Untitled

Abstract

Recent studies have suggested that MAP kinase phosphatase 1 (MKP-1) is overexpressed in prostate cancer. To evaluate the role of MKP-1 in regulating cell death and tumor growth in prostate cancer, MKP-1 was conditionally overexpressed in the human prostate cancer cell line DU145. Overexpression of MKP-1 in DU145 cells blocked activation of stress-activated protein kinase (SAPK/JNK). MKP-1 overexpression in DU-145 cells was also found to inhibit Fas ligand (FasL)-induced apoptosis, as well as block the activation of caspases by Fas engagement. In addition, MKP-1 blocked the activation of apoptosis by transfected MEKK-1 and ASK-1, presumably through its inhibition of the SAPK/JNK family of enzymes. MKP-1 blocked the ability of FasL to induce loss of mitochondrial transmembrane potential (delta Psi(m)), suggesting that MKP-1 acts upstream of mitochondrial pro-apoptotic events induced by FasL and that the SAPK/JNK pathway may form the signaling link between Fas receptor and mitochondrial dysfunction. Thus, MKP-1 overexpression in prostate cancer may play a role in promoting prostate carcinogenesis by inhibiting FasL-induced cell death.

MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer

“…MKP1 expression has been reported to be high in different types of tumors. For example, DU145, a hormone-refractory prostate cancer cell line, shows high levels of MKP1 (MagiGalluzzi et al, 1997;Srikanth et al, 1999). Inhibition of MKP1 expression is able to sensitize DU145 cells to Fas ligand and TNF-a induced apoptosis (Srikanth et al, 1999), as well as in renal cancer cells (Mizuno et al, 2004).…”

“…For example, DU145, a hormone-refractory prostate cancer cell line, shows high levels of MKP1 (MagiGalluzzi et al, 1997;Srikanth et al, 1999). Inhibition of MKP1 expression is able to sensitize DU145 cells to Fas ligand and TNF-a induced apoptosis (Srikanth et al, 1999), as well as in renal cancer cells (Mizuno et al, 2004). Overexpression of MKP1 in primary human ovarian carcinoma correlates with shorter progressionfree survival times (Denkert et al, 2002) and, finally, increases the expression of MKP1 and MKP2 correlated with low JNK activity in breast cancer (Wang et al, 2003).…”

“…Although MKP1 levels in normal cells are low, increased levels of MKP1 have been found in human ovarian carcinoma, breast and prostate cancer (Srikanth et al, 1999;Denkert et al, 2002;Wang et al, 2003). In this report, we have investigated the expression and function of MKP1 in the chemotherapy response to cisplatin in NSCLC.…”

Transcriptional Induction of Mitogen-activated Protein Kinase Phosphatase 1 by Retinoids

“…For example, expression of MKP-1 in cancer cells is correlated with their resistance to apoptosis (57,58). Franklin et al (59) showed that exogenous, conditional expression of MKP-1 conferred resistance of leukemia cells against UV-induced apoptosis.…”

NSC-87877 Inhibits Dual-specificity Phosphatase 23 (DUSP23) that Regulates ERK

“…5 MKPs exhibit distinct substrate specificities for various mitogen-activated protein kinases (MAPKs), different tissue distribution, subcellular localization, and different modes of inducibility of their expressions by extracellular stimuli. 6,7,8,9 The three major groups of MAPK that are expressed in mammals are p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK). MAPKs are key signaling enzymes that regulate proliferation, cell survival and death, differentiation, development, immune function, gene expression, and other signaling cascades.…”