Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells
A M Aslanian, B S Fletcher, M S Kilberg, A M Aslanian, B S Fletcher, M S Kilberg
Abstract
Childhood acute lymphoblastic leukaemia (ALL) is treated by combination chemotherapy with a number of drugs, always including the enzyme L-asparaginase (ASNase). Although the initial remission rate is quite high, relapse and associated drug resistance are a significant problem. In vitro studies have demonstrated increased asparagine synthetase (AS) expression in ASNase-resistant cells, which has led to the hypothesis that elevated AS activity permits drug-resistant survival. The data presented show that not only is elevated AS expression a property of ASNase-resistant MOLT-4 human leukaemia cells, but that short-term (12 h) treatment of the cells with ASNase causes a relatively rapid induction of AS expression. The results also document that the elevated expression of AS in ASNase-resistant cells is not fully reversible, even 6 weeks after ASNase removal from the culture medium. Furthermore, ASNase resistance, assessed as both drug-insensitive cell growth rates and decreased drug-induced apoptosis, parallels this irreversible AS expression. Mimicking the elevated AS activity in ASNase-resistant cells by overexpression of the human AS protein by stable retroviral transformation of parental MOLT4 cells is sufficient to induce the ASNase-resistance phenotype. These data document that ASNase resistance in ALL cells is a consequence of elevated AS expression and that although other drug-induced metabolic changes occur, they are secondary to the increased asparagine biosynthetic rate.
References
- Biochem Pharmacol. 1969 Oct;18(10):2578-80
- Cancer Res. 1971 Jul;31(7):942-9
- Anal Biochem. 1978 Jun 15;87(1):206-10
- Cancer Res. 1981 Aug;41(8):3104-6
- Leukemia. 1989 Apr;3(4):294-7
- Cancer Res. 1989 Aug 1;49(15):4363-8
- Mol Cell Biol. 1989 Jul;9(7):2922-7
- Somat Cell Mol Genet. 1990 Jan;16(1):59-65
- Cancer. 1990 Jun 15;65(12):2615-8
- Cancer Res. 1991 Feb 1;51(3):985-9
- Mol Cell Biol. 1991 Dec;11(12):6059-66
- Nucleic Acids Res. 1992 Oct 11;20(19):5234
- Cancer Chemother Pharmacol. 1993;32(2):129-33
- Mol Cell Biol. 1993 Jun;13(6):3202-12
- J Clin Oncol. 1994 Jun;12(6):1312-22
- Biochem J. 1994 Dec 15;304 ( Pt 3):745-50
- Leukemia. 1995 Feb;9(2):360-1
- Blood. 1995 Apr 15;85(8):2025-37
- Exp Cell Res. 1995 Oct;220(2):283-91
- Cancer. 1995 Dec 15;76(12):2393-417
- Crit Rev Oncol Hematol. 1997 Jan;25(1):11-26
- Am J Physiol. 1997 May;272(5 Pt 1):C1691-9
- Blood. 1997 Oct 1;90(7):2723-9
- Immunity. 1998 Apr;8(4):461-71
- Blood. 1998 Jul 1;92(1):259-66
- Biochem Biophys Res Commun. 1999 Jul 5;260(2):534-9
- Biochem Biophys Res Commun. 1968 Apr 5;31(1):43-7
- J Exp Med. 1968 Jun 1;127(6):1055-72
- Cancer. 1970 Feb;25(2):306-20
- Cancer. 1971 Oct;28(4):819-24
Source: PubMed