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)

As transmembrane heterodimers, integrins bind to both extracellular ligands and intracellular proteins. We are currently investigating the interaction between integrins and the intracellular protein calreticulin. A prostatic carcinoma cell line (PC-3) was used to demonstrate that calreticulin can be found in the alpha3 immunoprecipitates of cells plated on collagen type IV, but not when plated on vitronectin. Conversely, alphav immunoprecipitates contained calreticulin only when cells were plated on vitronectin, i. e. not when plated on collagen IV. The interactions between these integrins and calreticulin were independent of actin cytoskeleton assembly and were transient, being maximal approx. 10-30 min after the cells came into contact with the substrates prior to complete cell spreading and formation of firm adhesive contacts. We demonstrate that okadaic acid, an inhibitor of intracellular serine/threonine protein phosphatases, inhibited the alpha3beta1-mediated adhesion of PC-3 cells to collagen IV and the alpha2beta1-mediated attachment of Jurkat cells to collagen I. This inhibition by okadaic acid was accompanied by inhibition of the ligand-specific interaction of calreticulin with the respective integrins in the two cell types. Additionally, we found that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) resulted in prolongation of the calreticulin-integrin interaction, and enhancement of PC-3 cell attachment to collagen IV. We conclude that calreticulin interacts transiently with integrins during cell attachment and spreading. This interaction depends on receptor occupation, is ligand-specific, and can be modulated by protein phosphatase and MEK activity.
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PMID:Ligand-specific, transient interaction between integrins and calreticulin during cell adhesion to extracellular matrix proteins is dependent upon phosphorylation/dephosphorylation events. 1022 57

Calcitriol or 1,25-dihydroxycholecalciferol (vitamin D) is classically known for its effects on bone and mineral metabolism. Epidemiological data suggest that low vitamin D levels increase the risk and mortality from prostate cancer. Calcitriol is also a potent anti-proliferative agent in a wide variety of malignant cell types including prostate cancer cells. In prostate model systems (PC-3, LNCaP, DU145, MLL) calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol's effects are associated with an increase in cell cycle arrest, apoptosis, differentiation and in the modulation of growth factor receptors. Calcitriol induces a significant G0/G1 arrest and modulates p21(Waf/Cip1) and p27(Kip1), the cyclin dependent kinase inhibitors. Calcitriol induces PARP cleavage, increases the bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs, P-Erk-1/2) and phosphorylated Akt (P-Akt), induces caspase-dependent MEK cleavage and up-regulation of MEKK-1, all potential markers of the apoptotic pathway. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In combination with calcitriol, dexamethasone results in a significant time- and dose-dependent increase in VDR protein and an enhanced apoptotic response as compared to calcitriol alone. Calcitriol can also significantly increase cytotoxic drug-mediated anti-tumor efficacy. As a result, phase I and II trials of calcitriol either alone or in combination with the carboplatin, paclitaxel, or dexamethasone have been initiated in patients with androgen-dependent and -independent prostate cancer and advanced cancer. Patients were evaluated for toxicity, maximum tolerated dose (MTD), schedule effects, and PSA response. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the MTD is still being delineated and dexamethasone or paclitaxel appear to ameliorate toxicity. Studies continue to define the MTD of calcitriol whichcan be safely administered on this intermittent schedule either alone or with other agents and to evaluate the mechanisms of calcitriol effects in prostate cancer.
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PMID:Vitamin D-related therapies in prostate cancer. 1246 54

The helix-loop-helix protein Id-1 has been suggested to play a positive role in cell proliferation and tumorigenesis of many types of human cancers. However, little is known about the molecular mechanism involved in the function of Id-1. In this study, using four stable Id-1 transfectant clones, we investigated the involvement of MAPK signaling pathway in the Id-1 induced serum independent prostate cancer cell growth. Our results demonstrated that both transient and stable ectopic Id-1 expression in prostate cancer LNCaP cells led to activation of the Raf/MEK1/2 signaling pathway. In addition, inhibition of MEK1/2 phosphorylation by one of its inhibitors, PD098059, resulted in the decreased cell cycle S phase fraction and cell growth rate, suggesting that activation of MAPK signaling pathway is essential for Id-1 induced prostate cancer cell proliferation. Furthermore, treatment with antisense oligonucleotide complementary to Id-1 mRNA in PC-3 and DU145 cells resulted in a decreased Id-1 expression which was accompanied by decreased Egr-1 protein. Our results suggest for the first time that the function of Id-1 is associated with MAPK signaling pathway activation and indicate a possible novel mechanism in which Id-1 regulates prostate cancer cell growth and tumorigenesis.
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PMID:Activation of MAPK signaling pathway is essential for Id-1 induced serum independent prostate cancer cell growth. 1246 69

