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Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma

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Abstract

Cancer is a group of cells which grow in an uncontrolled manner and invades to the adjacent organs to form malignant tumors. Tumor hypoxia results due to contrast between the cellular oxygen expenditure and oxygen supply to the cells. Hypoxia inducible factor (HIF) is a heterodimeric transcription factor encompass of oxygen sensitive α subunit and constitutively expressed β subunit both of which are basic helix-loop-helix protein. The stability of HIF is primarily regulated by post translational prolyl hydroxylation, catalyzed by prolyl hydroxylase 2 (Phd-2). Phd-2 is a group of enzymes that acts as an oxygen sensor. Cancer cells have altered metabolism as they fulfil their energy needs through glycolysis and lipid biogenesis. HIF-1α is known to upregulate glycolysis by activating the transcription of enzymes on the glycolytic pathway and through lipogenesis. Cancer cells have over expressed fatty acid synthase owing to altered glycolytic pathway. Considering the above, it is hypothesized that chemical activation of Phd-2 can curtail down HIF-1α and subsequently fatty acid synthase expression.

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Abbreviations

ATP:

Adinosine tri phosphate

NADPH:

Nicotinamide adenine di phosphate

HIF:

Hypoxia inducible factor

pVHL:

Von Hippel Lindau tumor suppressor protein

FASN:

Fatty acid synthase

VEGF:

Vascular Endothelial Growth Factor

HRE:

Hypoxia response element

Phd-2:

Prolyl hydroxylase 2

2OG:

2-oxoglutarate

EGCG:

Epigallocatechin-3-gallate

SREBP:

Sterol regulatory element binding protein

References

  1. Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer. Cancer Res. 1990;50(23):7415–21.

    CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  3. Alberts B, Johnson A, Lewis J, et al. How Cells Obtain Energy from Food. In: Molecular biology of the cell. 4th ed. New York: Garland Science; 2002. http://www.ncbi.nlm.nih.gov/books/NBK26882/.

  4. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–9.

    Article  CAS  PubMed  Google Scholar 

  5. Young CD, Anderson SM. Sugar and fat-that’s where it’s at: metabolic changes in tumors. Breast Cancer Res. 2008;10(1):202.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11(5):407–20.

    Article  CAS  PubMed  Google Scholar 

  7. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3(3):187–97.

    Article  CAS  PubMed  Google Scholar 

  8. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177–85.

    Article  PubMed  Google Scholar 

  9. Medes G, Thomas A, Weinhouse S. Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res. 1953;13(1):27–9.

    CAS  PubMed  Google Scholar 

  10. Kuhajda FP. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition. 2000;16(3):202–8.

    Article  CAS  PubMed  Google Scholar 

  11. Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci. 1994;91(14):6379–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Swinnen JV, Vanderhoydonc F, Elgamal AA, Eelen M, Vercaeren I, Joniau S, et al. Selective activation of the fatty acid synthesis pathway in human prostate cancer. Int J Cancer. 2000;88(2):176–9.

    Article  CAS  PubMed  Google Scholar 

  13. Rossi S, Graner E, Febbo P, Weinstein L, Bhattacharya N, Onody T, et al. Fatty Acid Synthase Expression Defines Distinct Molecular Signatures in Prostate Cancer1 1 NCI (Director’s Challenge CA84995-04, SPORE in Prostate Cancer CA90381-01A1, and PO1 CA89021-02), Novartis Investigator, and CaPCURE awards. Mol Cancer Res. 2003;1(10):707–15.

    CAS  PubMed  Google Scholar 

  14. Clanton TL, Hogan MC, Gladden LB. Regulation of cellular gas exchange, oxygen sensing, and metabolic control. Compr Physiol. 2013;3:1135–90. doi:10.1002/cphy.c120030.

    CAS  PubMed  Google Scholar 

  15. Bruick RK. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev. 2003;17(21):2614–23.

    Article  CAS  PubMed  Google Scholar 

  16. Zepeda AB, Pessoa A, Castillo RL, Figueroa CA, Pulgar VM, Farías JG. Cellular and molecular mechanisms in the hypoxic tissue: role of HIF-1 and ROS. Cell Biochem Funct. 2013;31(6):451–9.

    Article  CAS  PubMed  Google Scholar 

  17. Jokilehto T, Jaakkola PM. The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med. 2010;14(4):758–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26(2):225–39.

    Article  CAS  PubMed  Google Scholar 

  19. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  20. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677–84.

    Article  CAS  PubMed  Google Scholar 

  21. Kaelin WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30(4):393–402.

    Article  CAS  PubMed  Google Scholar 

  22. Welsh R, Jensen F, Cooper N, Oldstone M, Banapour B, Sernatiriger J, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379:4.

