HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 275, Issue 37, 28708-28714, September 15, 2000

This Article Full Text Full Text (PDF) All Versions of this Article: 275/37/28708    most recent M004120200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McCloskey, D. E. Articles by Pegg, A. E. Search for Related Content PubMed PubMed Citation Articles by McCloskey, D. E. Articles by Pegg, A. E. Social Bookmarking                      What's this?

Altered Spermidine/Spermine N¹-Acetyltransferase Activity as a Mechanism of Cellular Resistance to Bis(ethyl)polyamine Analogues^*

Diane E. McCloskey and Anthony E. Pegg

From the Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

To develop a model system to investigate mechanisms of antiproliferative action of bis(ethyl)polyamine analogues, intermittent analogue treatments followed by recovery periods in drug-free medium were used to select an N¹,N¹²-bis(ethyl)spermine-resistant derivative of the Chinese hamster ovary cell line C55.7. The resulting C55.7Res line was at least 10-fold resistant to N¹,N¹²-bis(ethyl)spermine and N¹,N¹¹-bis(ethyl)norspermine. The stability of the resistance in the absence of selection pressure was 9 months, indicating that a heritable genotypic change was responsible for the resistance phenotype. Polyamine transport alterations and multi-drug resistance were eliminated as causes of the resistance. Spermidine/spermine N¹-acetyltransferase (SSAT) activity and regulation were altered in C55.7Res cells as basal activity was decreased, and no activity induction resulted from exposure to analogue concentrations, which caused 300-fold enzyme induction in parental cells. SSAT mRNA levels in the absence and presence of analogue were unchanged, but no SSAT protein was detected in C55.7Res cells. A point mutation, which results in the change leucine156 (a fully conserved residue) to phenylalanine, was identified in the C55.7Res SSAT cDNA. Expression of wtSSAT activity in C55.7Res cells restored sensitivity to bis(ethyl)polyamines. These results provided definitive evidence that SSAT activity is a critical target of the cytotoxic action of these analogues.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF281149.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				A. E. Pegg Spermidine/spermine-N1-acetyltransferase: a key metabolic regulator Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E995 - E1010. [Abstract] [Full Text] [PDF]

				G. Marverti, M. G. Monti, A. E. Pegg, D. E. McCloskey, S. Bettuzzi, A. Ligabue, A. Caporali, D. D'Arca, and M. S. Moruzzi Spermidine/spermine N1-acetyltransferase transient overexpression restores sensitivity of resistant human ovarian cancer cells to N1,N12-bis(ethyl)spermine and to cisplatin Carcinogenesis, October 1, 2005; 26(10): 1677 - 1686. [Abstract] [Full Text] [PDF]

				K. Kee, B. A. Foster, S. Merali, D. L. Kramer, M. L. Hensen, P. Diegelman, N. Kisiel, S. Vujcic, R. V. Mazurchuk, and C. W. Porter Activated Polyamine Catabolism Depletes Acetyl-CoA Pools and Suppresses Prostate Tumor Growth in TRAMP Mice J. Biol. Chem., September 17, 2004; 279(38): 40076 - 40083. [Abstract] [Full Text] [PDF]

				J. Fukuchi, R. A. Hiipakka, J. M. Kokontis, K. Nishimura, K. Igarashi, and S. Liao TATA-binding Protein-associated Factor 7 Regulates Polyamine Transport Activity and Polyamine Analog-induced Apoptosis J. Biol. Chem., July 16, 2004; 279(29): 29921 - 29929. [Abstract] [Full Text] [PDF]

				S. Hector, C. W. Porter, D. L. Kramer, K. Clark, J. Prey, N. Kisiel, P. Diegelman, Y. Chen, and L. Pendyala Polyamine catabolism in platinum drug action: Interactions between oxaliplatin and the polyamine analogue N1,N11-diethylnorspermine at the level of spermidine/spermine N1-acetyltransferase Mol. Cancer Ther., July 1, 2004; 3(7): 813 - 822. [Abstract] [Full Text] [PDF]

				K. Kee, S. Vujcic, S. Merali, P. Diegelman, N. Kisiel, C. T. Powell, D. L. Kramer, and C. W. Porter Metabolic and Antiproliferative Consequences of Activated Polyamine Catabolism in LNCaP Prostate Carcinoma Cells J. Biol. Chem., June 25, 2004; 279(26): 27050 - 27058. [Abstract] [Full Text] [PDF]

				Y. Chen, D. L. Kramer, J. Jell, S. Vujcic, and C. W. Porter Small Interfering RNA Suppression of Polyamine Analog-Induced Spermidine/Spermine N1-Acetyltransferase Mol. Pharmacol., November 1, 2003; 64(5): 1153 - 1159. [Abstract] [Full Text] [PDF]

				D. E. McCloskey and A. E. Pegg Properties of the Spermidine/Spermine N1-Acetyltransferase Mutant L156F That Decreases Cellular Sensitivity to the Polyamine Analogue N1, N11-Bis(ethyl)norspermine J. Biol. Chem., April 11, 2003; 278(16): 13881 - 13887. [Abstract] [Full Text] [PDF]

				K. Niiranen, M. Pietila, T. J. Pirttila, A. Jarvinen, M. Halmekyto, V.-P. Korhonen, T. A. Keinanen, L. Alhonen, and J. Janne Targeted Disruption of Spermidine/Spermine N1-Acetyltransferase Gene in Mouse Embryonic Stem Cells. EFFECTS ON POLYAMINE HOMEOSTASIS AND SENSITIVITY TO POLYAMINE ANALOGUES J. Biol. Chem., July 5, 2002; 277(28): 25323 - 25328. [Abstract] [Full Text] [PDF]

				S. Vujcic, M. Halmekyto, P. Diegelman, G. Gan, D. L. Kramer, J. Janne, and C. W. Porter Effects of Conditional Overexpression of Spermidine/Spermine N1-Acetyltransferase on Polyamine Pool Dynamics, Cell Growth, and Sensitivity to Polyamine Analogs J. Biol. Chem., December 1, 2000; 275(49): 38319 - 38328. [Abstract] [Full Text] [PDF]