Nucleated cells employ several strategies to evade killing by homologous complement. We studied complement resistance in the human carcinoma cell lines (CA) T47D (mammary), SKOV3 (ovarian), and PC-3 (prostate) with emphasis on the following mechanisms of defense: 1. Expression and shedding of the membrane complement regulatory proteins (mCRP) CD46, CD55 and CD59; 2. Resistance based on protein phosphorylation; 3. Cell surface expression of sialic acid residues; 4. Desensitization to complement upon exposure to sublytic complement doses. Anti-mCRP antibody blocking experiments demonstrated that CD59 is the main mCRP protecting these CA from complement. Soluble CD59 was also found in supernates of PC-3> SKOV3 > T47D cells. Second, inhibitors of PKC, PKA and MEK sensitized the CA to lysis, thus implicating these protein kinases in CA complement resistance. Third, removal of sialic acid residues with neuraminidase also sensitized CA to lysis. Finally, exposure of CA to sublytic doses of complement conferred on them enhanced resistance to lytic complement doses in a PKC-dependent process. Combined treatment of CA with anti-CD59 antibodies, PD98059 (a MEK inhibitor) and neuraminidase produced a large enhancement in CA sensitivity to complement. Our results show that CD59 and sialic acid residues present on the cell surface, and intracellular processes involving protein phosphorylation act additively to secure CA resistance to complement-mediated lysis. Therefore, the effectiveness of antibody- and complement-based cancer immunotherapy will markedly improve by suppression of the various complement resistance mechanisms.
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PMID:Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid. 1256 85

Because ErbB-2 receptor is involved in hormone-independency for growth and metastasis of prostate cancer cells, the aim was to investigate the effects of quercetin on ErbB-2 and ErbB-3 expression and its critical components such as MAP kinase and PI-3 kinase. Hemocytometric counts and [3H]-thymidine incorporation were used to determine the effects of quercetin, EGF and TGF-alpha on cell proliferation and DNA synthesis in PC-3 and LnCap cells. Changes in ErbB-2, ErbB-3 and components of MAPK and PI-3K pathways were analyzed by Western blot analysis. Treatment of PC-3 and LnCap cells with quercetin resulted in a dose-dependent growth inhibition. The rate of DNA synthesis was decreased by 40, 55 and 65% on treatment with 14.5, 29.0 and 58.0 microM of quercetin, respectively. Concomitantly, these treatments led to a dose-dependent decrease in ErbB-2, ErbB-3 and their basal autophosphorylation levels as compared to controls. Cyclin D1 expression and basal phosphorylation of c-Raf, MAPK, Elk-1 and Akt-1 in PC-3 cells was also inhibited by quercetin treatment. Co-treating PC-3 cells with quercetin significantly attenuated EGF- and TGF-alpha-induced growth and phosphorylation of ErbB-2, ErbB-3, c-Raf, MAPK kinase 1/2 (MEK1/2), MAPK, Elk-1 and Akt-1. Since ErbB receptor is important for growth, metastasis and drug resistance, inhibition of ErbB-2 and ErbB-3 by pharmacological doses of quercetin may provide a new approach for treatment of prostate cancers.
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PMID:Inhibition of ErbB-2 and ErbB-3 expression by quercetin prevents transforming growth factor alpha (TGF-alpha)- and epidermal growth factor (EGF)-induced human PC-3 prostate cancer cell proliferation. 1288 23

