@article {Small861, author = {George W. Small and Sivagurunathan Somasundaram and Dominic T. Moore and Yue Y. Shi and Robert Z. Orlowski}, title = {Repression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase-1 by Anthracyclines Contributes to Their Antiapoptotic Activation of p44/42-MAPK}, volume = {307}, number = {3}, pages = {861--869}, year = {2003}, doi = {10.1124/jpet.103.055806}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/307/3/861}, eprint = {https://jpet.aspetjournals.org/content/307/3/861.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }