Skip to main content
Download PDF

Metabolic features of cancer cells

Cancer Communications volume 38, Article number: 65 (2018) Cite this article

Abstract

Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to counteract metabolic and genotoxic stress during cancer progression. In this reprograming, cancer cells’ metabolism and other cellular activities are integrated and mutually regulated, and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions. This review and several others in this issue of Cancer Communications discuss these enzymes’ newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism, which play critical roles in various cellular activities, including gene expression, anabolism, catabolism, redox homeostasis, and DNA repair.

Introduction

Cancer cells produce energy through the Warburg effect, in which high rates of glycolysis and lactic acid fermentation occur in the cytosol regardless of the oxygen level [1,2,3]. Promoted by the Warburg effect and other altered metabolic activities, cancer cells have increased anabolism, which includes the synthesis of nucleotides, amino acids, and lipids, alter anti-metabolic stress responses to maintain hemostasis and survival, and reprogram gene expression in a metabolism-dependent way to support their proliferation. Notably, some metabolic enzymes and metabolites in cancer cells have recently been found to have additional functions, which are distinct from their original roles in metabolic reactions, that directly regulate a variety of cellular activities, including metabolism, gene expression, cell cycle progression, apoptosis, autophagy, and exosome secretion [4, 5]. In the current issue of Cancer Communications, this review and several others cover these newly identified features of cancer metabolism as well as the regulation of cancer metabolism and other critical cellular functions and highlight the non-canonical functions of metabolic enzymes and metabolites in cancer progression. Particularly, this review also underscore the main themes discussed by other reviews in the same issue.

Non-canonical functions of metabolic enzymes

Protein kinases regulate intracellular signal transduction pathways and every aspect of cellular activities, whereas metabolic enzymes are traditionally known as the catalyzers of the reactions in cell metabolism [4]. However, we previously demonstrated that metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), and fructokinase-A [also known as ketohexokinase (KHK)-A], can also function as protein kinases. We showed that upon activation of receptor tyrosine kinases, nucleus-translocated PKM2 in a complex with β-catenin phosphorylates histone H3 Thr11 to induce β-catenin-mediated gene expression. This leads to enhanced Warburg effect by upregulating the expression of glycolytic genes and accelerated G1-S transition via cyclin D1 upregulation [6,7,8]. In mitosis, PKM2 phosphorylates the spindle checkpoint protein BUB3 at Tyr207 to govern kinetochore-spindle attachment and the mitotic checkpoint, thereby promoting accurate chromosome segregation and the proliferation of tumor cells [9]. PKM2 is also involved in cytokinesis. PKM2 interacts with myosin light chain 2 in the contractile ring regions of mitotic cells and phosphorylates it at Tyr118. This phosphorylation promotes the contraction of the actomyosin complex at the cleavage furrow for the completion of cytokinesis [10]. We also demonstrated that PGK1 is a protein kinase to phosphorylate and activates pyruvate dehydrogenase kinase isozyme 1 at Thr338, leading to suppression of mitochondrial pyruvate metabolism. Under energy stress, PGK1 phosphorylates Beclin 1 at Ser30 to promote autophagy. The integrated regulation of glycolysis, mitochondrial metabolism, and autophagy by PGK1 is instrumental to the promotion of tumor cell proliferation and the maintenance of cell homeostasis [11, 12]. In addition to identifying the protein kinase activity of the glycolytic enzymes PKM2 and PGK1, we found that hepatocellular carcinoma cells shut down fructose metabolism by switching their expression of the high-activity KHK-C to that of the low-activity KHK-A isoform. KHK-A in the fructose metabolic pathway phosphorylates and activates phosphoribosyl pyrophosphate synthetase 1 to promote de novo nucleic acid synthesis and hepatocellular carcinoma development [2, 13].