25-Hydroxyvitamin D-1alpha-hydroxylase (lalpha-OHase) is expressed in prostate cells. The expression suggests that local production of 1,25-dihydroxyvitamin D could provide an important cell growth regulatory mechanism. However, there is differential expression of 1alpha-OHase activity among the primary cultures of prostate cells derived from cancerous, benign prostatic hypertrophy and normal tissue, and among noncancerous (PZHPV-7) and various cancer cell lines (PC-3, DU145). No activity was found in cancer cell line LNCaP. The observed marked decrease in 1alpha-OHase activity in prostate cancer cells suggests some defect of the 1alpha-OHase in these cells. Using luciferase reporter gene assay, we observed a step-wise decrease in the basal promoter activity in two truncated promoter fragments, AN2 (-1,100 bp) and AN5 (-394 bp), with the highest basal activities found in PZHPV-7 and with loss of promoter activity in LNCaP. In order to understand the mechanism underlying the differential promoter activities among different prostate cells, we investigated the possible role of phosphorylation of cyclic AMP response element binding protein (CREB) on the regulation of 1alpha-OHase promoter activity in the four prostate cell lines. First we compared the levels of CREB phosphorylation among PZHPV-7, DU145, PC-3 and LNCaP cells by Western blot analysis using antibody against phosphorylated CREB. We observed that CREB was phosphorylated to a greater extent in PZHPV-7 than in DU145 cells. No significant phosphorylation of CREB was found in PC-3 and LNCaP cells. Next, we utilized activators and inhibitors of protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase kinase (MAPKK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to determine which kinases might be involved in phosphorylating the CREB in PZHPV-7 cells. We demonstrated that forskolin (an activator of PKA) increased the AN2 basal promoter activity 50%, whereas H-89 (an inhibitor of PKA) inhibited the basal and forskolin-stimulated AN2 promoter activity 40% and 70%, respectively. We also showed that PD98059 (an inhibitor of MAPKK) decreased the AN2 promoter activity 70%. Phorbol 12-myristate 13-acetate (an activator of PKC), GF109203 (an inhibitor of PKC) and KN-93 (an inhibitor of CaMKII) had no effect on AN2 promoter activity in PZHPV-7 cells. Thus, our results suggest that differential phosphorylation of CREB through PKA and MAPK pathways may be involved in the regulation of 1alpha-OHase promoter activity.
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PMID:Vitamin D autocrine system and prostate cancer. 1289 25

Taxol (paclitaxel) and Taxotere (docetaxel) are considered as two of the most important anti-cancer chemotherapy drugs. The cytotoxic action of these drugs has been linked to their ability to inhibit microtubule depolymerization, causing growth arrest and subsequent cell death. Studies by a number of laboratories have also linked suppression of mitogen activated protein kinase (MAPK) signaling to enhanced Taxol toxicity. The present study examined the interactions of the semi-synthetic taxane Taxotere with MEK1/2 inhibitors in epithelial tumor cells. Concurrent treatment of MDA-MB-231 mammary and DU145 prostate carcinoma cells with Taxotere and MEK1/2 inhibitor resulted in protection from the anti-proliferative effects of Taxotere in MTT assays. In contrast, in MCF-7 mammary cells, concurrent Taxotere and MEK1/2 inhibitor treatment weakly enhanced the anti-proliferative effects of the taxane. Sequential treatment of MDA-MB-231 and MCF-7 cells with Taxotere followed by MEK1/2 inhibitor also enhanced the anti-proliferative effects of the taxane in MTT assays. However, no enhancement was observed in DU145 or PC-3 cells. Colony formation assays, including isobologram analyses, provided a more definitive demonstration that MCF-7 and MDA-MB-231 cells were sensitized to the toxic effects of Taxotere by U0126. Similar data were observed using Laulimalide, which binds to tubulin at a different site to Taxotere. The enhancement in Taxotere anti-proliferative effects by U0126 correlated with increased cell killing, 48-72h after treatment of cells that was blocked by inhibition of caspase 9, but not caspase 8, function. This observation was associated with prolonged suppression of ERK1/2 and AKT activity, without alteration in either p38 or JNK1/2 activity. Collectively these findings demonstrate that sequential administration of Taxotere followed by MEK1/2 inhibition can lead to increased cell death and loss of reproductive capacity in some, but not all, human tumor cells.
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PMID:Sequence dependent exposure of mammary carcinoma cells to Taxotere and the MEK1/2 inhibitor U0126 causes enhanced cell killing in vitro. 1468 75

