Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FADD has been shown to be phosphorylated at Ser194 at the G2/M transition of the cell cycle. Here we have investigated the contribution of this phosphorylation to apoptosis induced by anticancer drugs in two human prostate cancer cell lines, LNCaP and DU145. Both were arrested at G2/M and FADD was found to be phosphorylated at Ser194 on treatment with paclitaxel. Inhibition of paclitaxel-induced c-jun NH2-terminal kinase (JNK) activation by treatment with a specific inhibitor, SP600125, or overexpression of a dominant-negative mutant form of upstream kinases, MEK kinase 1 (MEKK1) and mitogen-activated protein kinase kinase (MKK) 7, significantly reduced the increase in phosphorylated FADD. It is noteworthy that pretreatment with paclitaxel significantly up-regulated MEKK1 expression, resulting in enhancement of etoposide- or cisplatin-induced MEKK1/MKK7-dependent JNK activation and apoptosis in LNCaP and DU145 cells. Interestingly, MEKK1 up-regulation and the synergistic effects of paclitaxel on anticancer drug-induced apoptosis were abolished by overexpression of mutant FADD (Ser194-->Ala). The results clearly show that FADD phosphorylation at Ser194 affects functions both upstream and downstream of the MEKK1/MKK7/JNK1 pathway and is closely associated with chemosensitivity in prostate cancer cells. This is the first report indicating that phosphorylated FADD plays an essential role in the mechanisms of amplifications of chemotherapy-induced apoptosis.
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PMID:Phosphorylation of FADD is critical for sensitivity to anticancer drug-induced apoptosis. 1500 34

Clinical studies have shown that tumor hypoxia is associated with invasive growth and metastasis and may be an important prognostic factor adversely influencing survival in patients with tumors. To investigate the mechanisms involved in hypoxia-induced invasive growth and metastasis, hypoxia-mediated urokinase plasmalogen activator receptor (uPAR) expression, cellular invasiveness, and mitogen activated protein kinase (MAPK) activation were measured in a prostate cancer cell line, PC3MLN4. The levels of uPAR expression and cellular invasiveness were increased in hypoxic cells. Hypoxia-induced cellular invasiveness was blocked by an anti-uPAR monoclonal antibody. Phosphorylations of ERK and p38 kinases were also more extensive in hypoxic cells than in normoxic cells. Hypoxia-induced uPAR up-regulation was inhibited by pre-treatments with a specific inhibitor of MEK, PD98059 and a specific inhibitor of p38 MAP kinase, SB203580. Cell growth also increased in hypoxic cells. From these results, hypoxia increased tumor cell invasion by up-regulating uPAR expression, which might be mediated through ERK and p38 kinase signaling pathways in PC3MLN4 prostate cancer cell line.
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PMID:Involvement of MAPK pathway in hypoxia-induced up-regulation of urokinase plasminogen activator receptor in a human prostatic cancer cell line, PC3MLN4. 1503 72

Vasoactive intestinal peptide (VIP) upregulates the expression of vascular endothelial cell growth factor (VEGF(189), VEGF(165) and VEGF(121)) mRNAs in human prostate cancer LNCaP cells, as shown by reverse transcriptase-polymerase chain reaction (RT-PCR). Real-time RT-PCR indicated that the effect was maximal by 1-2 h and must be accounted for increased transcription since VIP decreased VEGF(165) mRNA stability. VIP stimulated VEGF(165) protein synthesis as measured by ELISA. VIP regulation of VEGF expression was mediated by VPAC(1) receptor and was cAMP/protein kinase A (PKA) dependent. Phosphoinositide 3-kinase (PI3-K) and mitogen-activated protein kinase MEK1/2 systems may also be involved as shown with specific kinase inhibitors. These actions together with the observation of VIP-induced neuroendocrine differentiation in LNCaP cells suggest a proangiogenic potential of VIP in prostate cancer.
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PMID:Vasoactive intestinal peptide increases vascular endothelial growth factor expression and neuroendocrine differentiation in human prostate cancer LNCaP cells. 1509 99