The non-metabolic functions of metabolic enzymes is reviewed by Lu et al. in the current issue of Cancer Communications. The metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) has both kinase and phosphatase activity. PFKFB4 uses its kinase activity to synthesize fructose 2,6-bisphosphate from fructose-6-phosphate and adenosine triphosphate (ATP) and its phosphatase activity to hydrolyze fructose 2,6-bisphosphate into fructose-6-phosphate and inorganic phosphate [14]. PFKFB4 functions as a protein kinase and phosphorylates steroid receptor coactivator-3 at S857 to activate activating transcription factor 4, leading to the enhanced expression of genes encoding the metabolic enzymes necessary for purine synthesis [14]. We recently demonstrated that the α-ketoglutarate (α-KG) dehydrogenase complex, which is known to catalyze the conversion of α-KG to succinyl-coenzyme A (CoA) in the mitochondria, interacts with the histone acetyltransferase lysine acetyltransferase 2a (KAT2A, also known as GCN5) in the nucleus and locally produces succinyl-CoA. KAT2A uses α-KG dehydrogenase–generated succinyl-CoA for histone succinylation at the Lys79 in the promoter regions of more than 6000 genes, thereby promoting tumor growth [15]. In addition, acetyl-CoA-producing enzymes, such as acetyl-CoA synthetase short chain family member 2 (ACSS2) [16,17,18], ATP citrate lyase (ACLY) [19, 20], and the pyruvate dehydrogenase complex [21], translocate to the nucleus to regulate gene expression [5]. In response to ionizing radiation-induced DNA damage, fumarase translocates from the cytosol to the nucleus [22], where fumarase binds to the histone variant H2A.Z. Fumarase-produced fumarate at DNA damage regions inhibits α-KG-dependent, lysine-specific demethylase 2B (KDM2B) histone demethylase activity, resulting in increased dimethylation of histone H3K36 and accumulation of the DNA-dependent protein kinase complex for subsequent non-homologous end joining DNA repair and cell survival [23].

Metabolic enzymes can also directly regulate oncogenic signaling. In response to epidermal growth factor receptor (EGFR) activation, the platelet isoform of phosphofructokinase 1 (PFKP), which is a rate-limiting enzyme in glycolysis, is stabilized by the inhibition of ubiquitylation-proteasomal degradation and is acetylated by lysine acetyltransferase 5 at a lysine residue (K395) and translocates to the plasma membrane, where PFKP is phosphorylated at residue Y64 by EGFR [24, 25]. Phosphorylated PFKP binds to a Src homology 2 domain of p85α and recruits p85α to the plasma membrane, resulting in activation of phosphoinositide 3-kinase (PI3K). PI3K-dependent AKT activation promotes glucose transporter 1 (GLUT1) expression and enhances phosphofructokinase 2 (PFK2) phosphorylation and the production of fructose-2,6-bisphosphate, which in turn promotes phosphofructokinase 1 activation and the Warburg effect [25].

Thus, discoveries from our group and others demonstrate that cancer cells alter the subcellular localization of some metabolic enzymes and utilize the non-canonical functions of these enzymes to regulate diverse cellular activities, including the activation of oncogenic signaling, direct regulation of cell metabolism, modulation of gene expression, promotion of cell cycle progression and cytokinesis, and control of DNA repair [26].

Non-canonical functions of metabolites

Metabolites act as cofactors and the regulators of various enzymes, including those implicated in chromatin modification and gene expression. In this issue of Cancer Communications, Wang and Lei summarize the impact that cancer-induced metabolic changes have in altering modifications on histones and DNA [27].

Methyltransferases and demethylases can reversibly regulate the methylation of DNA and histones and subsequent gene expression. S-adenosyl methionine (SAM) is a universal methyl donor and is synthesized from methionine and ATP by methionine adenosyltransferases (MATs) [28]. S-adenosyl homocysteine (SAH), which is a potent inhibitor of all methyltransferases, is formed by the demethylation of SAM. The intracellular SAM/SAH ratio, which is tightly regulated by the metabolism of methionine, threonine, and serine, dynamically regulates methyltransferase activity [29,30,31]. The removal of histone and DNA methylation by the Jumonji C family members and the ten-eleven translocation (TET) methylcytosine hydroxylases uses a dioxigenation reaction that requires metabolite co-factor α-KG [32], which is produced by glucose and glutamine catabolism. This demethylation can be inhibited by metabolites structurally related to α-KG, including succinate, fumarate, and 2-hydroxyglutarate, the latter of which is a product primarily from the isocitrate dehydrogenase genes IDH1 and IDH2 [33, 34]. In addition, high succinate and fumarate levels can be induced by tumor-associated loss-of-function mutations in the succinate dehydrogenase gene SDH and fumarase gene FH in SDH- and FH-deficient tumors, respectively [31, 35].