    Google Scholar 

  23. Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004;5(5):343–54.

    Article  CAS  PubMed  Google Scholar 

  24. Fandrey J, Gorr TA, Gassmann M. Regulating cellular oxygen sensing by hydroxylation. Cardiovasc Res. 2006;71(4):642–51.

    Article  CAS  PubMed  Google Scholar 

  25. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 2000;14(1):34–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–8.

    Article  CAS  PubMed  Google Scholar 

  27. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72.

    Article  CAS  PubMed  Google Scholar 

  28. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.

    Article  CAS  PubMed  Google Scholar 

  29. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001;13(2):167–71.

    Article  CAS  PubMed  Google Scholar 

  30. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci. 1995;92(12):5510–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hewitson KS, McNeill LA, Riordan MV, Tian YM, Bullock AN, Welford RW, et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem. 2002;277(29):26351–5.

    Article  CAS  PubMed  Google Scholar 

  32. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science. 2002;295(5556):858–61.

    Article  CAS  PubMed  Google Scholar 

  33. Masson N, Ratcliffe PJ. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O2 levels. J Cell Sci. 2003;116(15):3041–9.

    Article  CAS  PubMed  Google Scholar 

  34. Safran M, Kaelin WG Jr. HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Investig. 2003;111(6):779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40.

    Article  CAS  PubMed  Google Scholar 

  37. Myllyharju J. Prolyl 4-hydroxylases, master regulators of the hypoxia response. Acta Physiol. 2013;208(2):148–65.

    Article  CAS  Google Scholar 

  38. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279(37):38458–65.

    Article  CAS  PubMed  Google Scholar 

  39. Koivunen P, Tiainen P, Hyvärinen J, Williams KE, Sormunen R, Klaus SJ, et al. An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor α. J Biol Chem. 2007;282(42):30544–52.

    Article  CAS  PubMed  Google Scholar 

  40. McDonough MA, Li V, Flashman E, Chowdhury R, Mohr C, Liénard BM, et al. Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci. 2006;103(26):9814–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, Hütter J, et al. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun. 2002;296(2):343–9.

    Article  CAS  PubMed  Google Scholar 

  42. Chowdhury R, McDonough MA, Mecinović J, Loenarz C, Flashman E, Hewitson KS, et al. Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. Structure. 2009;17(7):981–9.

    Article  CAS  PubMed  Google Scholar 

  43. Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci USA. 2006;103(3):654–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359(25):2685–92.

    Article  CAS  PubMed  Google Scholar 

  45. Chan DA, Kawahara TL, Sutphin PD, Chang HY, Chi JT, Giaccia AJ. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell. 2009;15(6):527–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mazzone M, Dettori D, de Oliveira RL, Loges S, Schmidt T, Jonckx B, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136(5):839–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Klotzsche-von Ameln A, Muschter A, Mamlouk S, Kalucka J, Prade I, Franke K, et al. Inhibition of HIF prolyl hydroxylase-2 blocks tumor growth in mice through the antiproliferative activity of TGFβ. Cancer Res. 2011;71(9):3306–16.

    Article  CAS  PubMed  Google Scholar 

  48. Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, et al. Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH Is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res. 2008;14(20):6634–9.

    Article  CAS  PubMed  Google Scholar 

  49. Gossage L, Zaitoun A, Fareed KR, Turley H, Aloysius M, Lobo DN, et al. Expression of key hypoxia sensing prolyl-hydroxylases PHD1,-2 and-3 in pancreaticobiliary cancer. Histopathology. 2010;56(7):908–20.

    Article  PubMed  Google Scholar 

  50. Chirala SS, Jayakumar A, Gu ZW, Wakil SJ. Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer. Proc Natl Acad Sci. 2001;98(6):3104–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mattick JS, Tsukamoto Y, Nickless J, Wakil S. The architecture of the animal fatty acid synthetase. I. Proteolytic dissection and peptide mapping. J Biol Chem. 1983;258(24):15291–9.

    CAS  PubMed  Google Scholar 

  52. Nemoto T, Terashima S, Kogure M, Hoshino Y, Kusakabe T, Suzuki T, et al. Overexpression of fatty acid synthase in oesophageal squamous cell dysplasia and carcinoma. Pathobiology. 2000;69(6):297–303.

    Article  Google Scholar 

  53. Rangan VS, Joshi AK, Smith S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry. 2001;40(36):10792–9.

    Article  CAS  PubMed  Google Scholar 

  54. Tsukamoto Y, Wong H, Mattick J, Wakil S. The architecture of the animal fatty acid synthetase complex. IV. Mapping of active centers and model for the mechanism of action. J Biol Chem. 1983;258(24):15312–22.

