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The role of polyamines in gastric cancer

Abstract

Advancements in our understanding of polyamine molecular and cellular functions have led to increased interest in targeting polyamine metabolism for anticancer therapeutic benefits. The polyamines putrescine, spermidine, and spermine are polycationic alkylamines commonly found in all living cells and are essential for cellular growth and survival. This review summarizes the existing research on polyamine metabolism and function, specifically the role of polyamines in gastric immune cell and epithelial cell function. Polyamines have been implicated in a multitude of cancers, but in this review, we focus on the role of polyamine dysregulation in the context of Helicobacter pylori-induced gastritis and subsequent progression to gastric cancer. Due to the emerging implication of polyamines in cancer development, there is an increasing number of promising clinical trials using agents to target the polyamine metabolic pathway for potential chemoprevention and anticancer therapy.

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Fig. 1: The polyamine metabolic pathway.
Fig. 2: The role of polyamines on H. pylori-induced GC.

References

  1. 1.

    Rawla P, Barsouk A. Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol. 2019;14:26–38.

    CAS  PubMed  Google Scholar 

  2. 2.

    Correa P. Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award lecture on cancer epidemiology and prevention. Cancer Res. 1992;52:6735–40.

    CAS  PubMed  Google Scholar 

  3. 3.

    Correa P, Piazuelo BM, Wilson KT. Pathology of gastric intestinal metaplasia: clinical implications. Am J Gastroenterol. 2010;105:493–8.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Correa P, Shiao Y. Phenotypic and genotypic events in gastric carcinogenesis. Cancer Res. 1994;54:1941s–3s.

    CAS  PubMed  Google Scholar 

  5. 5.

    Piazuelo MB, Bravo LE, Mera RM, Camargo MC, Bravo JC, Delgado AG, et al. The Colombian chemoprevention trial: 20-year follow-up of a cohort of patients with gastric precancerous lesions. Gastroenterology. 2021;160:1106–17.

    PubMed  Article  Google Scholar 

  6. 6.

    Ge S, Xia X, Ding C, Zhen B, Zhou Q, Feng J, et al. A proteomic landscape of diffuse-type gastric cancer. Nat Commun. 2018;9:1012.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Hooi JKY, Lai WY, Ng WK, Suen MMY, Underwood FE, Tanyingoh D, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology. 2017;153:420–9.

    PubMed  Article  Google Scholar 

  8. 8.

    Wroblewski LE, Peek RM, Wilson KT. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev. 2010;23:713–39.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl J Med. 2001;345:784–9.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Romero-Gallo J, Harris EJ, Krishna U, Washington MK, Perez-Perez GI, Peek RM. Effect of Helicobacter pylori eradication on gastric carcinogenesis. Lab Invest. 2008;88:328–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Ma J-L, Zhang L, Brown LM, Li J-Y, Shen L, Pan K-F, et al. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst. 2012;104:488–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    You W, Brown LM, Zhang L, Li J, Jin M, Chang Y, et al. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst. 2006;98:974–83.

    PubMed  Article  Google Scholar 

  13. 13.

    Mera R, Fontham ETH, Bravo LE, Bravo JC, Piazuelo MB, Camargo MC, et al. Long term follow up of patients treated for Helicobacter pylori infection. Gut. 2005;54:1536–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Camargo MC, Piazuelo MB, Mera RM, Fontham ETH, Delgado AG, Yepez MC, et al. Effect of smoking on failure of H. pylori therapy and gastric histology in a high gastric cancer risk area of Colombia. Acta Gastroenterol Latinoam. 2007;37:238–45.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Blaser MJ. Ecology of Helicobacter pylori in the human stomach. J Clin Invest. 1997;100:759–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Mera RM, Bravo LE, Camargo MC, Bravo JC, Delgado AG, Romero-Gallo J, et al. Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut. 2018;67:1239–46.

    PubMed  Article  Google Scholar 

  17. 17.

    Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol. 2015;16:e60–70.

    PubMed  Article  Google Scholar 

  18. 18.

    Kountouras J, Zavos C, Chatzopoulos D. New concepts of molecular biology on gastric carcinogenesis. Hepatogastroenterology 2005;52:1305–12.

