PT  - JOURNAL ARTICLE
AU  - Small, George W.
AU  - Somasundaram, Sivagurunathan
AU  - Moore, Dominic T.
AU  - Shi, Yue Y.
AU  - Orlowski, Robert Z.
TI  - Repression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase-1 by Anthracyclines Contributes to Their Antiapoptotic Activation of p44/42-MAPK
AID  - 10.1124/jpet.103.055806
DP  - 2003 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 861--869
VI  - 307
IP  - 3
4099  - http://jpet.aspetjournals.org/content/307/3/861.short
4100  - http://jpet.aspetjournals.org/content/307/3/861.full
SO  - J Pharmacol Exp Ther2003 Dec 01; 307
AB  - Anthracyclines are commonly used chemotherapeutics, and in some models enhance p44/42-mitogen-activated protein kinase (MAPK) pathway signaling by effects on upstream kinases. To evaluate the impact of anthracyclines on p44/42-MAPK in breast cancer, A1N4-myc human mammary and BT-474 and MDA-MB-231 breast carcinoma cells were studied. Treatment with doxorubicin or epirubicin resulted in increased phospho-p44/42-MAPK levels in a time- and concentration-dependent manner. This was associated with p44/42 activation, as reflected by increased p90 ribosomal protein S6 kinase and Bad phosphorylation. Activation of p44/42 appeared to be antiapoptotic, since MAPK stimulation with epidermal growth factor or a dominant-positive p42 construct inhibited apoptosis. Modest activation of the upstream MAPK kinase MEK was noted under some conditions, but inhibition of MEK did not abolish p44/42 activation, suggesting a contribution from another mechanism. Anthracyclines were found to decrease expression of MAPK phosphatase-1 (MKP-1) both in vitro and in vivo. MKP-1 mRNA levels were decreased in anthracycline-treated cells, and transcription from the MKP-1 promoter was repressed. Inhibition of MKP-1 expression through the use of small interfering RNAs decreased the ability of anthracyclines to induce phospho-p44/42. Wild-type mouse embryo fibroblasts (MEFs) treated with doxorubicin showed increased phospho-p44/42-MAPK levels, but MEFs from MKP-1 heterozygous and homozygous knockout mice had blunted p44/42 activation. These studies support the ability of anthracyclines to activate antiapoptotic p44/42-MAPK phosphorylation in breast cancer, and indicate that this occurs in part through the novel mechanism of repression of MKP-1 transcription. The American Society for Pharmacology and Experimental Therapeutics