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Molecular Pharmacology

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Research ArticleArticle

Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role

George W. Small, Yue Y. Shi, Natalie A. Edmund, Sivagurunathan Somasundaram, Dominic T. Moore and Robert Z. Orlowski
Molecular Pharmacology December 2004, 66 (6) 1478-1490; DOI: https://doi.org/10.1124/mol.104.003400
George W. Small
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Yue Y. Shi
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Natalie A. Edmund
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Sivagurunathan Somasundaram
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Dominic T. Moore
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Robert Z. Orlowski
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Abstract

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.

  • Received June 1, 2004.
  • Accepted September 23, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (6)
Molecular Pharmacology
Vol. 66, Issue 6
1 Dec 2004
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Research ArticleArticle

Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role

George W. Small, Yue Y. Shi, Natalie A. Edmund, Sivagurunathan Somasundaram, Dominic T. Moore and Robert Z. Orlowski
Molecular Pharmacology December 1, 2004, 66 (6) 1478-1490; DOI: https://doi.org/10.1124/mol.104.003400

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Research ArticleArticle

Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role

George W. Small, Yue Y. Shi, Natalie A. Edmund, Sivagurunathan Somasundaram, Dominic T. Moore and Robert Z. Orlowski
Molecular Pharmacology December 1, 2004, 66 (6) 1478-1490; DOI: https://doi.org/10.1124/mol.104.003400
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