The Effect of ATM and ERK1/2 Inhibition on Mitoxantrone-Induced Cell Death of Leukaemic Cells

作者：Seifrtova M; Havelek R; Chmelarova M; Muthna D; Stoklasova A; Zemankova S; Rezacova M^*

来源：Folia Biologica, 2011, 57(2): 74-81.

• mitoxantrone
• ATM
• ERK1/2
• p53
• leukaemia

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 mitoxantrone-induced 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.

• 出版日期2011