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Chronic exposure to agmatine results in the selection of agmatine-resistant hepatoma cells

Amino Acids volume 42, pages 769–774 (2012)Cite this article

An Erratum to this article was published on 22 February 2012

Abstract

During our study of the cytostatic effect of agmatine, we were able to isolate an agmatine resistant clone from a parental hepatoma cell line, HTC. These cells, called Agres, had slower growth rate than the parental cells when cultured in normal medium. The modification in polyamine content induced by agmatine was much lower in these cells and ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine/spermine acetyltransferase activities were much less affected. By investigating the mechanism responsible for these modifications, it was shown that agmatine and polyamines were not taken up by Agres cells. Their resistance to the antiproliferative effects of agmatine may thus arise from a lack of the polyamine transport system. Moreover, Agres cells were able to take up both glutamic acid and arginine at a rate significantly higher than that detected for HTC cells, most likely to provide components for compensatory increase of PA synthesis. These results emphasize the importance of polyamine transport for cell growth.

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Abbreviations

DFMO:

Difluoromethylornithine

MGBG:

Methylglyoxal bisguanylhydrazone

ODC:

Ornithine decarboxylase

PUT:

Putrescine

SAMDC:

S-adenosylmethionine decarboxylase

SPD:

Spermidine

SPM:

Spermine

SSAT:

Spermidine/spermine acetyltransferase

HTC:

Rat hepatoma cells

PA:

Polyamines

ECL:

Enhanced chemiluminescence

Agres:

Agmatine resistant cell line

References

  • Agostinelli E, Marques MP, Calheiros R, Gil FP, Tempera G, Viceconte N, Battaglia V, Grancara S, Toninello A (2010) Polyamines: fundamental characters in chemistry and biology. Amino Acids 38:393–403

    PubMed  Article  CAS  Google Scholar 

  • Battaglia V, Grancara S, Mancon M, Cravanzola C, Colombatto S, Grillo MA, Tempera G, Agostinelli E, Toninello A (2010a) Agmatine transport in brain mitochondria: a different mechanism from that in liver mitochondria. Amino Acids 38:423–430

    PubMed  Article  CAS  Google Scholar 

  • Battaglia V, Grancara S, Satriano J, Saccoccio S, Agostinelli E, Toninello A (2010b) Agmatine prevents the Ca(2 +)-dependent induction of permeability transition in rat brain mitochondria. Amino Acids 38:431–437

    PubMed  Article  CAS  Google Scholar 

  • Belting M, Mani K, Jönsson M, Cheng F, Sandgren S, Jonsson S, Ding K, Delcros JG, Fransson LA (2003) Glypican-1 is a vehicle for polyamine uptake in mammalian cells. A pivotal role for nitrosothiol-derived nitric oxide. J Biol Chem 278:47181–47189

    PubMed  Article  CAS  Google Scholar 

  • Cabella C, Gardini G, Corpillo D, Testore G, Bedino S, Solinas SP, Cravanzola C, Vargiu C, Grillo MA, Colombatto S (2001) Transport and metabolism of agmatine in rat hepatocyte cultures. Eur J Biochem 268:940–994

    PubMed  Article  CAS  Google Scholar 

  • Casero RAJ, Marton LJ (2007) Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov 6:373–390

    PubMed  Article  CAS  Google Scholar 

  • Cukierman E, Khan DR (2010) The benefits and challenges associated with the use of drug delivery systems in cancer therapy. Biochem Pharmacol 80:762–770

    PubMed  Article  CAS  Google Scholar 

  • Gardini G, Cabella C, Cravanzola C, Vargiu C, Belliardo S, Testore G, Solinas SP, Toninello A, Grillo MA, Colombatto S (2001) Agmatine induces apoptosis in rat hepatocyte cultures. J Hepatol 35:482–489

    PubMed  Article  CAS  Google Scholar 

  • Gardini G, Cravanzola C, Autelli R, Testore G, Cesa R, Morando L, Solinas SP, Muzio G, Grillo MA, Colombatto S (2003) Agmatine inhibits the proliferation of rat hepatoma cells by modulation of polyamine metabolism. J Hepatol 39:793–799

    PubMed  Article  CAS  Google Scholar 

  • Grillo MA, Colombatto S (2004) Metabolism and function in animal tissues of agmatine, a biogenic amine formed from arginine. Amino Acids 26:3–8

    PubMed  Article  CAS  Google Scholar 

  • Iyer RK, Kim HK, Tsoa RW, Grody WW, Cederbaum SD (2002) Cloning and characterization of human agmatinase. Mo Gen Metab 75:209–218

    Article  CAS  Google Scholar 

  • Jänne J, Alhonen L, Pietilä M, Keinänen TA (2004) Genetic approaches to the cellular functions of polyamines in mammals. Eur J Biochem 271:877–894

    PubMed  Article  Google Scholar 

  • Li G, Regunathan S, Barrow CJ, Eshragi J, Cooper R, Reis DJ (1994) Agmatine: an endogenous clonidine displacing substance in the brain. Science 263:966–969

    PubMed  Article  CAS  Google Scholar 

  • Lopez-Contreras AJ, Ramos-Molina B, Cremades A, Penafield R (2008) Antizyme inhibitor 2 (AZIN2/ODCp) stimulates polyamine uptake in mammalian cells. J Biol Chem 283:20761–20769

    PubMed  Article  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1952) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    Google Scholar 

