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Altered spermidine/spermine N1-acetyltransferase activity as a mechanism of cellular resistance to

D E McCloskey1, A E Pegg

  • 1Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. dem15@psu.edu

The Journal of Biological Chemistry
|July 11, 2000
PubMed

Insights

Researchers developed a drug-resistant cell line to study anticancer drugs. They found a mutation in the spermidine/spermine N(1)-acetyltransferase (SSAT) enzyme, proving it

Area of Science:

  • Cell biology
  • Molecular pharmacology
  • Cancer research

Background:

  • Bis(ethyl)polyamine analogues exhibit antiproliferative effects.
  • Understanding resistance mechanisms is crucial for drug development.

Purpose of the Study:

  • To develop a model system for investigating resistance to bis(ethyl)polyamine analogues.
  • To elucidate the role of spermidine/spermine N(1)-acetyltransferase (SSAT) in analogue resistance.

Main Methods:

  • Selection of a resistant Chinese hamster ovary cell line (C55.7Res) to N(1), N(12)-bis(ethyl)spermine.
  • Analysis of polyamine transport, SSAT activity, mRNA, and protein levels.
  • Sequencing of SSAT cDNA to identify mutations.
  • Complementation studies by expressing wild-type SSAT in resistant cells.

Main Results:

  • C55.7Res cells showed stable, heritable resistance to bis(ethyl)polyamines, independent of transport or multi-drug resistance.
  • Basal SSAT activity was decreased in C55.7Res cells, with no induction upon analogue exposure.
  • No SSAT protein was detected in resistant cells, despite unchanged mRNA levels.
  • A point mutation (L156F) in SSAT cDNA was identified in C55.7Res cells.
  • Restoration of wild-type SSAT activity re-sensitized cells to the analogues.

Conclusions:

  • SSAT enzyme activity is a critical target for the antiproliferative action of bis(ethyl)polyamine analogues.
  • A mutation in SSAT can confer resistance to these compounds.
  • The C55.7Res cell line is a valuable tool for studying SSAT-mediated drug resistance mechanisms.

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