    CAS  PubMed  Google Scholar 

  19. 19.

    Li D, Lo W, Rudloff U. Merging perspectives: genotype-directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E-cadherin-EGFR crosstalk. Clin Transl Med. 2018;7:7.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Etemadi A, Safiri S, Sepanlou SG, Ikuta K, Bisignano C, Shakeri R, et al. The global, regional, and national burden of stomach cancer in 195 countries, 1990–2017: a systematic analysis for the Global Burden of Disease study 2017. Lancet. Gastroenterol Hepatol. 2020;5:42–54.

    Google Scholar 

  21. 21.

    Hardbower DM, Peek RM, Wilson KT. At the bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J Leukoc Biol. 2014;96:201–12.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Gobert AP, Wilson KT. Human and Helicobacter pylori interactions determine the outcome of gastric diseases. Curr Top Microbiol Immunol. 2017;400:27–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Pegg AE, McCann PP. Polyamine metabolism and function. Am J Physiol Cell Physiol. 1982;243:C212–21.

    CAS  Article  Google Scholar 

  24. 24.

    Michael AJ. Polyamines in eukaryotes, bacteria, and archaea. J Biol Chem. 2016;291:14896–903.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Pegg AE. Mammalian polyamine metabolism and function. IUBMB Life 2009;61:880–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Wei G, Hobbs CA, Defeo K, Hayes CS, Gilmour SK. Polyamine-mediated regulation of protein acetylation in murine skin and tumors. Mol Carcinog. 2007;46:611–7.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Munder M. Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol. 2009;158:638–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Jenkinson CP, Grody WW, Cederbaum SD. Comparative properties of arginases. Comp Biochem Physiol B Biochem Mol Biol. 1996;114:107–32.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Pegg AE. Regulation of ornithine decarboxylase. J Biol Chem. 2006;281:14529–32.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Asim M, Chaturvedi R, Hoge S, Lewis ND, Singh K, Barry DP, et al. Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos·c-Jun activator protein-1 complex that causes apoptosis in macrophages. J Biol Chem. 2010;285:20343–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Wang X, Ying W, Dunlap KA, Lin G, Satterfield MC, Burghardt RC, et al. Arginine decarboxylase and agmatinase: an alternative pathway for de novo biosynthesis of polyamines for development of mammalian conceptuses. Biol Reprod. 2014;90:84.

    PubMed  Google Scholar 

  32. 32.

    LoGiudice N, Le L, Abuan I, Leizorek Y, Roberts SC. Alpha-difluoromethylornithine, an irreversible inhibitor of polyamine biosynthesis, as a therapeutic strategy against hyperproliferative and infectious diseases. Med Sci. (Basel) 2018;6:12.

    Google Scholar 

  33. 33.

    Matsui I, Wiegand L, Pegg AE. Properties of spermidine N-acetyltransferase from livers of rats treated with carbon tetrachloride and its role in the conversion of spermidine into putrescine. J Biol Chem. 1981;256:2454–9.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Vujcic S, Liang P, Diegelman P, Kramer DL, Porter CW. Genomic identification and biochemical characterization of the mammalian polyamine oxidase involved in polyamine back-conversion. Biochem J. 2003;370:19–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Kramer DL, Diegelman P, Jell J, Vujcic S, Merali S, Porter CW. Polyamine acetylation modulates polyamine metabolic flux, a prelude to broader metabolic consequences. J Biol Chem. 2008;283:4241–51.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Wang Y, Murray-Stewart T, Devereux W, Hacker A, Frydman B, Woster PM, et al. Properties of purified recombinant human polyamine oxidase, PAOh1/SMO. Biochem Biophys Res Commun. 2003;304:605–11.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Gobert AP, Al-Greene NT, Singh K, Coburn LA, Sierra JC, Verriere TG, et al. Distinct immunomodulatory effects of spermine oxidase in colitis induced by epithelial injury or infection. Front Immunol. 2018;9:1242.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Vakal S, Jalkanen S, Dahlström KM, Salminen TA. Human copper-containing amine oxidases in drug design and development. Molecules 2020;25:1293.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  39. 39.

