![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The Lineberger Comprehensive Cancer Center (G.W.S., Y.Y.S., N.A.E., S.S., D.T.M., R.Z.O.) and the Department of Medicine, Division of Hematology/Oncology (R.Z.O.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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 for publication June 1, 2004.
Accepted for publication September 23, 2004.
Address correspondence to: Dr. Robert Z. Orlowski, University of North Carolina at Chapel Hill, 22-003 Lineberger Comprehensive Cancer Center, CB # 7295, Mason Farm Road, Chapel Hill, NC 27599-7295. E-mail: r_orlowski{at}med.unc.edu
This article has been cited by other articles:
|
|
 |
|
  A. J. Jakubowiak, T. Kendall, A. Al-Zoubi, Y. Khaled, S. Mineishi, A. Ahmed, E. Campagnaro, C. Brozo, T. Braun, M. Talpaz, et al. Phase II Trial of Combination Therapy With Bortezomib, Pegylated Liposomal Doxorubicin, and Dexamethasone in Patients With Newly Diagnosed Myeloma J. Clin. Oncol., October 20, 2009; 27(30): 5015 - 5022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Rojo, I. Gonzalez-Navarrete, R. Bragado, A. Dalmases, S. Menendez, M. Cortes-Sempere, C. Suarez, C. Oliva, S. Servitja, V. Rodriguez-Fanjul, et al. Mitogen-Activated Protein Kinase Phosphatase-1 in Human Breast Cancer Independently Predicts Prognosis and Is Repressed by Doxorubicin Clin. Cancer Res., May 15, 2009; 15(10): 3530 - 3539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Boutros, E. Chevet, and P. Metrakos Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer Pharmacol. Rev., September 1, 2008; 60(3): 261 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Sloss, F. Wang, R. Liu, L. Xia, M. Houston, D. Ljungman, M. A. Palladino, and J. C. Cusack Jr. Proteasome Inhibition Activates Epidermal Growth Factor Receptor (EGFR) and EGFR-Independent Mitogenic Kinase Signaling Pathways in Pancreatic Cancer Cells Clin. Cancer Res., August 15, 2008; 14(16): 5116 - 5123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Lomonaco, S. Kahana, M. Blass, Y. Brody, H. Okhrimenko, C. Xiang, S. Finniss, P. M. Blumberg, H.-K. Lee, and C. Brodie Phosphorylation of Protein Kinase C{delta} on Distinct Tyrosine Residues Induces Sustained Activation of Erk1/2 via Down-regulation of MKP-1: ROLE IN THE APOPTOTIC EFFECT OF ETOPOSIDE J. Biol. Chem., June 20, 2008; 283(25): 17731 - 17739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z. Orlowski and D. J. Kuhn Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade Clin. Cancer Res., March 15, 2008; 14(6): 1649 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vogt, P. R. McDonald, A. Tamewitz, R. P. Sikorski, P. Wipf, J. J. Skoko III, and J. S. Lazo A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells Mol. Cancer Ther., February 1, 2008; 7(2): 330 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z. Orlowski, A. Nagler, P. Sonneveld, J. Blade, R. Hajek, A. Spencer, J. San Miguel, T. Robak, A. Dmoszynska, N. Horvath, et al. Randomized Phase III Study of Pegylated Liposomal Doxorubicin Plus Bortezomib Compared With Bortezomib Alone in Relapsed or Refractory Multiple Myeloma: Combination Therapy Improves Time to Progression J. Clin. Oncol., September 1, 2007; 25(25): 3892 - 3901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cardoso, V. Durbecq, J.-F. Laes, B. Badran, L. Lagneaux, F. Bex, C. Desmedt, K. Willard-Gallo, J. S. Ross, A. Burny, et al. Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner Mol. Cancer Ther., December 1, 2006; 5(12): 3042 - 3051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Yang, P. O'Neill, W. Jin, R. Foty, D. J. Medina, Z. Xu, M. Lomas, G. M. Arndt, Y. Tang, M. Nakada, et al. Extracellular Matrix Metalloproteinase Inducer (CD147) Confers Resistance of Breast Cancer Cells to Anoikis through Inhibition of Bim J. Biol. Chem., April 7, 2006; 281(14): 9719 - 9727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-H. Choi, E.-M. Hur, J.-H. Lee, D.-J. Jun, and K.-T. Kim Protein kinase C{delta}-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death J. Cell Sci., April 1, 2006; 119(7): 1329 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Codony-Servat, M. A. Tapia, M. Bosch, C. Oliva, J. Domingo-Domenech, B. Mellado, M. Rolfe, J. S. Ross, P. Gascon, A. Rovira, et al. Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells. Mol. Cancer Ther., March 1, 2006; 5(3): 665 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Duggan, W. M. Gallagher, E. J.P. Fox, M. M. Abdel-Latif, J. V. Reynolds, and D. Kelleher Low pH induces co-ordinate regulation of gene expression in oesophageal cells Carcinogenesis, February 1, 2006; 27(2): 319 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Z. Orlowski Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation Hematology, January 1, 2006; 2006(1): 338 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Vogt, A. Tamewitz, J. Skoko, R. P. Sikorski, K. A. Giuliano, and J. S. Lazo The Benzo[c]phenanthridine Alkaloid, Sanguinarine, Is a Selective, Cell-active Inhibitor of Mitogen-activated Protein Kinase Phosphatase-1 J. Biol. Chem., May 13, 2005; 280(19): 19078 - 19086. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Z. Orlowski, P. M. Voorhees, R. A. Garcia, M. D. Hall, F. J. Kudrik, T. Allred, A. R. Johri, P. E. Jones, A. Ivanova, H. W. Van Deventer, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies Blood, April 15, 2005; 105(8): 3058 - 3065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wu, T. Pew, M. Zou, D. Pang, and S. D. Conzen Glucocorticoid Receptor-induced MAPK Phosphatase-1 (MPK-1) Expression Inhibits Paclitaxel-associated MAPK Activation and Contributes to Breast Cancer Cell Survival J. Biol. Chem., February 11, 2005; 280(6): 4117 - 4124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z. Orlowski The Ubiquitin Proteasome Pathway from Bench to Bedside Hematology, January 1, 2005; 2005(1): 220 - 225. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