Defining the mechanisms that confer metastatic ability on cancer cells is an important goal towards prevention of metastasis. A gene array screen between a non-metastatic prostate cancer cell and its metastatic derivative line revealed decreased expression of Raf kinase inhibitor protein (RKIP) in the metastatic cell line. This finding is consistent with the possibility that loss of RKIP is associated with metastasis. RKIP is expressed in many tissues including brain, lung, and liver. RKIP blocks Raf-induced phosphorylation of MEK. In addition to its modulation of Raf signaling, RKIP modulates both G-protein signaling and NF-kappaB activity. The impact that RKIP has on multiple signaling pathways grants it the ability to play a role in several cellular functions including membrane biosynthesis, spermatogenesis, and neural signaling. Novel cellular functions for RKIP continue to be identified, several of which contribute to cancer biology. For example, RKIP promotes apoptosis of cancer cells, which suggests that loss of RKIP in cancer will protect cancer cells against cell death. Additionally, restoration of RKIP expression ina metastatic prostate cancer cell line does not effect primary tumor growth, but it does inhibit prostate cancer metastasis. These parameters identify RKIP as a metastasis suppressor gene, which suggest that it or proteins it interacts with are putative molecular targets to control metastasis. These findings are supported by the observation that RKIP expression is decreased in metastases of prostate cancer patients, compared to normal prostate or the primary prostate tumor. In this review, RKIP biology and its role in cancer will be described.
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PMID:Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. 1515 Nov 33

Benign prostate hyperplasia and prostate cancer are major public health problems. We report herein that daily treatment of male rats with 50, 100 or 150 mg quercetin per kg body weight resulted in serum concentrations of quercetin equivalent to 25.3 microM, 43.3 microM and 54.3 microM respectively. Concomitantly, serum testosterone levels were increased by 1.79-, 1.83- and 3.48-fold, while serum dihydrotestosterone (DHT) levels were 125%, 92% and 73% of the control. A slight increase in prostate weight coupled with dilated prostate lumens full of secretory materials were observed. Finasteride alone caused a significant decrease in serum DHT level and prostate weight. Co-administration of quercetin with finasteride prevented the finasteride-induced decrease in serum DHT levels but significantly enhanced the reduction in wet prostate weight, which was reduced by 26.9% in finasteride-treated animals to 31.8%, 40.0% and 48.2% after finasteride given together with the three doses of quercetin. The combined treatment altered cell cycle-regulated proteins in a wide spectrum. The expressions of cyclin D1, CDK-4, cdc-2 and phospho-cdc-2 at tyrosine 15, phospho-MEK1/2, phospho-MAP kinase, phospho-pRb at serine 780 and serine 807/811 were significantly inhibited, while the levels of p15, p21 and p27 were increased. In conclusion, quercetin-finasteride treatments caused wide cell cycle deregulation in rat prostates, which, in turn, decreased the proliferation rate, changed the secretion activities of epithelial cells and resulted in a marked reduction in wet prostate weight. The results suggest that quercetin synergizes with finasteride to reduce the wet prostate weight through a cell cycle-related pathway, which may be androgen independent.
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PMID:Reduction of rat prostate weight by combined quercetin-finasteride treatment is associated with cell cycle deregulation. 1571 25

