Cellular Physiology and Biochemistry
Original Paper
Inhibition of Glutamine Synthetase Triggers Apoptosis in Asparaginase-Resistant CellsRotoli B.M.a · Uggeri J.b · Dall’Asta V.a · Visigalli R.a · Barilli A.a · Gatti R.b · Orlandini G.b · Gazzola G.C.a · Bussolati O.aUnits of General and Clinical Pathologya and Histology b, Department of Experimental Medicine, Universitagrave; degli Studi di Parma
Dr. Ovidio Bussolati Unit of General and Clinical Pathology, Universitagrave; degli Studi di Parma Via Volturno, 39, 43100 Parma (Italy)p>Tel. +39/521 903783, Fax: +39/521 903742 E-Mail ovidio.bussolati@unipr.it |
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Abstract
The resistance to L-asparaginase (ASNase) has been associated to the overexpression of asparagine synthetase (AS), although the role played by other metabolic adaptations has not been yet defined. Both in ASNase-sensitive Jensen rat sarcoma cells and in ARJ cells, their ASNase-resistant counterparts endowed with a five-fold increased AS activity, ASNase treatment rapidly depletes intracellular asparagine. Under these conditions, cell glutamine is also severely reduced and the activity of glutamine synthetase (GS) is very low. After 24h of treatment, while sensitive cells have undergone massive apoptosis, ARJ cells exhibit a marked increase in GS activity, associated with overexpression of GS protein but not of GS mRNA, and a partial restoration of glutamine and asparagine. However, when ARJ cells are treated with both ASNase and L-methionine-sulfoximine (MSO), an inhibitor of GS, no restoration of cell amino acids occurs and the cell population undergoes a typical apoptosis. No toxicity is observed upon MSO treatment in the absence of ASNase. The effects of MSO are not referable to depletion of cell glutathione or inhibition of AS. These findings indicate that, in the presence of ASNase, the inhibition of GS triggers apoptosis. GS may thus constitute a target for the suppression of ASNase-resistant phenotypes.
© 2005 S. Karger AG, Basel
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Article / Publication Details
Published online: June 01, 2005
Issue release date: July 2005
Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 0
ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)
For additional information: https://www.karger.com/CPB
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