Declined Asparagine Synthetase mRNA Expression and Enhanced Sensitivity to Asparaginase in HL-60 Cells Committed to Monocytic Differentiation

• Published in: Anticancer research Vol. 29; no. 4; pp. 1303 - 1308
• Main Authors: HASHIMOTO, Ken, SUZUKI, Fumika, SAKAGAMI, Hiroshi
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.04.2009
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Asparaginase - pharmacology; Aspartate-Ammonia Ligase - antagonists & inhibitors; Aspartate-Ammonia Ligase - genetics; Aspartate-Ammonia Ligase - metabolism; Biological and medical sciences; Cell Differentiation; Drug Synergism; Drug Therapy, Combination; HL-60 Cells - metabolism; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Medical sciences; Monocytes - cytology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Tumors; Antineoplastic agent; differentiation; Carbon-nitrogen ligases; Serine endopeptidases; Monocyte; TPA; Enzyme; Cell differentiation; HL60 cell line; t-Plasminogen activator; Peptidases; Aspartate-ammonia ligase; Sensitivity; Cancerology; Messenger RNA; Ligases; Cell death; Hydrolases; asparagine synthetase; HL-60; Asparaginase; Apoptosis
• ISSN: 0250-7005; 1791-7530

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.