    Park MH, Cooper HL, Folk JE. Identification of hypusine, an unusual amino acid, in a protein from human lymphocytes and of spermidine as its biosynthetic precursor. Proc Natl Acad Sci USA 1981;78:2869–73.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Park MH, Lee YB, Joe YA. Hypusine is essential for eukaryotic cell proliferation. Biol Signals 1997;6:115–23.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Chen K, Liu A. Biochemistry and function of hypusine formation on eukaryotic initiation factor 5A. Biol Signals 1997;6:105–9.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Murphey RJ, Gerner EW. Hypusine formation in protein by a two-step process in cell lysates. J Biol Chem. 1987;262:15033–6.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Abbruzzese A, Park MH, Folk JE. Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. J Biol Chem. 1986;261:3085–9.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Nakanishi S, Cleveland JL. Targeting the polyamine-hypusine circuit for the prevention and treatment of cancer. Amino Acids 2016;48:2353–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Jenkins ZA, Hååg PG, Johansson HE. Human eIF5A2 on chromosome 3q25-q27 is a phylogenetically conserved vertebrate variant of eukaryotic translation initiation factor 5A with tissue-specific expression. Genomics 2001;71:101–9.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Maier B, Ogihara T, Trace AP, Tersey SA, Robbins RD, Chakrabarti SK, et al. The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice. J Clin Invest. 2010;120:2156–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Xu A, Jao DL-E, Chen KY. Identification of mRNA that binds to eukaryotic initiation factor 5A by affinity co-purification and differential display. Biochem J. 2004;384:585–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Xu A, Chen KY. Hypusine is required for a sequence-specific interaction of eukaryotic initiation factor 5A with postsystematic evolution of ligands by exponential enrichment RNA. J Biol Chem. 2001;276:2555–61.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Aksu M, Trakhanov S, Görlich D. Structure of the exportin Xpo4 in complex with RanGTP and the hypusine-containing translation factor eIF5A. Nat Commun. 2016;7:11952.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Park MH, Wolff EC. Hypusine, a polyamine-derived amino acid critical for eukaryotic translation. J Biol Chem. 2018;293:18710–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Pelechano V, Alepuz P. eIF5A facilitates translation termination globally and promotes the elongation of many non-polyproline-specific tripeptide sequences. Nucleic Acids Res. 2017;45:7326–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Schuller AP, Wu CC-C, Dever TE, Buskirk AR, Green R. eIF5A functions globally in translation elongation and termination. Mol Cell 2017;66:194–205.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Gutierrez E, Shin B-S, Woolstenhulme CJ, Kim J-R, Saini P, Buskirk AR, et al. eIF5A promotes translation of polyproline motifs. Mol Cell 2013;51:35–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Cano VSP, Jeon GA, Johansson HE, Henderson CA, Park J-H, Valentini SR, et al. Mutational analysis of human eIF5A-1: identification of amino acid residues critical for hypusine modification and eIF5A activity. FEBS J. 2008;275:44–58.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Schnier J, Schwelberger HG, Smit-McBride Z, Kang HA, Hershey JW. Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol Cell Biol. 1991;11:3105–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Sasaki K, Abid MR, Miyazaki M. Deoxyhypusine synthase gene is essential for cell viability in the yeast Saccharomyces cerevisiae. FEBS Lett 1996;384:151–4.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Park J-H, Aravind L, Wolff EC, Kaevel J, Kim YS, Park MH. Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci USA 2006;103:51–6.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Nishimura K, Lee SB, Park JH, Park MH. Essential role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic development. Amino Acids 2012;42:703–10.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Henning S, Pällmann N, Miller KK, Hermans-Borgmeyer I, Venz S, Sendoel A, et al. A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation. Dis Model Mech. 2014;7:963–76.

    Google Scholar 

  60. 60.

