Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance.
The mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is overexpressed in a large proportion of breast cancers, and in some systems interferes with chemotherapy-mediated proapoptotic signaling through c-Jun-NH(2)-terminal kinase (JNK). We therefore sought to examine whether MKP-1 is a mediator of breast cancer chemoresistance using A1N4-myc human mammary epithelial cells, and BT-474 and MDA-MB-231 breast carcinoma cells. Transient or stable overexpression of MKP-1 reduced caspase activation and DNA fragmentation while enhancing viability in the face of treatment with alkylating agents (mechlorethamine), anthracylines (doxorubicin), and microtubule inhibitors (paclitaxel). This overexpression was associated with suppression of JNK activation, and JNK blockade alone induced similar effects. In contrast, reduction of MKP-1 levels using a small interfering RNA, or its targeted inactivation, enhanced sensitivity to these drugs, and this was associated with increased JNK activity. Pharmacologic reduction of MKP-1 by pretreatment with a novel p38 MAPK inhibitor, SD-282, suppressed MKP-1 activation by mechlorethamine, enhanced active JNK levels, and increased alkylating agent-mediated apoptosis. Combination treatment with doxorubicin and mechlorethamine had similar effects, and the enhanced efficacy of this regimen was abolished by forced overexpression of MKP-1. These results suggest that the clinical efficacy of combinations of alkylating agents and anthracyclines are due to the ability of the latter to target MKP-1. Moreover, they support the hypothesis that MKP-1 is a significant mediator of breast cancer chemoresistance, and provide a rationale for development and translation of other agents targeting MKP-1 into the clinical arena to overcome resistance and induce chemosensitization.
Small
George W
GW
The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Shi
Yue Y
YY
Higgins
Linda S
LS
Orlowski
Robert Z
RZ
D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008466:Mechlorethamine / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007211:Indoles; C514526:indole-5-carboxamide; D008466:Mechlorethamine; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D017239:Paclitaxel