Inhibition of FASN suppresses migration, invasion and growth in hepatoma carcinoma cells by deregulating the HIF-1α/IGFBP1 pathway. Int J Oncol. 50:883–892. 2017. View Article : Google Scholar : PubMed/NCBI

96 

Carracedo A, Cantley LC and Pandolfi PP: Cancer metabolism: Fatty acid oxidation in the limelight. Nat Rev Cancer. 13:227–232. 2013. View Article : Google Scholar : PubMed/NCBI

97 

Ito K and Suda T: Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol. 15:243–256. 2014. View Article : Google Scholar : PubMed/NCBI

98 

Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, Mason J, Huang P, Sawyer SK, Fuerth B, Faubert B, et al: Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25:1041–1051. 2011. View Article : Google Scholar : PubMed/NCBI

99 

McGarry JD and Brown NF: The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem. 244:1–14. 1997. View Article : Google Scholar : PubMed/NCBI

100 

Coller HA: Is cancer a metabolic disease? Am J Pathol. 184:4–17. 2014. View Article : Google Scholar : PubMed/NCBI

101 

Tan DJ, Bai RK and Wong LJ: Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer. Cancer Res. 62:972–976. 2002.PubMed/NCBI

102 

Liu VW, Shi HH, Cheung AN, Chiu PM, Leung TW, Nagley P, Wong LC and Ngan HY: High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res. 61:5998–6001. 2001.PubMed/NCBI

103 

Richard SM, Bailliet G, Páez GL, Bianchi MS, Peltomäki P and Bianchi NO: Nuclear and mitochondrial genome instability in human breast cancer. Cancer Res. 60:4231–4237. 2000.PubMed/NCBI

104 

Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y and Hayashi J: ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science. 320:661–664. 2008. View Article : Google Scholar : PubMed/NCBI

105 

Swalwell H, Kirby DM, Blakely EL, Mitchell A, Salemi R, Sugiana C, Compton AG, Tucker EJ, Ke BX, Lamont PJ, et al: Respiratory chain complex I deficiency caused by mitochondrial DNA mutations. Eur J Hum Genet. 19:769–775. 2011. View Article : Google Scholar : PubMed/NCBI

106 

Kwong JQ, Henning MS, Starkov AA and Manfredi G: The mitochondrial respiratory chain is a modulator of apoptosis. J Cell Biol. 179:1163–1177. 2007. View Article : Google Scholar : PubMed/NCBI

107 

Osellame LD, Blacker TS and Duchen MR: Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab. 26:711–723. 2012. View Article : Google Scholar : PubMed/NCBI

108 

Shen YH, Wang XL and Wilcken DE: Nitric oxide induces and inhibits apoptosis through different pathways. FEBS Lett. 433:125–131. 1998. View Article : Google Scholar : PubMed/NCBI

109 

Seiler N and Raul F: Polyamines and apoptosis. J Cell Mol Med. 9:623–642. 2005. View Article : Google Scholar : PubMed/NCBI

110 

Agostinelli E, Tempera G, Molinari A, Salvi M, Battaglia V, Toninello A and Arancia G: The physiological role of biogenic amines redox reactions in mitochondria. New perspectives in cancer therapy. Amino Acids. 33:175–187. 2007. View Article : Google Scholar : PubMed/NCBI

111 

Grancara S, Ohkubo S, Artico M, Ciccariello M, Manente S, Bragadin M, Toninello A and Agostinelli E: Milestones and recent discoveries on cell death mediated by mitochondria and their interactions with biologically active amines. Amino Acids. 48:2313–2326. 2016. View Article : Google Scholar : PubMed/NCBI

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January 2018
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APA
Sreedhar, A., & Sreedhar, A. (2018). Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells (Review). Biomedical Reports, 8, 3-10. https://doi.org/10.3892/br.2017.1022
MLA
Sreedhar, A., Zhao, Y."Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells (Review)". Biomedical Reports 8.1 (2018): 3-10.
Chicago
Sreedhar, A., Zhao, Y."Dysregulated metabolic enzymes and metabolic reprogramming in cancer cells (Review)". Biomedical Reports 8, no. 1 (2018): 3-10. https://doi.org/10.3892/br.2017.1022