Accumulating data suggest that local production of 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)(2)D) could provide an important cell growth regulatory mechanism in an autocrine fashion in prostate cells. Previously, we demonstrated a differential expression of 1alpha-OHase enzymatic activity among noncancerous (PZHPV-7) and cancer cells (PC-3, DU145, LNCaP), which appears to correlate with 1alpha-OHase m-RNA synthesis and its promoter activities. Since it is well-established that EGF regulates the proliferation of prostate cells via autocrine and paracrine loops and 1alpha,25(OH)(2)D inhibites prostate cell proliferation, we investigated if EGF also regulated 1alpha-OHase expression in prostate cells. We found that EGF upregulated 1alpha-OHase promoter activity and enzyme activity in PZ-HPV-7 and that 1alpha,25(OH)(2)D(3) inhibited EGF-dependent up-regulation of 1alpha-OHase enzymatic activity. Moreover, the EGF-stimulated promoter activity was inhibited 70% by the MAPKK inhibitor, PD98059, suggesting that the MAPK pathway may be one pathway involved in the regulation of prostatic 1alpha-OHase by EGF to increase1alpha,25(OH)(2)D synthesis as a feedback regulator of cell growth. Because EGF has no effect on 1alpha-OHase promoter activity in LNCaP cells, we propose that the ability of EGF to stimulate 1alpha,25(OH)(2)D synthesis may be abolished or diminished in cancer cells.
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PMID:Regulation of 25-hydroxyvitamin D-1alpha-hydroxylase by epidermal growth factor in prostate cells. 1522 59

Axl is a tyrosine kinase receptor and although it is expressed in malignancy such as leukemia, colon cancer, melanoma, endometrial, prostate and thyroid cancers, its role has not been completely elucidated yet and appears to be complex. The ligand of Axl, Gas6, is a 75 KDa multimodular protein with an N-terminal gamma-carboxy-glutamic acid that is essential for binding. Gas6 has a mitogenic effect on several normal cell lines. The receptor Axl is expressed in primary prostate carcinoma and in prostate cancer cell lines as such as PC-3 and DU 145. We demonstrated a mitogenic activity determined by Gas6/Axl interaction in these undifferentiated metastatic human prostatic cancer cell lines. This effect is proportional to Axl expression, not due to inhibition of apoptosis, and induces AKT and MAPK phosphorylation. However, only MEK phosphorylation seems to be essential for growth signaling. Our results suggest that Axl overexpression and activation by Gas6 could be involved in progression of prostate neoplastic disease.
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PMID:Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. 1560 94

In this study, we show that androgens up-regulate insulin-like growth factor-I receptor (IGF-IR) expression and sensitize prostate cancer cells to the biological effects of IGF-I. Both dihydrotestosterone and the synthetic androgen R1881 induced an approximately 6-fold increase in IGF-IR expression in androgen receptor (AR)-positive prostate cancer cells LNCaP. In accordance with IGF-IR up-regulation, treatment with the nonmetabolizable androgen R1881 sensitized LNCaP cells to the mitogenic and motogenic effects of IGF-I, whereas an IGF-IR blocking antibody effectively inhibited these effects. By contrast, these androgens did not affect IGF-IR expression in AR-negative prostate cancer cells PC-3. Reintroduction of AR into PC-3 cells by stable transfection restored the androgen effect on IGF-IR up-regulation. R1881-induced IGF-IR up-regulation was partially inhibited by the AR antagonist Casodex (bicalutamide). Two other AR antagonists, cyproterone acetate and OH-flutamide, were much less effective. Androgen-induced IGF-IR up-regulation was not dependent on AR genomic activity, because two AR mutants, AR-C619Y and AR-C574R, devoid of DNA binding activity and transcriptional activity were still able to elicit IGF-IR up-regulation in HEK293 kidney cells in response to androgens. Moreover, androgen-induced IGF-IR up-regulation involves the activation of the Src-extracellular signal-regulated kinase pathway, because it was inhibited by both the Src inhibitor PP2 and the MEK-1 inhibitor PD98059. The present observations strongly suggest that AR activation may stimulate prostate cancer progression through the altered IGF-IR expression and IGF action. Anti-androgen therapy may be only partially effective, or almost ineffective, in blocking important biological effects of androgens, such as activation of the IGF system.
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PMID:Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. 1575 83


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