Expression of mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) in primary human ovarian carcinoma

Denkert, Carsten; Schmitt, Wolfgang; Berger, Stefan; Reles, Angela; Pest, Sören; Siegert, Antje; Lichtenegger, W.; Dietel, Manfred; Hauptmann, Steffen

doi:10.1002/ijc.10746

Cited by 98 publications

(77 citation statements)

References 18 publications

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“…V Moncho-Amor et al several malignancies, including breast, prostate and NSCLC (Loda et al, 1996;Denkert et al, 2002;Chattopadhyay et al, 2006). Lung cancer is a major cause of cancer mortality and accounts for about 20% of all cancer deaths worldwide.…”

Section: Dusp1 Participates In Tumor Progression In Nsclcmentioning

confidence: 99%

“…DUSP1 is a nuclear mitogen and stress-inducible MAP kinase phosphatase highly expressed in different types of human tumors, including non-small-cell lung cancer (NSCLC), breast, ovarian, bladder, osteosarcoma and in prostate cancer in early stages of disease (Loda et al, 1996;Denkert et al, 2002;Chattopadhyay et al, 2006). We have previously demonstrated that DUSP1 has an essential function in NSCLC biology (Chattopadhyay et al, 2006), both in tumor growth and in response to cisplatin treatment.…”

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confidence: 99%

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DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer

Moncho-Amor

Cáceres²,

Bandrés

et al. 2010

Oncogene

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DUSP1/MKP1 is a dual-specific phosphatase that regulates MAPKs activity, with an increasingly recognized role in tumor biology. To understand more about the involvement of DUSP1 in lung cancer, we performed gene expression analyses of parental and DUSP1-interfered H460 non-small-cell lung cancer (NSCLC) cells. Downregulation of DUSP1 induced changes in the expression levels of genes involved in specific biological pathways, including angiogenesis, MAP kinase phosphatase activity, cell-cell signaling, growth factor and tyrosine-kinase receptor activity. Changes in the expression of some of these genes were due to modulation of c-Jun-N-terminal kinase and/or p38 activity by DUSP1. Complementary functional assays were performed to focus on the implication of DUSP1 in angiogenesis and metastasis. In H460 cells, interference of DUSP1 resulted in a diminished capacity to invade through Matrigel, to grow tumors in nude mice and also to induce metastasis through tail-vein injection. Furthermore, the angiogenic potential of H460 cells was also impaired, correlating with a decrease in VEGFC production and indicating that DUSP1 could be required to induce angiogenesis. Finally, we studied whether a similar relationship occurred in patients. In human NSCLC specimens, DUSP1 was mainly expressed in those tumor cells close to CD31 vascular structures and a statistically significant correlation was found between VEGFC and DUSP1 expression. Overall, these results provide evidence for a role of DUSP1 in angiogenesis, invasion and metastasis in NSCLC.

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Section: Dusp1 Participates In Tumor Progression In Nsclcmentioning

confidence: 99%

mentioning

confidence: 99%

DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer

Moncho-Amor

Cáceres²,

Bandrés

et al. 2010

Oncogene

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“…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). Evidence presented recently demonstrated the MKP1 deficient MEFs are also more sensitive to apoptosis induction by anysomicin than parental cells, owing to a higher activation of JNK and p38 (Wu and Bennett, 2005).…”

Section: Mkp1 Controls Sensitivity To Cisplatin In Nsclc S Chattopadhmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 97%