    Pällmann N, Braig M, Sievert H, Preukschas M, Hermans-Borgmeyer I, Schweizer M, et al. Biological relevance and therapeutic potential of the hypusine modification system. J Biol Chem. 2015;290:18343–60.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Coni S, Serrao SM, Yurtsever ZN, Di Magno L, Bordone R, Bertani C, et al. Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation. Cell Death Dis. 2020;11:1045.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Qiu S, Liu J, Xing F. Antizyme inhibitor 1: a potential carcinogenic molecule. Cancer Sci. 2017;108:163–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Patchett SE, Alstead EM, Butruk L, Przytulski K, Farthing MJ. Ornithine decarboxylase as a marker for premalignancy in the stomach. Gut. 1995;37:13–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Miao X-P, Li J-S, Li H-Y, Zeng S-P, Zhao Y, Zeng J-Z. Expression of ornithine decarboxylase in precancerous and cancerous gastric lesions. World J Gastroenterol. 2007;13:2867–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Chaturvedi R, Asim M, Hoge S, Lewis ND, Singh K, Barry DP, et al. Polyamines impair immunity to Helicobacter pylori by inhibiting L-arginine uptake required for nitric oxide production. Gastroenterology 2010;139:1686–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Hardbower DM, Asim M, Luis PB, Singh K, Barry DP, Yang C, et al. Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc Natl Acad Sci USA 2017;114:E751–60.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Elitsur Y, Majumdar AP, Tureaud J, Dosescu J, Neace C, Velusamy L, et al. Tyrosine kinase and ornithine decarboxylase activation in children with Helicobacter pylori gastritis. Life Sci. 1999;65:1373–80.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Konturek PC, Rembiasz K, Konturek SJ, Stachura J, Bielanski W, Galuschka K, et al. Gene expression of ornithine decarboxylase, cyclooxygenase-2, and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy. Dig Dis Sci. 2003;48:36–46.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Hirasawa R, Tatsuta M, Iishi H, Yano H, Baba M, Uedo N, et al. Increase in apoptosis and decrease in ornithine decarboxylase activity of the gastric mucosa in patients with atrophic gastritis and gastric ulcer after successful eradication of Helicobacter pylori. Am J Gastroenterol. 1999;94:2398–402.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Takashima T, Fujiwara Y, Watanabe T, Tominaga K, Oshitani N, Higuchi K, et al. High molecular protein of Helicobacter pylori responsible for inhibition of ornithine decarboxylase activity of human gastric cultured cells. Aliment Pharm Ther. 2002;16:167–73.

    CAS  Article  Google Scholar 

  71. 71.

    Xu X, Liu Z, Fang M, Yu H, Liang X, Li X, et al. Helicobacter pylori CagA induces ornithine decarboxylase upregulation via Src/MEK/ERK/c-Myc pathway: implication for progression of gastric diseases. Exp Biol Med (Maywood) 2012;237:435–41.

    CAS  Article  Google Scholar 

  72. 72.

    Gobert AP, Cheng Y, Wang J-Y, Boucher J-L, Iyer RK, Cederbaum SD, et al. Helicobacter pylori induces macrophage apoptosis by activation of arginase II. J Immunol. 2002;168:4692–700.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Cheng Y, Chaturvedi R, Asim M, Bussière FI, Scholz A, Xu H, et al. Helicobacter pylori-induced macrophage apoptosis requires activation of ornithine decarboxylase by c-Myc. J Biol Chem. 2005;280:22492–6.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Chaturvedi R, de Sablet T, Asim M, Piazuelo MB, Barry DP, Verriere TG, et al. Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase. Oncogene. 2015;34:3429–40.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Murray-Stewart T, Sierra JC, Piazuelo MB, Mera RM, Chaturvedi R, Bravo LE, et al. Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer. Oncogene. 2016;35:5480–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Sierra JC, Piazuelo MB, Luis PB, Barry DP, Allaman MM, Asim M, et al. Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling. Oncogene. 2020;39:4465–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Chaturvedi R, Cheng Y, Asim M, Bussière FI, Xu H, Gobert AP, et al. Induction of polyamine oxidase 1 by Helicobacter pylori causes macrophage apoptosis by hydrogen peroxide release and mitochondrial membrane depolarization. J Biol Chem. 2004;279:40161–73.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Chaturvedi R, Asim M, Barry DP, Frye JW, Casero RA, Wilson KT. Spermine oxidase is a regulator of macrophage host response to Helicobacter pylori: enhancement of antimicrobial nitric oxide generation by depletion of spermine. Amino Acids 2014;46:531–42.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Xu F, Xu Y, Xiong J-H, Zhang J-H, Wu J, Luo J, et al. AOC1 contributes to tumor progression by promoting the AKT and EMT pathways in gastric cancer. Cancer Manag Res. 2020;12:1789–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Jung MH, Kim SC, Jeon GA, Kim SH, Kim Y, Choi KS, et al. Identification of differentially expressed genes in normal and tumor human gastric tissue. Genomics 2000;69:281–6.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Okugawa Y, Toiyama Y, Shigeyasu K, Yamamoto A, Shigemori T, Yin C, et al. Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer. J Transl Med. 2018;16:366.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Lundell L, Rosengren E. Polyamine levels in human gastric carcinoma. Scand J Gastroenterol. 1986;21:829–32.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Linsalata M, Russo F, Notarnicola M, Berloco P, Di Leo A. Polyamine profile in human gastric mucosa infected by Helicobacter pylori. Ital J Gastroenterol Hepatol. 1998;30:484–9.

