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Chromosomal instability causes sensitivity to metabolic stress

Oncogene volume 34, pages 4044–4055 (2015)Cite this article

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Abstract

Chromosomal INstability (CIN), a hallmark of cancer, refers to cells with an increased rate of gain or loss of whole chromosomes or chromosome parts. CIN is linked to the progression of tumors with poor clinical outcomes such as drug resistance. CIN can give tumors the diversity to resist therapy, but it comes at the cost of significant stress to tumor cells. To tolerate this, cancer cells must modify their energy use to provide adaptation against genetic changes as well as to promote their survival and growth. In this study, we have demonstrated that CIN induction causes sensitivity to metabolic stress. We show that mild metabolic disruption that does not affect normal cells, can lead to high levels of oxidative stress and subsequent cell death in CIN cells because they are already managing elevated stress levels. Altered metabolism is a differential characteristic of cancer cells, so our identification of key regulators that can exploit these changes to cause cell death may provide cancer-specific potential drug targets, especially for advanced cancers that exhibit CIN.

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References

  1. Mertens F, Mandahl N, Mitelman F, Heim S . Cytogenetic analysis in the examination of solid tumors in children. Pediatr Hematol Oncol 1994; 11: 361–377.

    Article  CAS  PubMed  Google Scholar 

  2. Weaver BA, Cleveland DW . Does aneuploidy cause cancer? Curr Opin Cell Biol 2006; 18: 658–667.

    Article  CAS  PubMed  Google Scholar 

  3. Thompson SL, Compton DA . Examining the link between chromosomal instability and aneuploidy in human cells. J Cell Biol 2008; 180: 665–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Weaver B, Cleveland DW . Aneuploidy: instigator and inhibitor of tumorigenesis. Cancer Res 2007; 67: 10103–10105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sotillo R, Schvartzman JM, Socci ND, Benezra R . Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 2010; 464: 436–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wassmann K, Benezra R . Mitotic checkpoints: from yeast to cancer. Curr Opin Genet Dev 2001; 11: 83–90.

    Article  CAS  PubMed  Google Scholar 

  7. Baker DJ, Jin F, Jeganathan KB, van Deursen JM . Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 2009; 16: 475–486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Swanton C, Nicke B, Schuett M, Eklund AC, Ng C, Li Q et al. Chromosomal instability determines taxane response. Proc Natl Acad Sci USA 2009; 106: 8671–8676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z . A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 2006; 38: 1043–1048.

    Article  CAS  PubMed  Google Scholar 

  10. Shaukat Z, Wong HW, Nicolson S, Saint RB, Gregory SL . A screen for selective killing of cells with chromosomal instability induced by a spindle checkpoint defect. PLoS ONE 2012; 7: e47447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Buffin E, Emre D, Karess RE . Flies without a spindle checkpoint. Nat Cell Biol 2007; 9: 565–572.

    Article  CAS  PubMed  Google Scholar 

  12. Warburg O . On the origin of cancer cells. Science 1956; 123: 309–314.

    Article  CAS  PubMed  Google Scholar 

  13. Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 2009; 325: 1555–1559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y . Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 2007; 178: 93–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Puzio-Kuter AM . The role of p53 in metabolic regulation. Genes Cancer 2011; 2: 385–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pfau SJ, Amon A . Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep 2012; 13: 515–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther 2008; 7: 110–120.

    Article  CAS  PubMed  Google Scholar 

  18. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 2010; 107: 2037–2042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010; 2: 31ra34.

    Article  CAS  PubMed  Google Scholar 

  20. Kaplan O, Navon G, Lyon RC, Faustino PJ, Straka EJ, Cohen JS . Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism. Cancer Res 1990; 50: 544–551.

    CAS  PubMed  Google Scholar 

  21. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009; 27: 3297–3302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 2010; 207: 339–344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Holen K, Saltz LB, Hollywood E, Burk K, Hanauske A-R . The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest New Drugs 2008; 26: 45–51.

    Article  CAS  PubMed  Google Scholar 

  24. Schläfli P, Borter E, Spielmann P, Wenger RH . The PAS-domain kinase PASKIN: a new sensor in energy homeostasis. Cell Mol Life Sci 2009; 66: 876–883.

