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

Abstract

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 NH 2 -terminal kinase (JNK) but not ERK and p38. Furthermore, apoptosis induced by cisplatin was significant in MKP-1 À/À MEFs, whereas such change was minimal in MKP-1 +/+ MEFs. More importantly, cisplatininduced 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)

Regulation of innate immune response by MAP kinase phosphatase-1

“…MKP-1 was found to be overexpressed in a number of human cancer tissue or cell lines [87], and to contribute to the tumorigenicity of pancreatic cancer cells [88]. Recently, Wang et al have shown that MKP-1-deficient embryonic fibroblasts more readily undergo apoptosis than wild-type cells upon exposure to cisplatin [89], a chemotherapeutic drug widely used in cancer treatment. Thus, the selective inhibition of MKP-1 expression or activity may represent a valuable strategy to overcome drug resistance and improve the efficacy of cancer chemotherapy.…”

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

“…Negative regulation of MAP kinases, including JNK, is mediated primarily by MAP kinase phosphatases (MKPs), a group of 11 dual-specificity phosphatases that dephosphorylate the regulatory threonine and tyrosine residues. 22 MKP-1 was the first of this family to be associated with cell cycle progression (G 0 to G 1 transition) and resistance to cytotoxicity by a variety of genotoxic stresses, [23][24][25] through modulating the MAP kinase activity, 26,27 which contributes to carcinogenetic processes. 28,29 However, MKP-1 may cause cellular differentiation through inhibiting ERK, a promoter of the cell cycle and growth, resulting in strong suppression of tumor development.…”

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

“…Our data argue against this possibility, as we detected similar ROSgenerating ability and expression of antioxidant enzymes in the anthracycline-sensitive and resistant AML cell lines. Aberrant expression/function of the large number of MAP3K kinases upstream to JNK (MEKK's, MLK's, DLK, ASK1/2, TAK1 and TPL2), 7 or of the downstream-negative regulators of JNK signaling (for example, MAPK-phosphatase family proteins) in resistant AML cells, 35 may also represent other mechanisms of JNK suppression in resistant AML blasts. However, it is also possible that the suppression of anthracycline-induced JNK signaling is more complex.…”