    CAS  PubMed  Google Scholar 

  84. 84.

    Wilson KT, Crabtree JE. Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology 2007;133:288–308.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000prime Rep. 2014;6:13.

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Anderson CF, Mosser DM. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J Leukoc Biol. 2002;72:101–6.

    CAS  PubMed  Google Scholar 

  88. 88.

    Gobert AP, Finley JL, Latour YL, Asim M, Smith TM, Verriere TG, et al. Hypusination orchestrates the antimicrobial response of macrophages. Cell Rep. 2020;33:108510.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Bussière FI, Chaturvedi R, Cheng Y, Gobert AP, Asim M, Blumberg DR, et al. Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation. J Biol Chem. 2005;280:2409–12.

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Xu C, Yan Y, Yang Y, Liu B, Xin J, Chen S, et al. Downregulation of ornithine decarboxylase by pcDNA-ODCr inhibits gastric cancer cell growth in vitro. Mol Biol Rep. 2011;38:949–55.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Lewis ND, Asim M, Barry DP, de Sablet T, Singh K, Piazuelo MB, et al. Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II. J Immunol. 2011;186:3632–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Gamble LD, Purgato S, Murray J, Xiao L, Yu DMT, Hanssen KM, et al. Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. Sci Transl Med. 2019;11:eaau1099.

    PubMed  Article  Google Scholar 

  93. 93.

    Devens BH, Weeks RS, Burns MR, Carlson CL, Brawer MK. Polyamine depletion therapy in prostate cancer. Prostate Cancer Prostatic Dis. 2000;3:275–9.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Milovic V, Turchanowa L. Polyamines and colon cancer. Biochem Soc Trans. 2003;31:381–3.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Saydjari R, Alexander RW, Upp JR, Poston GJ, Barranco SC, Townsend CM, et al. The effect of tumor burden on ornithine decarboxylase activity in mice. Cancer Invest. 1991;9:415–9.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Xu H, Chaturvedi R, Cheng Y, Bussiere FI, Asim M, Yao MD, et al. Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA Damage: implications for gastric carcinogenesis. Cancer Res. 2004;64:8521–5.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Wang JY, Johnson LR. Luminal polyamines stimulate repair of gastric mucosal stress ulcers. Am J Physiol. 1990;259:G584–592.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Hardbower DM, Singh K, Asim M, Verriere TG, Olivares-Villagómez D, Barry DP, et al. EGFR regulates macrophage activation and function in bacterial infection. J Clin Invest. 2016;126:3296–312.

    PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Barry DP, Asim M, Leiman DA, de Sablet T, Singh K, Casero RA, et al. Difluoromethylornithine is a novel inhibitor of Helicobacter pylori growth, CagA translocation, and interleukin-8 induction. PLoS ONE 2011;6:e17510.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Sierra JC, Suarez G, Piazuelo MB, Luis PB, Baker DR, Romero-Gallo J, et al. α-Difluoromethylornithine reduces gastric carcinogenesis by causing mutations in Helicobacter pylori cagY. Proc Natl Acad Sci USA 2019;116:5077–85.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Ehrnström RA, Veress B, Arvidsson S, Sternby NH, Andersson T, Lindström CG. Dietary supplementation of carbonate promotes spontaneous tumorigenesis in a rat gastric stump model. Scand J Gastroenterol. 2006;41:12–20.

