Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role
| Autor: | George W. Small, S Somasundaram, Robert Z. Orlowski, Yue Y. Shi, Dominic T. Moore, Natalie A. Edmund |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Proteasome Endopeptidase Complex
Programmed cell death Proteolysis Transplantation Heterologous Genes myc Mice Nude Apoptosis Breast Neoplasms Cell Cycle Proteins Biology Cell Line Immediate-Early Proteins Bortezomib Mice Cell Line Tumor Protein Phosphatase 1 Phosphoprotein Phosphatases medicine Animals Humans Protease Inhibitors Breast Protein kinase A Cell Line Transformed Mice Knockout Pharmacology medicine.diagnostic_test Kinase Dual Specificity Phosphatase 1 Fibroblasts Boronic Acids Recombinant Proteins Proteasome Pyrazines Mitogen-activated protein kinase biology.protein Proteasome inhibitor Cancer research Molecular Medicine Protein Tyrosine Phosphatases medicine.drug |
| Zdroj: | Molecular Pharmacology. 66:1478-1490 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.104.003400 |
| Popis: | Inhibitors of the proteasome, a multicatalytic proteinase complex responsible for intracellular proteolysis, activate programmed cell death in part through the c-Jun-N-terminal kinase (JNK). Proteasome inhibitors also induce mitogen-activated protein kinase phosphatase-1 (MKP-1), however, which can inactivate JNK, and we therefore considered the hypothesis that MKP-1 induction may be antiapoptotic. Over-expression of MKP-1 in A1N4-myc human mammary epithelial and BT-474 breast carcinoma cells decreased proteasome inhibitor-mediated apoptosis. On the other hand, BT-474 cells stably expressing an MKP-1 small interfering RNA (siMKP-1) and MKP-1 knockout mouse embryo fibroblasts underwent enhanced apoptosis compared with their respective controls. MKP-1-mediated inhibition of apoptosis was associated with decreased phospho-JNK levels, whereas MKP-1 suppression or inactivation enhanced phospho-JNK. Anthracyclines repress MKP-1 transcription, suggesting that they could enhance proteasome inhibitor-mediated apoptosis. Such combinations induced increased cell death in association with enhanced phospho-JNK and decreased MKP-1 levels. Inhibition of JNK signaling decreased the proapoptotic activity of the anthracycline/proteasome inhibitor regimen. Xenograft studies showed the combination was more effective at inducing tumor growth delay, associated with suppression of MKP-1 and enhancement of apoptosis and phospho-JNK. Infection of anthracycline/proteasome inhibitor-treated A1N4-myc cells with Adenoviral-MKP-1 suppressed apoptosis and phospho-JNK. Finally, the anthracycline/proteasome inhibitor regimen activated apoptosis and phospho-JNK to a greater extent in BT-474/siMKP-1 cells than controls. These findings for the first time demonstrate that proteasome inhibitor-mediated induction of MKP-1 is antiapoptotic through inhibition of JNK. Furthermore, they suggest that a proteasome inhibitor/anthracycline regimen holds potential for enhanced antitumor activity in part through repression of MKP-1, supporting clinical evaluation of such combinations. |
| Databáze: | OpenAIRE |
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