The mechanism by which neurotensin (NT) promotes the growth of prostate cancer epithelial cells is not yet defined. Here, androgen-independent PC3 cells, which express high levels of the type 1 NT-receptor (NTR1), are used to examine the involvement of epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (ERK, SAPK/JNK and p38), PI3 kinase and PKC in the mitogenic effect of NT. NT dose dependently (0.1-30 nM) enhanced phosphorylation of EGFR, ERK and Akt, reaching maximal levels within 3 min as measured by Western blotting. These effects were associated with an accumulation of EGF-like substance(s) in the medium (assayed by EGFR binding) and a 2-fold increase in DNA synthesis (assayed by [3H]thymidine incorporation). The DNA synthesis enhancement by NT was non-additive with that of EGF. The NT-induced stimulation of EGFR/ERK/Akt phosphorylation and DNA synthesis was inhibited by EGFR-tyrosine kinase inhibitors (AG1478, PD153035), metallo-endopeptidase inhibitor phosphoramidon and by heparin, but not by neutralizing anti-EGF antibody. Thus, transactivation of EGFR by NT involved heparin-binding EGF (HB-EGF or amphiregulin) rather than EGF. The effects of NT on EGFR/ERK/Akt activation and DNA synthesis were attenuated by PLC-inhibitor (U73122), PKC-inhibitors (bisindolylmaleimide, staurosporine, rottlerin), MEK inhibitor (U0126) and PI3 kinase inhibitors (wortmannin, LY 294002). We conclude that NT stimulated mitogenesis in PC3 cells by a PKC-dependent ligand-mediated transactivation of EGFR, which led to stimulation of the Raf-MEK-ERK pathway in a PI3 kinase-dependent manner.
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PMID:Involvement of MAP-kinase, PI3-kinase and EGF-receptor in the stimulatory effect of Neurotensin on DNA synthesis in PC3 cells. 1517 34

The metastatic cascade is a complicated process that involves many steps from gain of the metastatic phenotype in the primary tumor cells through establishment of macroscopic tumor at the distant target organ. A group of genes, termed metastasis suppressor genes (MSG), encode for proteins that inhibit various steps of the metastatic cascade. Accordingly, loss of MSG promotes the metastatic phenotype. Although several MSG have been identified, the mechanisms through which they enhance metastasis are not clearly defined. Gene array analysis of a low metastatic LNCaP prostate cancer cell line compared to its highly metastatic derivative C4-2B prostate cancer cell line revealed decreased expression of raf kinase inhibitor protein (RKIP) in the C4-2B cell line. RKIP blocks the activation of several signaling pathways including MEK, G-proteins and NFkappaB. Immunohistochemical analysis of prostate cancer primary tumors and metastases revealed that RKIP protein expression was decreased in metastases. Restoration of RKIP expression in the C4-2B cell line diminished metastasis in a murine model. These results demonstrate that RKIP is a MSG. Loss of RKIP enhanced both angiogenesis and vascular invasion, and protected against apoptosis. These findings suggest that targeting the RKIP pathway may diminish the metastatic cascade. However, challenges exist as to the best method to target RKIP expression. Restoration of RKIP expression in all cancer cells in vivo is challenging. A plausible strategy is to use small molecules that target proteins in signaling pathways that are dysregulated due to loss of RKIP.
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PMID:Metastasis suppressor genes: a role for raf kinase inhibitor protein (RKIP). 1526 97

Raf kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding protein (PEBP) family. RKIP plays a pivotal modulatory role in several protein kinase signaling cascades. RKIP binds inhibits Raf-1-mediated phosphorylation of MEK through binding to Raf-1. Protein kinase C (PKC) phosphorylates RKIP, resulting in release of Raf-1 and activation of MEK and ERK. The phosphorylated RKIP binds to and inhibits G-protein-coupled receptor kinase, resulting in sustained G-protein signaling. The regulatory role that RKIP has in cell signaling is reflected in its role in physiology and pathophysiology. RKIP is involved in neural development, cardiac function and spermatogenesis and appears to have serine protease activity. In addition to its roles in physiology, dysregulated RKIP expression has the potential to contribute to pathophysiological processes including Alzheimer's disease and diabetic nephropathy. RKIP has been shown to fit the criteria of being a metastasis suppressor gene, including having decreased expression in prostate cancer metastases and restoring RKIP expression in a prostate cancer cell line diminishes metastasis in a murine model. Clearly, RKIP has multiple molecular and cellular functions. In this review, RKIP's molecular roles in intracellular signaling, its physiological functions and its role in disease are described.
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PMID:The role of Raf kinase inhibitor protein (RKIP) in health and disease. 1531