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

et al. 2006

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Non-small-cell lung cancer (NSCLC) represents the most frequent and therapy-refractive sub-class of lung cancer. Improving apoptosis induction in NSCLC represents a logical way forward in treating this tumor. Cisplatin, a commonly used therapeutic agent in NSCLC, induces activation of N-terminal-c-Jun kinase (JNK) that, in turn, mediates induction of apoptosis. In analysing surgical tissue samples of NSCLC, we found that expression of MKP1/CL100, a negative regulator of JNK, showed a strong nuclear staining for tumor cells, whereas, in normal bronchial epithelia, MKP1 was localized in the cytoplasm as well as in nuclei. In the NSCLC-derived cell lines H-460 and H-23, we found that MKP1 was constitutively expressed. Expressing a small-interfering RNA (siRNA) vector for MKP1 in H-460 cells resulted in a more efficient activation by cisplatin of JNK and p38 than in the parental cells, and this correlated with a 10-fold increase in sensitivity to cisplatin. A similar response was also observed in H-460 and H-23 cells when treated with the MKP1 expression inhibitor RO-31-8220. Moreover, expression of a siRNA-MKP2, an MKP1-related phosphatase, had no effect on H-460 cell viability response to cisplatin. Tumors induced by H-460 cells expressing MKP1 siRNA grew slower in nu À /nu À mice and showed more susceptibility to cisplatin than parental cells, and resulted in an impaired growth of the tumor in mice. On the other hand, overexpression of MKP1 in the H-1299 NSCLC-derived cell line resulted in further resistance to cisplatin. Overall, the results showed that inhibition of MKP1 expression contributes to a slow down in cell growth in mice and an increase of cisplatin-induced cell death in NSCLC. As such, MKP1 can be an attractive target in sensitizing cells to cisplatin to increase the effectiveness of the drug in treating NSCLC.

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“…For example, high levels of MKP-1 have been found in prostate (4), gastric (5), breast (6), and pancreatic cancer (7). In ovarian cancer samples, MKP-1 expression was correlated with decreased progression-free survival (8). High levels of MKP-1 expression were also found in the early phases of prostate, colon, and bladder carcinogenesis (9).…”

Section: Mitogen-activated Protein Kinase Phosphatase (Mkp)mentioning

confidence: 99%

The Benzo[c]phenanthridine Alkaloid, Sanguinarine, Is a Selective, Cell-active Inhibitor of Mitogen-activated Protein Kinase Phosphatase-1

Vogt

Tamewitz

Skoko

et al. 2005

Journal of Biological Chemistry

174

117

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Mitogen-activated protein kinase phosphatase (MKP)1 -1 is a dual specificity phosphatase that is overexpressed in many human tumors and protects cells from apoptosis by the anticancer agent cisplatin (1), UV irradiation (2), and proteasome inhibitors (3). Over the past five years, reports have become more numerous describing high levels of MKP-1 in human tumors. For example, high levels of MKP-1 have been found in prostate (4), gastric (5), breast (6), and pancreatic cancer (7). In ovarian cancer samples, MKP-1 expression was correlated with decreased progression-free survival (8). High levels of MKP-1 expression were also found in the early phases of prostate, colon, and bladder carcinogenesis (9). Evidence that MKP-1 may actually support the transformed phenotype comes from a recent study by Liao et al. (7) who showed that PANC-1 human pancreatic cancer cells stably transfected with a full-length MKP-1 antisense construct had longer doubling times, decreased ability to form colonies in soft agar, and were unable to form tumors in nude mice. The precise mechanism by which loss of MKP-1 expression affects tumorigenicity, however, remains elusive. Several reports have implicated JNK/SAPK and p38 as the primary mediators of MKP-1 mediated cytoprotection (1-2). On the other hand, the data presented by Liao et al. (7) argue that the primary mechanism by which MKP-1 supports the transformed phenotype is mediated by ERK, but not JNK, as suppression of MKP-1 expression by antisense did not affect basal levels of phospho-JNK or phospho-p38, but instead increased basal ERK phosphorylation and prolonged ERK phosphorylation after epidermal growth factor stimulation in PANC-1 cells.The availability of a cell-active selective MKP-1 inhibitor would be a valuable tool for dissecting the complex regulatory processes involved in the attenuation of ERK, JNK, and p38 activation and for defining the contributions of MKP-1 and its cellular targets to the maintenance of the transformed phenotype. In light of recent findings, inhibitors of MKP-1 might also find applications as novel target-based antineoplastic therapies, either alone or in combination with clinically used antineoplastic agents (1-3).The search for MKP-1 inhibitors has been challenging for several reasons. In contrast to MKP-3, whose crystal structure has been reported and found to possess high structural similarity to the related VHR in its catalytic domain (10), no structural information is available for MKP-1. This may in part be due to difficulties in producing large amounts of recombinant enzyme and the need of MKPs to interact with their physiolog-

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Expression of mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) in primary human ovarian carcinoma

Cited by 98 publications

References 18 publications

DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer

DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer

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

The Benzo[c]phenanthridine Alkaloid, Sanguinarine, Is a Selective, Cell-active Inhibitor of Mitogen-activated Protein Kinase Phosphatase-1

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