Metabolites also serve as substrates or regulators of histone acetyltransferase and histone deacetylase, a pair of enzyme families that acetylate and deacetylate histones, respectively. The metabolic regulation of acetyl-CoA production from acetate, citrate, pyruvate, fatty acid β-oxidation, and the metabolism of amino acid and ketone bodies is instrumental for histone acetyltransferase activity. Accordingly, acetyl-CoA metabolism is tightly regulated both spatially and temporally to elicit responses from the transcription machinery to nutrient availability [5]. In contrast, butyrate and ketone body β-hydroxybutyrate, which is produced by fatty acid hydrolysis, directly inhibit class I and IIa histone deacetylases, and the deacetylases sirtuin 1 and sirtuin 2 are activated by high NAD+ levels and inhibited by nicotinamide (NAM), a precursor of NAD [5].

In addition to methylation and acetylation, covalent modifications of DNA and histones, including hydroxylation, crotonylation, β-hydroxybutyrylation, 2-hydroxyisobutyrylation, O-GlcNAcylation and polyadenosine diphosphate ribosylation, have been shown to be influenced by metabolic processes [5].

As Xia and Chen elucidate in this issue of Cancer Communications, metabolites can be key players in signaling pathways to provide a metabolic advantage to cancer cells, thereby promoting tumor cell proliferation, tumorigenesis, and tumor progression. For instance, ribulose-5-phosphate, an intermediate product of the downstream product of the pentose phosphate pathway, disrupts the active liver kinase B1 (LKB1)-sterile 20-related adapter (STRAD)-mouse protein-25 (MO25) complex and inhibits LKB1-adenosine monophosphate-activated protein kinase (AMPK) signaling. Leucine enhances mammalian target of rapamycin (mTOR) activity, likely by shifting the raptor-mTOR complex from a stable and inactive complex to an unstable and active complex. In addition, acetoacetate, an intermediate of ketogenesis, binds to the BRAF V600E mutant rather than its wild-type counterpart and subsequently promotes BRAF V600E’s binding to its substrate, mitogen-activated protein kinase kinase 1 (MEK1), thereby increasing MEK1/extracellular signal-regulated kinase (ERK)1/2 activity.

Metabolites are also involved in the regulation of metabolic enzymes. Xia and Chen report that the glycolytic intermediate product 3-phosphoglycerate competes with glucose 6-phosphate and inhibits 6-phosphogluconate dehydrogenase in the pentose phosphate pathway. Serine binds to PKM2, promoting the conversion of the PKM2 dimer to a tetramer and decreasing the Km value of PKM2 for its activator, phosphoenolpyruvate.

Thus, metabolites function as cofactors and regulators of metabolic and non-metabolic enzymes and regulate critical cellular activities in both cellular metabolism and other cellular functions.

Lipid metabolism in cancer

De novo lipid synthesis and uptake, which contribute to the intracellular lipid levels of mammalian cells, are upregulated in cancer cells [36]. Lipids are essential components in membrane biosynthesis, function as second messengers to transduce cellular signals, and serve as important energy sources. In the current issue of Cancer Communications, Kuo and Ann discussed recent findings about the regulation of lipid metabolism, especially those regarding sterol regulatory element-binding proteins (SREBPs), which are transcriptional factors that are key players in the transcriptional control of genes that regulate lipid uptake, such as the low-density lipoprotein receptor gene LDLR, and genes involved in lipid synthesis, such as those encoding ACLY, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN) [36]. SREBP activation is repressed by the ER–resident insulin-induced gene 1 (INSIG1) protein, which binds to SREBP cleavage-activating protein (SCAP) and is modulated by sterols to prevent the translocation and activation of SREBP [36]. The mTOR complex 1-S6K1 interaction is crucial for SREBP activation and sustained lipogenesis and hepatosteatosis under conditions of insulin resistance. In cancer cells, many oncogenic signaling molecules, such as p53, phosphatase and tensin homolog (PTEN), PI3K, and KRAS, converge on the PI3KAKT/mTOR pathway and activate SREBP-mediated lipid biosynthesis to meet lipid demands for cell growth [37]. Oncogenic EGFR signaling increases the N-glycosylation of SCAP, which facilitates the release of the SCAP-SREBP1/2 complex from INSIG1, and induces the SREBP1/2-dependent expression of enzymes required for lipogenesis and the expression of low-density lipoprotein receptor for cholesterol uptake [36].

