Declined asparagine synthetase mRNA expression and enhanced sensitivity to asparaginase in HL-60 cells committed to monocytic differentiation.
During 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of human promyelocytic leukemia HL-60 cells toward maturing monocytes/macrophages, asparagine synthetase (ASNS) mRNA expression declined time and dose-dependently. The effect of TPA was inhibited by inhibitors for PKC and MEK 1/2, but not by those for JNK and p38 MAPK. Combination treatment with TPA and asparaginase synergistically enhanced the growth retardation accompanied by apoptotic cell death characterized by internucleosomal DNA fragmentation. These data suggest the possible involvement of MEK1/2 MAPK in the inhibitory effect of TPA on ASNS mRNA expression and that the induction of the down-regulation of ASNS (via MEK1/2 activation) may be a new strategy for the treatment of leukemia blast cells.
Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan. kenhashi@dent.meikai.ac.jp
Ken
K
Hashimoto
Fumika
F
Suzuki
Hiroshi
H
Sakagami
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001215:Asparaginase / Q000494:pharmacology*; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018922:HL-60 Cells / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase; D013755:Tetradecanoylphorbol Acetate