    Article  PubMed  Google Scholar 

  25. Hao H-X, Rutter J . The role of PAS kinase in regulating energy metabolism. IUBMB Life 2008; 60: 204–209.

    Article  CAS  PubMed  Google Scholar 

  26. O’Keefe L V, Colella A, Dayan S, Chen Q, Choo A, Jacob R et al. Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species. Hum Mol Genet 2011; 20: 497–509.

    Article  PubMed  Google Scholar 

  27. Stanton RC . Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life 2012; 64: 362–369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wong HW-S, Shaukat Z, Wang J, Saint R, Gregory SL . JNK signaling is needed to tolerate chromosomal instability. Cell Cycle 2013; 13: 1–10.

    Google Scholar 

  29. Iijima K, Zhao L, Shenton C, Iijima-Ando K . Regulation of energy stores and feeding by neuronal and peripheral CREB activity in Drosophila. PLoS ONE 2009; 4: e8498.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hao H-X, Cardon CM, Swiatek W, Cooksey RC, Smith TL, Wilde J et al. PAS kinase is required for normal cellular energy balance. Proc Natl Acad Sci USA 2007; 104: 15466–15471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hockenbery DM . Targeting mitochondria for cancer therapy. Environ Mol Mutagen 2010; 51: 476–489.

    Article  CAS  PubMed  Google Scholar 

  32. Gogvadze V, Orrenius S, Zhivotovsky B . Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 2008; 18: 165–173.

    Article  CAS  PubMed  Google Scholar 

  33. Terhzaz S, Cabrero P, Chintapalli VR, Davies SA, Dow JT . Mislocalization of mitochondria and compromised renal function and oxidative stress resistance in Drosophila SesB mutants. Physiol Genomics 2010; 41: 33–41.

    Article  CAS  PubMed  Google Scholar 

  34. Radyuk SN, Rebrin I, Klichko VI, Sohal BH, Michalak K, Benes J et al. Mitochondrial peroxiredoxins are critical for the maintenance of redox state and the survival of adult Drosophila. Free Radic Biol Med 2010; 49: 1892–1902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sheltzer JM, Torres EM, Dunham MJ, Amon A . Transcriptional consequences of aneuploidy. Proc Natl Acad Sci USA 2012; 109: 12644–12649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Coe JP, Rahman I, Sphyris N, Clarke AR, Harrison DJ . Glutathione and p53 independently mediate responses against oxidative stress in ES cells. Free Radic Biol Med 2002; 32: 187–196.

    Article  CAS  PubMed  Google Scholar 

  37. Wu D, Cederbaum AI . Oxidative stress mediated toxicity exerted by ethanol-inducible CYP2E1. Toxicol Appl Pharmacol 2005; 207 (2 Suppl): 70–76.

    Article  PubMed  Google Scholar 

  38. Owusu-Ansah E, Banerjee U . Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 2009; 461: 537–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Miwa S, St-Pierre J, Partridge L, Brand MD . Superoxide and hydrogen peroxide production by Drosophila mitochondria. Free Radic Biol Med 2003; 35: 938–948.

    Article  CAS  PubMed  Google Scholar 

  40. Oromendia AB, Dodgson SE, Amon A . Aneuploidy causes proteotoxic stress in yeast. Genes Dev 2012; 26: 2696–2708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu J, Wang X, Shigenaga MK, Yeo HC, Mori A, Ames BN . Immobilization stress causes oxidative damage to lipid, protein, and DNA in the brain of rats. FASEB J 1996; 10: 1532–1538.

    Article  CAS  PubMed  Google Scholar 

  42. Tanaka T, Halicka HD, Huang X, Traganos F, Darzynkiewicz Z . Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants. Cell Cycle 2008; 5: 1940–1945.

    Article  Google Scholar 

  43. Janssen A, van der Burg M, Szuhai K, Kops GJ, Medema RH . Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 2011; 333: 1895–1898.