Under the state of fasting or starvation, SREBP1 and lipogenesis are inhibited. AMPK is a highly conserved sensor of cellular energy status. It can directly phosphorylate and suppress SREBP1c gene expression and SREBP-dependent hepatosteatosis [37]. Kuo and Ann describe that under energy stress, fatty acid oxidation, which comprises a cyclical series of catabolic reactions to shorten fatty acids, produces the reduced form of nicotinamide adenine dinucleotide (NADH), 1,5-dihydro-flavin adenine dinucleotide (FADH2), nicotinamide adenine dinucleotide phosphate (NADPH), and ATP. NADH and FADH2 enter the electron transport chain to produce ATP in the mitochondria. NADPH, as a reducing agent, counteracts the increased ROS in cancer cells that result from metabolic stress and hypoxia [38]. Carnitine palmitoyltransferase 1, a rate-limiting enzyme in fatty acid oxidation, conjugates fatty acids and translocates them to the mitochondria to facilitate cancer metabolic reprograming. Lipid droplets are an important source of fatty acid. Understanding the mechanism underlying the lipolysis of lipid droplets in cancer will provide insight into the dynamic regulation of lipid metabolism during cancer growth and progression.

Redox homeostasis in cancer

Cancer cells have high levels of oxidative stress [39, 40]. This oxidative stress is exerted by accumulated ROS, which is induced by hypoxia, metabolic defects, and endoplasmic reticulum stress [41]. Cancer cells elevate the levels of ROS scavengers for survival in response to the increased ROS levels [41]. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional regulator of enzymes, is activated in response to oxidative and electrophilic stress and plays an essential role in cellular redox homeostasis [42]. Elevated Nrf2 activity has been detected in many types of human cancer [42,43,44,45,46]. In the nucleus, Nrf2 regulates the expression of genes, including those encoding NADPH-generating enzymes [47] and those involved in glutathione biosynthesis, to maintain reduced intracellular levels of glutathione. Glutathione and NADPH play essential roles in redox homeostasis and cell survival [48,49,50].

In glutathione synthesis, the transsulfuration pathway, which links the methionine cycle to glutathione metabolism, converts homocysteine to cysteine, the limiting reagent in the pathway [51]. Cysteine is also provided by solute carrier family 7 member 11 (SLC7A11; also known as system xc−), which is a sodium-independent antiporter of cysteine and glutamate and takes up extracellular cysteine in exchange for intracellular glutamate at a 1:1 ratio. As Koppula et al. review in this issue of Cancer Communications, SLC7A-derived glutathione can be used by glutathione peroxidase 4 to detoxify lipid hydroperoxides, thereby preventing ferroptosis [52].

Thus, cancer cells reprogram anti-oxidative responses by upregulating Nrf2 activity, the transsulfuration pathway, and SLC7A11 activity, thereby maintaining redox homeostasis for cell survival.

Conclusions

Cell metabolism and other cellular activities are integrated and mutually regulated, and metabolic enzymes and metabolites have non-canonical functions in these activities. Cancer cells reprogram cellular activities by specifically regulating the expression of metabolic enzymes (e.g., switching from KHK-C to KHK-A expression in hepatocellular carcinoma cells) and altering the subcellular localization of metabolic enzymes such as PKM2, PGK1, fumarase, α-KG dehydrogenase, and ACSS2. These relocalized metabolic enzymes directly govern critical cellular activities to support tumor development in a manner dependent on their originally defined metabolic or non-metabolic enzymatic activity (e.g., protein kinase activity). In addition, metabolic enzymes, such as PFKP, and metabolites, such as acetoacetate, can act as signaling components to directly mediate oncogenic signaling or directly regulate other enzymes’ activities in a subcellular compartment-dependent manner. Metabolism-dependent modifications of key modulators, such as the N-glycosylation-dependent activation of SREBP1, control biogenesis and maintain the redox homeostasis of cancer cells. These newly identified features of cancer cell metabolism will facilitate the identification of specific interventions that disrupt these cancer cell-specific features for more efficient cancer treatment.

References

  1. Yang W, Lu Z. Pyruvate kinase M2 at a glance. J Cell Sci. 2015;128(9):1655–60.

    Article  CAS  Google Scholar 

  2. Li X, Qian X, Lu Z. Fructokinase A acts as a protein kinase to promote nucleotide synthesis. Cell Cycle. 2016;15(20):2689–90.

    Article  CAS  Google Scholar 

  3. Li X, Zheng Y, Lu Z. PGK1 is a new member of the protein kinome. Cell Cycle. 2016;15(14):1803–4.

    Article  CAS  Google Scholar 

  4. Lu Z, Hunter T. Metabolic kinases moonlighting as protein kinases. Trends Biochem Sci. 2018;43(4):301–10.

    Article  CAS  Google Scholar 

  5. Wang HL, Wang YL, Zhang HK, Liu ZH, Lu ZW. Determination of thermal focal length under different depths of focus in asymmetrical flat-flat dynamically stable resonators. Opt Laser Technol. 2018;106:12–7.

