This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Wang, Z. Articles by Wu, G. S. Search for Related Content PubMed PubMed Citation Articles by Wang, Z. Articles by Wu, G. S.

Mitogen-Activated Protein Kinase Phosphatase-1 Is Required for Cisplatin Resistance

¹ Program in Molecular Biology and Human Genetics, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan and ² Children's Research Institute, Department of Pediatrics, The Ohio State University, Columbus, Ohio

Requests for reprints: Gen Sheng Wu, Program in Molecular Biology and Human Genetics, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201. Phone: 313-833-0715, ext. 2328; Fax: 313-831-7518; E-mail: wug{at}karmanos.org.

Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is a member of the MKP family that negatively regulates MAPK signaling. MKP-1 has been implicated in cell survival in response to stressful stimuli, including anticancer treatment, but its role in cisplatin resistance is not fully understood. Here, we show that cisplatin induces MKP-1 in several human cancer cell lines. Induction of MKP-1 by cisplatin was through the transcriptional mechanism regulated by extracellular signal-regulated kinase (ERK). Overexpression of MKP-1 rendered human lung cancer cells resistant to cisplatin. Conversely, down-regulation of MKP-1 by small interfering RNA silencing sensitized human lung cancer cells to cisplatin-induced cell death. Using primary mouse embryonic fibroblasts (MEF) from MKP-1 knockout mice, we show that induction of MKP-1 by cisplatin correlates with inactivation of c-Jun NH₂-terminal kinase (JNK) but not ERK and p38. Furthermore, apoptosis induced by cisplatin was significant in MKP-1^–/– MEFs, whereas such change was minimal in MKP-1^+/+ MEFs. More importantly, cisplatin-induced cell death is inhibited by blocking JNK but not ERK and p38 activities. Collectively, our results establish a critical role of JNK in cisplatin-induced apoptosis and suggest that MKP-1 is required for cisplatin resistance. (Cancer Res 2006; 66(17): 8870-7)

This article has been cited by other articles:

				R. Liu, H.-Q. Zheng, Z. Zhou, J.-T. Dong, and C. Chen KLF5 Promotes Breast Cell Survival Partially through Fibroblast Growth Factor-binding Protein 1-pERK-mediated Dual Specificity MKP-1 Protein Phosphorylation and Stabilization J. Biol. Chem., June 19, 2009; 284(25): 16791 - 16798. [Abstract] [Full Text] [PDF]

				H.-M. Ko, S.-H. Oh, H.-S. Bang, N.-I. Kang, B.-H. Cho, S.-Y. Im, and H.-K. Lee Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1 J. Immunol., June 15, 2009; 182(12): 7957 - 7962. [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]

				Y. J. Arnoldussen, P. I. Lorenzo, M. E. Pretorius, H. Waehre, B. Risberg, G. M. Maelandsmo, H. E. Danielsen, and F. Saatcioglu The Mitogen-Activated Protein Kinase Phosphatase Vaccinia H1-Related Protein Inhibits Apoptosis in Prostate Cancer Cells and Is Overexpressed in Prostate Cancer Cancer Res., November 15, 2008; 68(22): 9255 - 9264. [Abstract] [Full Text] [PDF]

				A. Chiloeches, A. Sanchez-Pacheco, B. Gil-Araujo, A. Aranda, and M. Lasa Thyroid Hormone-Mediated Activation of the ERK/Dual Specificity Phosphatase 1 Pathway Augments the Apoptosis of GH4C1 Cells by Down-Regulating Nuclear Factor-{kappa}B Activity Mol. Endocrinol., November 1, 2008; 22(11): 2466 - 2480. [Abstract] [Full Text] [PDF]

				C. Peklak-Scott, P. K. Smitherman, A. J. Townsend, and C. S. Morrow Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin Mol. Cancer Ther., October 1, 2008; 7(10): 3247 - 3255. [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]

				J. Xu, J.-Y. Zhou, W.-Z. Wei, S. Philipsen, and G. S. Wu Sp1-Mediated TRAIL Induction in Chemosensitization Cancer Res., August 15, 2008; 68(16): 6718 - 6726. [Abstract] [Full Text] [PDF]

				Z. Wang, N. Cao, D. Nantajit, M. Fan, Y. Liu, and J. J. Li Mitogen-activated Protein Kinase Phosphatase-1 Represses c-Jun NH2-terminal Kinase-mediated Apoptosis via NF-{kappa}B Regulation J. Biol. Chem., July 25, 2008; 283(30): 21011 - 21023. [Abstract] [Full Text] [PDF]

				D. F. Calvisi, F. Pinna, F. Meloni, S. Ladu, R. Pellegrino, M. Sini, L. Daino, M. M. Simile, M. R. De Miglio, P. Virdis, et al. Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase-Mediated Control of Growth in Human Hepatocellular Carcinoma Cancer Res., June 1, 2008; 68(11): 4192 - 4200. [Abstract] [Full Text] [PDF]

				E. Mortaz, F. A. Redegeld, H. Sarir, K. Karimi, D. Raats, F. P. Nijkamp, and G. Folkerts Cigarette smoke stimulates the production of chemokines in mast cells J. Leukoc. Biol., March 1, 2008; 83(3): 575 - 580. [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]

				J. Wang, J.-Y. Zhou, and G. S. Wu ERK-Dependent MKP-1 Mediated Cisplatin Resistance in Human Ovarian Cancer Cells Cancer Res., December 15, 2007; 67(24): 11933 - 11941. [Abstract] [Full Text] [PDF]

				K. Shimada, M. Nakamura, E. Ishida, T. Higuchi, M. Tanaka, I. Ota, and N. Konishi c-Jun NH2 Terminal Kinase Activation and Decreased Expression of Mitogen-Activated Protein Kinase Phosphatase-1 Play Important Roles in Invasion and Angiogenesis of Urothelial Carcinomas Am. J. Pathol., September 1, 2007; 171(3): 1003 - 1012. [Abstract] [Full Text] [PDF]