    Article  CAS  PubMed  Google Scholar 

  44. Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 2012; 482: 53–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kasai H, Nishimura S . Hydroxylation of deoxyguanosine at the C-8 position by ascorbic acid and other reducing agents. Nucleic Acids Res 1984; 12: 2137–2145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kops GJPL, Weaver B, Cleveland DW . On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005; 5: 773–785.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. Vander Heiden MG, Cantley LC, Thompson CB . Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li M, Fang X, Baker DJ, Guo L, Gao X, Wei Z et al. The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc Natl Acad Sci USA 2010; 107: 14188–14193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 2007; 317: 916–924.

    Article  CAS  PubMed  Google Scholar 

  51. Williams B, Prabhu V, Hunter K . Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 2008; 322: 703–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang J, Yuan W, Chen Z, Wu S, Chen J, Ge J et al. Overexpression of G6PD is associated with poor clinical outcome in gastric cancer. Tumour Biol 2012; 33: 95–101.

    Article  PubMed  Google Scholar 

  53. Kuo W, Lin J, Tang TK . Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice. Int J Cancer 2000; 85: 857–864.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang C, Zhang Z, Zhu Y, Qin S . Glucose-6-phosphate dehydrogenase: a biomarker and potential therapeutic target for cancer. Anticancer Agents Med Chem 2014; 14: 280–289.

    Article  CAS  PubMed  Google Scholar 

  55. Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M et al. G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Med 2012; 9: e1001339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Manganelli G, Masullo U, Passarelli S, Filosa S . Glucose-6-phosphate dehydrogenase deficiency: disadvantages and possible benefits. Cardiovasc Hematol Disord Drug Targets 2013; 13: 73–82.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang J . Suppression of phosphoenolpyruvate carboxykinase gene expression by reduced endogenous glutathione level. Biochim Biophys Acta 2007; 1772: 1175–1181.

    Article  CAS  PubMed  Google Scholar 

  58. Cairns R, Harris IS, Mak TW . Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85–95.

    Article  CAS  PubMed  Google Scholar 

  59. Ren J-G, Seth P, Everett P, Clish CB, Sukhatme VP . Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2. PLoS ONE 2010; 5: e12520.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Beumer KJ, Trautman JK, Bozas A, Liu J-L, Rutter J, Gall JG et al. Efficient gene targeting in Drosophila by direct embryo injection with zinc-finger nucleases. Proc Natl Acad Sci USA 2008; 105: 19821–19826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB . Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 2010; 49: 1603–1616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bauer G . Tumor cell-protective catalase as a novel target for rational therapeutic approaches based on specific intercellular ROS signaling. Anticancer Res 2012; 32: 2599–2634.

    CAS  PubMed  Google Scholar 

  63. Sajesh B V, Bailey M, Lichtensztejn Z, Hieter P, McManus KJ . Synthetic lethal targeting of superoxide dismutase 1 selectively kills RAD54B-deficient colorectal cancer cells. Genetics 2013; 195: 757–767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cheung-Ong K, Giaever G, Nislow C . DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol 2013; 20: 648–659.

    Article  CAS  PubMed  Google Scholar 

  65. Smart DK, Ortiz KL, Mattson D, Bradbury CM, Bisht KS, Sieck LK et al. Thioredoxin reductase as a potential molecular target for anticancer agents that induce oxidative stress. Cancer Res 2004; 64: 6716–6724.

    Article  CAS  PubMed  Google Scholar 

  66. Ozben T . Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci 2007; 96: 2181–2196.

    Article  CAS  PubMed  Google Scholar 

  67. Fang J, Nakamura H, Iyer AK . Tumor-targeted induction of oxystress for cancer therapy. J Drug Target 2007; 15: 475–486.

    Article  CAS  PubMed  Google Scholar 

  68. Sotgia F, Martinez-Outschoorn UE, Lisanti MP . Cancer metabolism: new validated targets for drug discovery. Oncotarget 2013; 4: 1309–1316.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Adelaide, Australia

    Z Shaukat, D Liu, A Choo, R Hussain, L O'Keefe, R Richards, R Saint & S L Gregory

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  1. Z Shaukat
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  2. D Liu
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Correspondence to S L Gregory.

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Shaukat, Z., Liu, D., Choo, A. et al. Chromosomal instability causes sensitivity to metabolic stress. Oncogene 34, 4044–4055 (2015). https://doi.org/10.1038/onc.2014.344

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