  • McCann MM, Pegg AE (1992) Ornithine decarboxylase as an enzyme target for therapy. Pharmacol Ther 54:195–215

    PubMed  Article  CAS  Google Scholar 

  • Mistry SK, Burwell TJ, Chambers RM, Rudolph-Owen L, Spaltmann F, Cook WJ, Morris SM Jr (2002) Cloning of human agmatinase. An alternate path for polyamine synthesis induced in liver by hepatitis B virus. Am J Physio Gastrointest Liver Physiol 282:G375–G381

    CAS  Google Scholar 

  • Pegg AE (1986) Recent advances in the biochemistry of polyamines in eukaryotes. Biochem J 234:249–262

    PubMed  CAS  Google Scholar 

  • Pegg AE, McCann MM (1992) S-adenosylmethionine decarboxylase as an enzyme target for therapy. Pharmacol Ther 56:359–377

    PubMed  Article  CAS  Google Scholar 

  • Piletz JE, Chikkala DN, Ernsberger P (1995) Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and α-2 adrenergic receptors. J Pharmacol Exp Ther 272:581–587

    PubMed  CAS  Google Scholar 

  • Porter CW, Ganis B, Libby PR, Bergeron RJ (1991) Correlation between polyamine analog-induced increase in spermidine/spermine N1-acetyltransferase activity, polyamine pool depletion, and growth inhibition in human melanoma cells lines. Cancer Res 51:3715–3720

    PubMed  CAS  Google Scholar 

  • Raash W, Regunathan S, Li G, Reis DJ (1995) Agmatine, the bacterial amine is widely distributed in mammalian tissues. Life Sci 56:2310–2330

    Google Scholar 

  • Regenass U, Caravatti G, Mett H, Stanek J, Schneider P, Müller M, Matter A, Vertino P, Porter CW (1992) New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity. Cancer Res 52:4712–4718

    PubMed  CAS  Google Scholar 

  • Reis DJ, Regunathan S (2000) Is agmatine a novel neurotransmitter in brain? Trends Pharmacol Sci 21:187–193

    PubMed  Article  CAS  Google Scholar 

  • Satriano J, Matsufuji S, Murakami Y, Lortie MJ, Schwartz D, Kelly CJ, Hayashi S, Blantz RC (1998) Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels. J Biol Chem 273:15313–15316

    PubMed  Article  CAS  Google Scholar 

  • Satriano J, Isome M, Casero RA Jr, Thomson SC, Blantz RC (2001) Polyamine transport system mediates agmatine transport in mammalian cells. Am J Physiol Cell Physiol 281:C329–C334

    PubMed  CAS  Google Scholar 

  • Tabor CW, Tabor H (1984) Polyamines. Annu Rev Biochem 53:749–790

    PubMed  Article  CAS  Google Scholar 

  • Vargiu C, Cabella C, Belliardo S, Cravanzola C, Grillo MA, Colombatto S (1999) Agmatine modulates polyamine content in hepatocytes by inducing spermidine/spermine acetyltransferase. Eur J Biochem 259:933–938

    PubMed  Article  CAS  Google Scholar 

  • Wolff AC, Armstrong DK, Fetting JH, Carducci MK, Riley CD, Bender JF, Casero RA Jr, Davidson NE (2003) A Phase II study of the polyamine analog NI, NII-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer. Clin Cancer Res 9:5922–5928

    PubMed  CAS  Google Scholar 

  • Zhu MY, Iyo A, Piletz JE, Regunathan S (2004) Expression of human arginine decarboxylase, the biosynthetic enzyme for agmatine. Biochim Biophys Acta 1670:156–164

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This work was partially supported by Istituto Superiore di Sanità “Project Italy-USA”, by Istituto Pasteur–Fondazione Cenci Bolognetti, by funds MIUR-PRIN (Cofin) and by Fondazione Bossolasco (Torino).

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Affiliations

  1. Department of Experimental Medicine and Oncology, University of Torino, via Michelangelo 27B, 10126, Turin, Italy

    Bandino Andrea, Bravoco Vittoria, Busletta Chiara, Compagnone Alessandra, Cravanzola Carlo, Meli Floriana, Parola Maurizio & Colombatto Sebastiano

  2. Department of Biological Chemistry, University of Padua, Viale G. Colombo 3, 35121, Padua, Italy

    Battaglia Valentina

  3. Department of Biochemical Sciences, Institute Biology and Molecular Pathology, Istituto Pasteur–Fondazione Cenci Bolognetti, SAPIENZA University of Rome and CNR, Piazzale Aldo Moro 5, 00185, Rome, Italy

    Agostinelli Enzo

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  1. Bandino Andrea
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  2. Battaglia Valentina
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  3. Bravoco Vittoria
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  8. Agostinelli Enzo
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  9. Parola Maurizio
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  10. Colombatto Sebastiano
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Corresponding author

Correspondence to Colombatto Sebastiano.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00726-012-1241-y.

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Andrea, B., Valentina, B., Vittoria, B. et al. Chronic exposure to agmatine results in the selection of agmatine-resistant hepatoma cells. Amino Acids 42, 769–774 (2012). https://doi.org/10.1007/s00726-011-0993-0

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  • DOI: https://doi.org/10.1007/s00726-011-0993-0

Keywords

  • Agmatine
  • Polyamines
  • Uptake
  • Glutamic acid
  • Arginine
  • HTC cells