Cellular Physiology and Biochemistry

Original Paper

Free Access

Inhibition of Glutamine Synthetase Triggers Apoptosis in Asparaginase-Resistant Cells

Rotoli 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.a

Author affiliations

Units of General and Clinical Pathologya and Histology b, Department of Experimental Medicine, Universitagrave; degli Studi di Parma

Corresponding Author

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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Cell Physiol Biochem 2005;15:281–292

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

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Abstract of Original Paper

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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