A cure for prostate cancer (CaP) will be possible only after a complete understanding of the mechanisms causing this disease to progress from androgen dependence to androgen independence. To carry on a careful characterization of the phenotypes of CaP cell lines before and after acquisition of androgen independence, we used two human CaP LNCaP sublines: LNCaP(nan), which is androgen dependent (AD), and LNCaP-HP, which is androgen independent (AI). In AD LNCaP(nan) cells, dihydrotestosterone (DHT) stimulated in an androgen receptor (AR)-dependent way a phosphorylation signaling pathway involving steroid receptor coactivator (Src)-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)-1/2-ERK-1/2-cAMP-response element binding-protein (CREB). Activation of this pathway was associated with increased [(3)H]thymidine incorporation and resistance to apoptosis. Use of dominant-negative forms of MEK-1/2 and CREB demonstrated in LNCaP(nan) cells that DHT induced [(3)H]thymidiine incorporation through a thus far unidentified molecule activated downstream of MEK-1/2, and antiapoptosis through phosphorylation of the transcription factor CREB. In contrast, in AI LNCaP-HP cells, the Src-MEK-1/2-ERK-1/2-CREB pathway was constitutively active. Because it was not further stimulated by addition of DHT, no increase of [(3)H]thymidine incorporation or apoptosis resistance was demonstrated in LNCaP-HP cells. Additional experiments showed that Src and the scaffold protein MNAR coimmunoprecipitated with AR, indicating a role for Src as an apical molecule in the Src-MEK-1/2-ERK-1/2-CREB pathway. Interestingly, differences between the two cell lines were that in LNCaP-HP cells presence of an AI phenotype and lack of response to DHT were associated with constitutive activation of the protein kinase Src and interaction among Src, AR, and MNAR. In contrast, in LNCaP(nan) cells, presence of an AD phenotype and ability to respond to DHT were associated with DHT-dependent activation of Src kinase activity and interaction among Src, AR, and MNAR. Intriguingly, in LNCaP(nan) cells, we found that transcription through the prototypical CREB-responsive promoter c-fos could be induced in a DHT-dependent way, and this action was inhibited by the AR antagonist Casodex and MEK-1 inhibitor PD98059. In contrast, transcription through the PSA P/E promoter, a prototypical AR-dependent promoter directly activated by agonist, was obliterated only by Casodex. Additional experiments with genital skin fibroblasts derived from patients with a variety of AR abnormalities indicated that nongenotropic AR signaling does not depend on an intact DNA-binding domain or on the ability of AR to translocate to the nucleus. The results suggest the following: (1) Constitutive activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is associated with the AI phenotype observed in LNCaP-HP cells. (2) Activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is DHT dependent in AD LNCaP(nan) cells. (3) DHT activation of this pathway is associated with induction of [(3)H]thymidine incorporation by a molecule activated downstream of MEK-1/2 and of antiapoptosis through activation of the transcription factor CREB in AD LNCaP(nan) cells. (4) AR regulates transcription either directly upon ligand binding and nuclear translocation or indirectly through kinase pathways leading to activation of downstream transcription factors. (5) Nuclear translocation and ability of the DNA-binding domain of AR to interact with DNA are not prerequisites for nongenotropic AR activity.
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PMID:Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. 1546 14

The G protein-coupled P2Y purinoceptors have wide physiological functions, but their role(s) in tumor progression remain unclear. Here, we report that stimulation of P2Y receptors enhances prostate cancer cell invasion in two human prostate carcinoma cell lines, which is mediated by ERK1/2 and p38 signaling pathways. P2Y agonists stimulated prostate cancer cell invasion, and increased the activities of ERK1/2 and p38 protein kinases. The stimulated cancer cell invasion was inhibited by the presence of MEK1 inhibitor PD98059 or p38 inhibitor SB203580. Expression of dominant-negative mutant of MEK1 (KA-MEK1), or up-regulation of MKP-5 (a dual-specificity phosphatase of p38), both reduced the invasion of cultured prostate cancer cells. These results suggest that P2Y receptors and their down-stream ERK1/2 and p38 protein kinases are important regulators promoting prostate cancer invasion.
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PMID:ERK1/2 and p38 pathways are required for P2Y receptor-mediated prostate cancer invasion. 1548 43


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