    CAS  PubMed  Google Scholar 

  55. Jenke-Kodama H, Sandmann A, Müller R, Dittmann E. Evolutionary implications of bacterial polyketide synthases. Mol Biol Evol. 2005;22(10):2027–39.

    Article  CAS  PubMed  Google Scholar 

  56. Fulmer T. Not so FAS. SciBX. 2009;2(11). doi:10.1038/scibx.2009.430.

  57. Menendez JA, Lupu R. Fatty acid synthase-catalyzed de novo fatty acid biosynthesis: from anabolic-energy-storage pathway in normal tissues to jack-of-all-trades in cancer cells. Arch Immunol Ther Exp (Warsz). 2004;52(6):414–26.

    CAS  Google Scholar 

  58. Menendez JA, Colomer R, Lupu R. Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids? Med Hypotheses. 2005;64(2):342–9.

    Article  CAS  PubMed  Google Scholar 

  59. Kuhajda FP. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 2006;66(12):5977–80.

    Article  CAS  PubMed  Google Scholar 

  60. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7(10):763–77.

    Article  CAS  PubMed  Google Scholar 

  61. Alo PL, Visca P, Marci A, Mangoni A, Botti C, Di Tondo U. Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer. 1996;77(3):474–82.

    Article  CAS  PubMed  Google Scholar 

  62. Milgraum LZ, Witters LA. Pasternack Ga, Kuhajda FP. Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin Cancer Res. 1997;3(11):2115–20.

    CAS  PubMed  Google Scholar 

  63. Rashid A, Pizer ES, Moga M, Milgraum LZ, Zahurak M, Pasternack GR, et al. Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am J Pathol. 1997;150(1):201.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Swinnen JV, Roskams T, Joniau S, Van Poppel H, Oyen R, Baert L, et al. Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer. 2002;98(1):19–22.

    Article  CAS  PubMed  Google Scholar 

  65. Kasinskas RW, Venkatasubramanian R, Forbes NS. Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture. Integr Biol. 2014;6(4):399–410.

    Article  CAS  Google Scholar 

  66. Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, et al. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 2008;68(4):1003–11.

    Article  CAS  PubMed  Google Scholar 

  67. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 2004;64(6):2070–5.

    Article  CAS  PubMed  Google Scholar 

  68. De Schrijver E, Brusselmans K, Heyns W, Verhoeven G, Swinnen JV. RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Res. 2003;63(13):3799–804.

    PubMed  Google Scholar 

  69. Menendez JA, Decker JP, Lupu R. In support of fatty acid synthase (FAS) as a metabolic oncogene: extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells. J Cell Biochem. 2005;94(1):1–4.

    Article  CAS  PubMed  Google Scholar 

  70. Mashima T, Seimiya H, Tsuruo T. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer. 2009;100(9):1369–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Moral R, Solanas M, Manzanares EM, Haro D, Escrich E. Influence of DMBA-induced mammary cancer on the liver CPT I, mit HMG-CoA synthase and PPARα mRNA expression in rats fed a low or high corn oil diet. Int J Mol Med. 2004;14(2):283–7.

    CAS  PubMed  Google Scholar 

  72. Lin CY, Smith S, Abraham S. Fatty acid synthetase from a mouse mammary adenocarcinoma. Cancer Res. 1975;35(11):3094–9.

    CAS  PubMed  Google Scholar 

  73. Lu S, Archer MC. Fatty acid synthase is a potential molecular target for the chemoprevention of breast cancer. Carcinogenesis. 2005;26(1):153–7.

    Article  CAS  PubMed  Google Scholar 

  74. Jayakumar A, Tai MH, Huang WY, Al-Feel W, Hsu M, Abu-Elheiga L, et al. Human fatty acid synthase: properties and molecular cloning. Proc Natl Acad Sci. 1995;92(19):8695–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chuang HY, Chang YF, Hwang JJ. Antitumor effect of orlistat, a fatty acid synthase inhibitor, is via activation of caspase-3 on human colorectal carcinoma-bearing animal. Biomed Pharmacother. 2011;65(4):286–92.

    Article  CAS  PubMed  Google Scholar 

  76. Kuhajda F. AMP-activated protein kinase and human cancer: cancer metabolism revisited. Int J Obes. 2008;32:S36–41.

    Article  CAS  Google Scholar 

  77. Wang ZY, Wang DM, Loo TY, Cheng Y, Chen LL, Shen JG, et al. Spatholobus suberectus inhibits cancer cell growth by inducing apoptosis and arresting cell cycle at G2/M checkpoint. J Ethnopharmacol. 2011;133(2):751–8.