    Article  CAS  Google Scholar 

  6. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell. 2012;150(4):685–96.

    Article  CAS  Google Scholar 

  7. Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 2012;14(12):1295–304.

    Article  CAS  Google Scholar 

  8. Lu Z. PKM2 functions as a histone kinase. Cell Cycle. 2012;11(22):4101–2.

    Article  CAS  Google Scholar 

  9. Jiang Y, Li X, Yang W, Hawke DH, Zheng Y, Xia Y, et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol Cell. 2014;53(1):75–87.

    Article  CAS  Google Scholar 

  10. Jiang Y, Wang Y, Wang T, Hawke DH, Zheng Y, Li X, et al. PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells. Nat Commun. 2014;5:5566.

    Article  CAS  Google Scholar 

  11. Qian X, Li X, Cai Q, Zhang C, Yu Q, Jiang Y, et al. Phosphoglycerate kinase 1 phosphorylates beclin1 to induce autophagy. Mol Cell. 2017. https://doi.org/10.1016/j.molcel.2017.01.027.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li X, Jiang Y, Meisenhelder J, Yang W, Hawke DH, Zheng Y, et al. Mitochondria-translocated PGK1 functions as a protein kinase to coordinate glycolysis and the TCA cycle in tumorigenesis. Mol Cell. 2016;61(5):705–19.

    Article  CAS  Google Scholar 

  13. Li X, Qian X, Peng LX, Jiang Y, Hawke DH, Zheng Y, et al. A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol. 2016;18(5):561–71.

    Article  CAS  Google Scholar 

  14. Dasgupta S, Rajapakshe K, Zhu B, Nikolai BC, Yi P, Putluri N, et al. Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 2018;556(7700):249–54.

    Article  CAS  Google Scholar 

  15. Wang Y, Guo YR, Liu K, Yin Z, Liu R, Xia Y, et al. KAT2A coupled with the alpha-KGDH complex acts as a histone H3 succinyltransferase. Nature. 2017;552(7684):273–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Li X, Yu W, Qian X, Xia Y, Zheng Y, Lee JH, et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol Cell. 2017;66(5):684 e9–697 e9.

    Article  Google Scholar 

  17. Mews P, Donahue G, Drake AM, Luczak V, Abel T, Berger SL. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature. 2017;546(7658):381–6.

    Article  CAS  Google Scholar 

  18. Li X, Qian X, Lu Z. Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy. 2017;13(10):1790–1.

    Article  CAS  Google Scholar 

  19. Sivanand S, Rhoades S, Jiang Q, Lee JV, Benci J, Zhang J, et al. Nuclear acetyl-CoA production by ACLY promotes homologous recombination. Mol Cell. 2017;67(2):252 e6–265 e6.

    Article  Google Scholar 

  20. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009;324(5930):1076–80.

    Article  CAS  Google Scholar 

  21. Sutendra G, Kinnaird A, Dromparis P, Paulin R, Stenson TH, Haromy A, et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell. 2014;158(1):84–97.

    Article  CAS  Google Scholar 

  22. Yogev O, Yogev O, Singer E, Shaulian E, Goldberg M, Fox TD, et al. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol. 2010;8(3):e1000328.

    Article  Google Scholar 

  23. Jiang Y, Qian X, Shen J, Wang Y, Li X, Liu R, et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat Cell Biol. 2015;17(9):1158–68.

    Article  CAS  Google Scholar 

  24. Lee JH, Liu R, Li J, Zhang C, Wang Y, Cai Q, et al. Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun. 2017;8(1):949.

    Article  Google Scholar 

  25. Lee JH, Liu R, Li J, Wang Y, Tan L, Li XJ, et al. EGFR-phosphorylated platelet isoform of phosphofructokinase 1 promotes PI3K activation. Mol Cell. 2018;70(2):197 e7–210 e7.

    Article  Google Scholar 

  26. Yang W, Lu Z. Nuclear PKM2 regulates the Warburg effect. Cell Cycle. 2013;12(19):3154–8.

    Article  CAS  Google Scholar 

  27. Gu SM, Han P, Ye ZP, Perkins LE, Li J, Wang HQ, et al. Climate change favours a destructive agricultural pest in temperate regions: late spring cold matters. J Pest Sci. 2018;91(4):1191–8.

