The effect of ATM and ERK1/2 inhibition on mitoxantrone-induced cell death of leukaemic cells
| Autor: | M, Seifrtová, R, Havelek, M, Chmelařová, J, Cmielová, D, Muthná, A, Stoklasová, S, Zemánková, M, Rezáčová |
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| Rok vydání: | 2011 |
| Předmět: |
G2 Phase
Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Tumor Suppressor Proteins Cell Cycle Antineoplastic Agents Apoptosis Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases DNA-Binding Proteins Jurkat Cells Cell Line Tumor Nitriles Butadienes Humans Mitoxantrone Signal Transduction |
| Zdroj: | Folia biologica. 57(2) |
| ISSN: | 0015-5500 |
| Popis: | The relationship between signal pathways MEK1/2-ERK1/2 and ATM-p53 in the response to DNA damage is not well understood. The aim of our study was to investigate the effect of mitoxantrone and two protein kinase inhibitors - caffeine (inhibitor of ATM kinase) and U0126 (inhibitor of MEK1/2 kinase) - on MOLT-4 and Jurkat leukaemic cell lines. In this work we show that the inhibition of MEK1/2 is associated with an increased mortality of cells after mitoxantrone treatment. Inhibition of ATM by caffeine delayed mitoxantrone-induced cell death in MOLT-4 cells. Mitoxantrone itself induced cell-cycle arrest and accumulation of the cells in late S and G2/M phase. Inhibition of ATM, but not of MEK1/2, abrogated mitoxantrone-induced cell-cycle arrest. Inhibition of MEK1/2 did not change mitoxantroneinduced up-regulation of p53 and p21, but inhibition of ATM markedly decreased up-regulation of p53 and p21, and p53 phosphorylation on serine 15 and serine 392. It can be concluded that: 1) mitoxantrone- induced phosphorylation of p53 on serine 15 and serine 392 is ATM dependent and MEK1/2-ERK1/2 independent. 2) ATM inhibition by caffeine prevents G2 cell arrest and in p53-positive cells MOLT-4 delays the onset of mitoxantrone-induced cell death. 3) Inhibition of MEK1/2-ERK1/2 cascade potentiates the cytostatic effect of mitoxantrone regardless of the p53 status. |
| Databáze: | OpenAIRE |
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