    Article  PubMed  Google Scholar 

  78. Wang YY, Kuhajda FP, Li JN, Pizer ES, Han WF, Sokoll LJ, et al. Fatty acid synthase (FAS) expression in human breast cancer cell culture supernatants and in breast cancer patients. Cancer Lett. 2001;167(1):99–104.

    Article  CAS  PubMed  Google Scholar 

  79. Ogino S, Nosho K, Meyerhardt JA, Kirkner GJ, Chan AT, Kawasaki T, et al. Cohort study of fatty acid synthase expression and patient survival in colon cancer. J Clin Oncol. 2008;26(35):5713–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bauerschlag DO, Maass N, Leonhardt P, Verburg FA, Pecks U, Zeppernick F, et al. Fatty acid synthase overexpression: target for therapy and reversal of chemoresistance in ovarian cancer. J Transl Med. 2015;13(1):146.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hou W, Fei M, Qin X, Zhu X, Greshock J, Liu P, et al. High overexpression of fatty acid synthase is associated with poor survival in Chinese patients with gastric carcinoma. Exp Ther Med. 2012;4(6):999–1004.

    PubMed  PubMed Central  Google Scholar 

  82. Liu H, Liu Y, Zhang JT. A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction. Mol Cancer Ther. 2008;7(2):263–70.

    Article  PubMed  Google Scholar 

  83. Genbacev O, Zhou Y, Ludlow JW, Fisher SJ. Regulation of human placental development by oxygen tension. Science. 1997;277(5332):1669–72.

    Article  CAS  PubMed  Google Scholar 

  84. Chen EY, Fujinaga M, Giaccia AJ. Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. Teratology. 1999;60(4):215–25.

    Article  CAS  PubMed  Google Scholar 

  85. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 1998;12(2):149–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394(6692):485–90.

    Article  CAS  PubMed  Google Scholar 

  87. Laderoute KR, Amin K, Calaoagan JM, Knapp M, Le T, Orduna J, et al. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol. 2006;26(14):5336–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Shi YH, Fang WG. Hypoxia-inducible factor-1 in tumour angiogenesis. World J Gastroenterol. 2004;10(8):1082–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004;9(Supplement 5):10–7.

    Article  CAS  PubMed  Google Scholar 

  90. Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80(2):51.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, et al. Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol Cell Biol. 2001;21(10):3436–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, et al. Hypoxia-inducible Factor-1-mediated Expression of the 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3 (PFKFB3) Gene ITS POSSIBLE ROLE IN THE WARBURG EFFECT. J Biol Chem. 2002;277(8):6183–7.

    Article  CAS  PubMed  Google Scholar 

  93. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002;16(10):1151–62.

    Article  CAS  PubMed  Google Scholar 

  94. Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J. 2003;22(16):4082–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nepal M, Gong YD, Park YR, Soh Y. An activator of PHD2, KRH102140, decreases angiogenesis via inhibition of HIF-1α. Cell Biochem Funct. 2011;29(2):126–34.

    Article  CAS  PubMed  Google Scholar 

  96. Choi H, Song BJ, Gong YD, Gwak W, Soh Y. Rapid degradation of hypoxia-inducible factor-1α by KRH102053, a new activator of prolyl hydroxylase 2. Br J Pharmacol. 2008;154(1):114–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Temes E, Martín-Puig S, Acosta-Iborra B, Castellanos MC, Feijoo-Cuaresma M, Olmos G, et al. Activation of HIF-prolyl hydroxylases by R59949, an inhibitor of the diacylglycerol kinase. J Biol Chem. 2005;280(25):24238–44.

    Article  CAS  PubMed  Google Scholar 

  98. Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010;6(4):551–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

MS, UD and SR carried out the literature review for this paper. PRG, GK and SAS guided them for literature survey. All authors read and approved the final manuscript.

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    1. Department of Pharmaceutical Sciences, School of Biosciences and Biotechnology, Babasaheb Bhimrao Ambedkar University (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226025, India

      Manjari Singh, Subhadeep Roy, Shubhini A. Saraf & Gaurav Kaithwas

    2. Department of Pharmaceutical Sciences, Faculty of Health Medical Sciences Indigenous and Alternative Medicine, SHIATS-Deemed to be University, Naini, Allahabad, Uttar Pradesh, India

      Uma Devi & Pushpraj S. Gupta

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    Manjari Singh and Uma Devi have contributed equally.

    SHIATS-Deemed to be University is formerly Allahabad Agricultural Institute.

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    Singh, M., Devi, U., Roy, S. et al. Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma. Breast Cancer 23, 820–829 (2016). https://doi.org/10.1007/s12282-016-0683-6

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    • DOI: https://doi.org/10.1007/s12282-016-0683-6

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