    PubMed  Article  CAS  Google Scholar 

  103. 103.

    Iishi H, Tatsuta M, Baba M, Yano H, Sakai N, Uehara H, et al. Ornithine decarboxylase inhibitor lessens the rat gastric carcinogenesis enhancement caused by tyrosine methyl ester. Int J Cancer. 1997;73:113–6.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Tatsuta M, Iishi H, Baba M, Yano H, Uehara H, Nakaizumi A. Ornithine decarboxylase inhibitor attenuates NaCl enhancement of gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine. Carcinogenesis 1995;16:2107–10.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Prakash NJ, Schechter PJ, Grove J, Koch-Weser J. Effect of alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on L1210 leukemia in mice. Cancer Res. 1978;38:3059–62.

    CAS  PubMed  Google Scholar 

  106. 106.

    Mamont PS, Duchesne M-C, Grove J, Bey P. Anti-proliferative properties of DL-α-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase. Biochem Biophys Res Commun. 1978;81:58–66.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Horn Y, Schechter PJ, Marton LJ. Phase I-II clinical trial with alpha-difluoromethylornithine-an inhibitor of polyamine biosynthesis. Eur J Cancer Clin Oncol. 1987;23:1103–7.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Nass MM. Analysis of methylglyoxal bis(guanylhydrazone)-induced alterations of hamster tumor mitochondria by correlated studies of selective rhodamine binding, ultrastructural damage, DNA replication, and reversibility. Cancer Res. 1984;44:2677–88.

    CAS  PubMed  Google Scholar 

  109. 109.

    Pless M, Belhadj K, Menssen HD, Kern W, Coiffier B, Wolf J, et al. Clinical efficacy, tolerability, and safety of SAM486A, a novel polyamine biosynthesis inhibitor, in patients with relapsed or refractory non-Hodgkin’s lymphoma: results from a phase II multicenter study. Clin Cancer Res. 2004;10:1299–305.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Zuylen L, van, Bridgewater J, Sparreboom A, Eskens FALM, Bruijn P de, Sklenar I. et al. Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/ leucovorin in metastatic colorectal cancer. Clin Cancer Res. 2004;10:1949–55.

    PubMed  Article  Google Scholar 

  111. 111.

    Millward MJ, Joshua A, Kefford R, Aamdal S, Thomson D, Hersey P, et al. Multi-centre phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma. Invest N Drugs. 2005;23:253–6.

    CAS  Article  Google Scholar 

  112. 112.

    Sholler GLS, Ferguson W, Bergendahl G, Bond JP, Neville K, Eslin D, et al. Maintenance DFMO increases survival in high-risk neuroblastoma. Sci Rep. 2018;8:14445.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Meyskens FL, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Philos Pa) 2008;1:32–8.

    CAS  Article  Google Scholar 

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Acknowledgements

This work was funded by NIH grants R01CA190612 (K.T.W.), P01CA116087 (K.T.W.), P01CA028842 (K.T.W.), and R21AI142042 (K.T.W.); Veterans Affairs Merit Review grants I01BX001453 and I01CX002171 (K.T.W.); Department of Defense grant W81XWH-18-1-0301 (K.T.W.); Crohn’s & Colitis Foundation Senior Research Award 703003 (K.T.W.); the Thomas F. Frist Sr. Endowment (K.T.W.); and the Vanderbilt Center for Mucosal Inflammation and Cancer (K.T.W.). K.T.W. also receives support from the Vanderbilt Digestive Disease Research Center (NIH grant P30DK058404). K.M.M. was supported by NIH grant T32CA009592.

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McNamara, K.M., Gobert, A.P. & Wilson, K.T. The role of polyamines in gastric cancer. Oncogene (2021). https://doi.org/10.1038/s41388-021-01862-x

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