Apoptosis and mitotic arrest are two independent effects of the protein phosphatases inhibitor okadaic acid in K562 leukemia cells.
Treatment of human myeloid leukemia K562 cells with the serine/threonine protein phosphatases inhibitor okadaic acid induced mitotic arrest followed by apoptosis in a synchronized manner. The effect was observed at drug concentrations that inhibited the protein phosphatase type 2A but not type 1. We investigated whether apoptosis was a consequence of the preceding mitosis arrest or was induced independently by okadaic acid. We found that (1) apoptosis, but not mitotic arrest, was inhibited in cells with constitutive expression of Bcl-2; (2) pretreatment of cells with the DNA synthesis inhibitor hydroxyurea blocked the mitotic arrest but not the apoptosis mediated by okadaic acid; (3) down-regulation of c-myc gene was associated with apoptosis, but not with mitotic arrest; and (4) inhibition of protein synthesis abrogated mitotic arrest, but not apoptosis. The results suggest that inhibition of protein phosphatase 2A by okadaic acid provokes mitotic arrest and apoptosis of leukemia cells by independent mechanisms.
Lerga
A
A
Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular-Unidad Asociada al Centro de Investigaciones Biológicas, Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
Richard
C
C
Delgado
M D
MD
Cañelles
M
M
Frade
P
P
Cuadrado
M A
MA
León
J
J
D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D019925:Cyclin A / Q000187:drug effects; D019926:Cyclin B / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D020014:K562 Cells; D008938:Mitosis; D015739:Nocodazole / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2; D013997:Time Factors
D019925:Cyclin A; D019926:Cyclin B; D004791:Enzyme Inhibitors; D006657:Histones; D019384:Nucleic Acid Synthesis Inhibitors; D019319:Okadaic Acid; D003513:Cycloheximide; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D015739:Nocodazole; D006918:Hydroxyurea