QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.055806v1 307/3/861    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Small, G. W. Articles by Orlowski, R. Z. Search for Related Content PubMed PubMed Citation Articles by Small, G. W. Articles by Orlowski, R. Z.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Repression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase-1 by Anthracyclines Contributes to Their Antiapoptotic Activation of p44/42-MAPK

The Lineberger Comprehensive Cancer Center (G.W.S., S.S., D.T.M., Y.Y.S., R.Z.O.) and Department of Medicine, Division of Hematology/Oncology (R.Z.O.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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.

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:

				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]

				D. J. Kuhn, S. A. Hunsucker, Q. Chen, P. M. Voorhees, M. Orlowski, and R. Z. Orlowski Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors Blood, May 7, 2009; 113(19): 4667 - 4676. [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]

				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]

				D. J. Kuhn, Q. Chen, P. M. Voorhees, J. S. Strader, K. D. Shenk, C. M. Sun, S. D. Demo, M. K. Bennett, F. W. B. van Leeuwen, A. A. Chanan-Khan, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma Blood, November 1, 2007; 110(9): 3281 - 3290. [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]

				I. Manov, Y. Bashenko, A. Eliaz-Wolkowicz, M. Mizrahi, O. Liran, and T. C. Iancu High-Dose Acetaminophen Inhibits the Lethal Effect of Doxorubicin in HepG2 Cells: The Role of P-glycoprotein and Mitogen-Activated Protein Kinase p44/42 Pathway J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1013 - 1022. [Abstract] [Full Text] [PDF]

				G. W. Small, Y. Y. Shi, L. S. Higgins, and R. Z. Orlowski Mitogen-Activated Protein Kinase Phosphatase-1 Is a Mediator of Breast Cancer Chemoresistance Cancer Res., May 1, 2007; 67(9): 4459 - 4466. [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]

				G. W. Small, Y. Y. Shi, N. A. Edmund, S. Somasundaram, D. T. Moore, and R. Z. Orlowski Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role Mol. Pharmacol., December 1, 2004; 66(6): 1478 - 1490. [Abstract] [Full Text] [PDF]

				R. Wadgaonkar, J. W. Pierce, K. Somnay, R. L. Damico, M. T. Crow, T. Collins, and J. G. N. Garcia Regulation of c-Jun N-terminal Kinase and p38 Kinase Pathways in Endothelial Cells Am. J. Respir. Cell Mol. Biol., October 1, 2004; 31(4): 423 - 431. [Abstract] [Full Text] [PDF]

				A. Jacob, A. Smolenski, S. M. Lohmann, and N. Begum MKP-1 expression and stabilization and cGK I{alpha} prevent diabetes- associated abnormalities in VSMC migration Am J Physiol Cell Physiol, October 1, 2004; 287(4): C1077 - C1086. [Abstract] [Full Text] [PDF]