L-Asparaginase inhibits the rapamycin-targeted signaling pathway.
L-Asparaginase is widely used in the treatment of acute lymphoblastic leukemia. L-Asparaginase preparation derived from E. coli converts asparagine (Asn) and glutamine (Gln) to aspartate (Asp) and glutamate (Glu), respectively, and causes rapid depletion of Asn and Gln. It thus suppresses growth of malignant cells that are more dependent on an exogenous source of Asn and Gln than are normal cells. It remains unclear, however, which signaling events in leukemic cells are affected by L-asparaginase. Recently, amino acid sufficiency has been demonstrated to selectively regulate p70 S6 kinase (p70(s6k)) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which are targeted by the anti-proliferative drug rapamycin. Here we demonstrate that addition of L-asparaginase to human leukemic cells inhibits activity of p70(s6k) and phosphorylation of 4E-BP1, but not activities of other cell growth-related serine/threonine kinases. The rate and kinetics of p70(s6k) inhibition by L-asparaginase were comparable to those seen by deprivation of Asn and/or Gln from cell culture media, suggesting that the effect of L-asparaginase on p70(s6k) is explained by depletion of Asn and/or Gln. Moreover, L-Asparaginase as well as rapamycin selectively suppressed synthesis of ribosomal proteins at the level of mRNA translation. These data indicate that L-asparaginase and rapamycin target a common signaling pathway in leukemic cells.
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, 80206, USA.
Y
Y
Iiboshi
P J
PJ
Papst
S P
SP
Hunger
N
N
Terada
D048868:Adaptor Proteins, Signal Transducing; D001215:Asparaginase / Q000494:pharmacology*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010750:Phosphoproteins / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D001215:Asparaginase; D020123:Sirolimus