    Article  Google Scholar 

  28. Grillo MA, Colombatto S. S-adenosylmethionine and its products. Amino Acids. 2008;34(2):187–93.

    Article  CAS  Google Scholar 

  29. Mentch SJ, Mehrmohamadi M, Huang L, Liu X, Gupta D, Mattocks D, et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 2015;22(5):861–73.

    Article  CAS  Google Scholar 

  30. Shiraki N, Shiraki Y, Tsuyama T, Obata F, Miura M, Nagae G, et al. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab. 2014;19(5):780–94.

    Article  CAS  Google Scholar 

  31. Janke R, Dodson AE, Rine J. Metabolism and epigenetics. Annu Rev Cell Dev Biol. 2015;31:473–96.

    Article  CAS  Google Scholar 

  32. Shi YG, Tsukada Y. The discovery of histone demethylases. Cold Spring Harb Perspect Biol. 2013. https://doi.org/10.1101/cshperspect.a017947.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Losman JA, Kaelin WG Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013;27(8):836–52.

    Article  CAS  Google Scholar 

  34. Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K. Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process. Ageing Res Rev. 2014;16:45–65.

    Article  CAS  Google Scholar 

  35. Sciacovelli M, Goncalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016;537(7621):544–7.

    Article  CAS  Google Scholar 

  36. Cheng C, Geng F, Cheng X, Guo D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun (Lond). 2018;38(1):27.

    Article  Google Scholar 

  37. Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology. Nat Rev Endocrinol. 2017;13(12):710–30.

    Article  CAS  Google Scholar 

  38. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer. 2013;13(4):227–32.

    Article  CAS  Google Scholar 

  39. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.

    Article  CAS  Google Scholar 

  40. Holmstrom KM, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol. 2014;15(6):411–21.

    Article  CAS  Google Scholar 

  41. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12(12):931–47.

    Article  CAS  Google Scholar 

  42. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12(8):564–71.

    Article  CAS  Google Scholar 

  43. Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008;29(6):1235–43.

    Article  CAS  Google Scholar 

  44. Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, et al. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Can Res. 2010;70(13):5486–96.

    Article  CAS  Google Scholar 

  45. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475(7354):106–9.

    Article  CAS  Google Scholar 

  46. Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol. 2011;193(2):275–84.

    Article  CAS  Google Scholar 

  47. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22(1):66–79.

    Article  CAS  Google Scholar 

  48. Moscat J, Karin M, Diaz-Meco MT. p62 in cancer: signaling adaptor beyond autophagy. Cell. 2016;167(3):606–9.

    Article  CAS  Google Scholar 

  49. Katsuragi Y, Ichimura Y, Komatsu M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 2015;282(24):4672–8.

    Article  CAS  Google Scholar 

  50. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39(4):199–218.

    Article  CAS  Google Scholar 

  51. Prudova A, Bauman Z, Braun A, Vitvitsky V, Lu SC, Banerjee R. S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proc Natl Acad Sci USA. 2006;103(17):6489–94.

    Article  CAS  Google Scholar 

  52. Koppula P, Zhang Y, Zhuang L, Gan B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun (Lond). 2018;38(1):12.

    Article  Google Scholar 

Download references

Authors’ contributions

YW, YX, and ZL wrote and revised this article. All authors read and approved the final manuscript.

Acknowledgements

This work was supported by the National Institute of Neurological Disorders and Stroke grant R01 NS089754 (to Z.L.); by the National Cancer Institute (NCI) grant 1R01 CA204996 (to Z.L.); and by the National Institutes of Health/NCI through MD Anderson’s Cancer Center Support grant P30CA016672 and Brain Cancer Specialized Program of Research Excellence grant 2P50 CA127001, 2018 UT Proteomics Network Pilot Fund (to Y.W.). Z.L. is a Ruby E. Rutherford Distinguished Professor.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Author information

Authors and Affiliations

  1. Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Yugang Wang, Yan Xia & Zhimin Lu

  2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Zhimin Lu

  3. Cancer Biology Program, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA

    Zhimin Lu

Authors
  1. Yugang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhimin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhimin Lu.

Rights and permissions

Open Access This 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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Xia, Y. & Lu, Z. Metabolic features of cancer cells. Cancer Commun 38, 65 (2018). https://doi.org/10.1186/s40880-018-0335-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s40880-018-0335-7

Keywords

Cancer Communications

ISSN: 2523-3548

Contact us