Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, also called statins, are commonly used as lipid-lowering drugs that inhibit cholesterol biosynthesis. An anticancer effect, as a pleiotropic function of certain statins, has been hypothesized. In the present study, we investigated the effect of simvastatin, one of the natural statins, on cell proliferation, cell cycle, invasive activity, and molecular expressions associated with cell-extracellular matrix adhesion, signal transduction, and DNA synthesis in Tu167 and JMAR cells from head and neck squamous cell carcinoma. The addition of simvastatin resulted in a dose-dependent inhibition of cell growth and migration into the extracellular matrix. Considerable morphological changes occurred after treatment with simvastatin, demonstrating loss of cell adhesion and disruption of actin filaments in cytoplasm. The inhibitory effect of simvastatin on cell proliferation seemed to be associated with cell cycle arrest and increased expression of p21, p27, and activated caspase-3. The expression of beta1-integrin, a counter adhesion for the extracellular matrix, phosphorylated FAK, and phosphorylated ERK was decreased by treatment with simvastatin. The proapoptotic effect of simvastatin was inhibited by treatment with mevalonate. cDNA microarray assay demonstrated that molecular changes resulting from treatment with simvastatin included the up-regulation of cell cycle regulators and apoptosis-inducing factors and the down-regulation of integrin-associated molecules and cell proliferation markers. Of down-regulated genes induced by simvastatin treatment, a significant depletion of thymidylate synthase was confirmed using western blot analysis. These results imply that simvastatin has the potential to be effective for the prevention of the growth and metastasis of cancer cells.
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PMID:Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. 1742 61

The mat2,3-region of Schizosaccharomyces pombe is flanked by two inverted repeat elements, IRL and IRR, which define the boundaries of the silent domain resulting from heterochromatin assembly in the region. We employed a genetic screen to isolate factors whose mutations allowed spreading of heterochromatin across boundary elements. Surprisingly, this screen revealed that mutations in the genes required for deoxyribonucleotide biosynthesis, cdc22 (encoding the large subunit of ribonucleotide reductase) and tds1 (putative thymidylate synthase), cause silencing of marker genes inserted outside of the silent domain. Chromatin-immunoprecipitation analysis showed that histone H3 lysine 9 methylation modification, an epigenetic mark associated with gene silencing, is enriched by two- to three-fold in the cdc22 mutant as compared to the level found in the wild-type strain in regions outside the silent domain. The spreading of heterochromatin across barriers required functional Atf1/Pcr1, ATF-CREB family proteins, but not the RNA-interference Dcr1, Ago1, or Rdp1 factors, previously implicated in silencing. These results implicate the deoxyribonucleotide biosynthesis pathway in limiting epigenetic controls at barrier elements at the mating-type region, but the mechanism remains unknown.
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PMID:Mutations in deoxyribonucleotide biosynthesis pathway cause spreading of silencing across heterochromatic barriers at the mating-type region of the fission yeast. 1803 Jun 66

We evaluated the usefulness of the level of thymidylate synthase(TS)and dihydropyrimidine dehydrogenase(DPD) activity as prognostic factors and indicators for selection of chemotherapy regimens. Between November 1997 and March 1999, fifty-seven patients with stages I - IIIa primary breast cancer were registered. Using recurrence risk categories, they were classified into TAM monotherapy, TAM+oral 5-FU, and TAM+CMF groups(each were standard regimens at the time), and underwent postoperative adjuvant chemotherapy. The relationship between prognosis and the TS level and DPD activity, in addition to conventional risk factors, was examined. The recurrence-free survival time curve showed significant differences when stratified by tumor diameter, ER expression, and TS levels, but not by menopausal status, nodal status, surgical method, p53 expression, DPD activity, or HER2 expression. These results suggest that the TS level is useful as a prognostic factor for breast cancer.
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PMID:[Clinical significance of intratumoral TS levels and DPD activity in breast cancer]. 1929 64

Cell cycle progression in mammalian cells from G(1) into S phase requires sensing and integration of multiple inputs, in order to determine whether to continue to cellular DNA replication and subsequently, to cell division. Passage to S requires transition through the restriction point, which at a molecular level consists of a bistable switch involving E2Fs and pRb family members. At the G(1)/S boundary, a number of genes essential for DNA replication and cell cycle progression are upregulated, promoting entry into S phase. Although the activating E2Fs are the most extensively characterized transcription factors driving G(1)/S expression, LSF is also a transcription factor essential for stimulating G(1)/S gene expression. A critical LSF target gene at this stage, Tyms, encodes thymidylate synthetase. In investigating how LSF is activated in a cell cycle-dependent manner, we recently identified a novel time delay mechanism for regulating its activity during G(1) progression, which is apparently independent of the E2F/pRb axis. This involves inhibition of LSF in early G(1) by two major proliferative signaling pathways: ERK and cyclin C/CDK, followed by gradual dephosphorylation during mid- to late-G(1). Whether LSF and E2F act independently or in concert to promote G(1)/S progression remains to be determined.
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PMID:Transcription factors LSF and E2Fs: tandem cyclists driving G0 to S? 1955 76

Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We have designed, synthesized, and evaluated two compounds that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor-beta (PDGFR-beta) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-beta, and hTS is better than or close to standards. In a COLO-205 xenograft mouse model, one of the analogs significantly decreased tumor growth (tumor growth inhibition (TGI) = 76% at 35 mg/kg), liver metastases, and tumor blood vessels compared with a standard drug and with control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents.
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PMID:Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents. 2009 23

Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR.
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PMID:Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. 2053 Jul 10

Response rates to cytotoxics in gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) vary; recent trials demonstrated lack of objective response rates in up to 70% of patients. Identification of predictive therapeutic biomarkers would be beneficial in the treatment of GEP. Selected markers with known or suspected capability of predicting response to cytotoxics or prognosis (Ki-67, p53, multidrug resistance protein-1 (MDR1), Akt, thymidylate synthase (TS), phosphatase and tensin homolog (PTEN), CA9, cluster of differentiation 34 (CD34), vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1, mismatch repair gene - human mutL homolog 1 (hLMH1), and Bcl-2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (n=46) or chemoembolization (n=14) for inoperable advanced and/or metastatic GEP and correlated with prognosis (survival and response rates). Therapy included systemic chemotherapy with streptozotocin (n=28), doxorubicin (n=14), 5-fluorouracil (n=18), and etoposide/cisplatinum (n=16), or chemoembolization (streptozotocin, 9; doxorubicin, 5). Factors associated with overall survival in the entire cohort were Ki-67, P<0.001; tumor grade, P<0.001; tumor differentiation, P<0.001; CA9, P=0.004; Akt, P=0.01; HIF-1, P<0.001; p53, P<0.0001; and hMLH1, P=0.005. Markers associated with treatment response included overall group: Akt and PTEN (P=0.05 and 0.05 respectively); streptozotocin: Akt (P=0.07), TS (P=0.02), and PTEN (P=0.017); doxorubicin: Ki-67 (P=0.05), Akt (P=0.06), and CA9 (P=0.02). At multivariate analysis, Akt was significantly associated with a nonresponse to therapy (objective response (OR): 0.2 (0.05-0.8)). For patients receiving only systemic chemotherapy (n=46), PTEN (0.04) and hLMH1 (0.03) were correlated with treatment response and for individual molecules were streptozotocin: PTEN (P=0.008) and hLMH1 (0.07); doxorubicin: Akt (P=0.09), CA9 (P=0.09), and hLMH1 (P=0.09). These results demonstrate a number of new prognostic biomarkers in GEP-NET, and in addition, response to chemotherapy was correlated with a simple panel of selected markers (such as CA9, Akt, PTEN, TS, and hLMH1).
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PMID:Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors. 2057 Sep 57

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that inhibits the growth and initiates the apoptosis of epithelial tumors, including squamous cell carcinoma of the head and neck region. However, resistance to this drug is often observed in a clinical setting. The primary mode of action of 5-FU is believed to be the inhibition of thymidylate synthase. Overexpression of the enzymes involved in thymidine synthesis has been shown in some cases to be associated with resistance. However, the detailed mechanisms of resistance of squamous cell carcinoma are not fully understood. In the present study, we examined the involvement of survival signaling pathways in the resistance of squamous carcinoma cells to 5-FU. 5-FU induced the activation of the ERK and Akt kinases in UM-SCC-23 human squamous carcinoma cells, indicating that this anticancer drug activates survival signaling pathways as well as apoptotic signals. In 5-FU-resistant UM-SCC-23 cells established by our group, ERK and Akt signals were constitutively activated. U0126 is an inhibitor of MEK, which is an upstream activator for ERK. U0126 failed to sensitize resistant UM-SCC-23 cells to 5-FU-induced apoptotic cell death. This is in sharp contrast to LY294002, which is an inhibitor of phosphatidylinositol 3-kinase, an upstream activator for Akt. LY294002 drastically enhanced 5-FU-induced apoptotic cell death in resistant UM-SCC-23 cells. These results indicate that the Akt survival signal plays an important role in the resistance of squamous carcinoma cells to 5-FU treatment, and suggest that the modification of Akt activity might provide a new strategy for human 5-FU-resistant squamous carcinoma therapy.
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PMID:AKT plays a pivotal role in the acquisition of resistance to 5-fluorouracil in human squamous carcinoma cells. 2147 74

Drug resistance related proteins P-glycoprotein (P170), multidrug resistance associated protein (MRP), glutathione S-transferase-pi (GST-pi), glutathione peroxidase (GPX), topoisomerase II (Topo II), thymidylate synthase (TS), O-6-methylguanine-DNA-methyltransferase (MGMT), the heat shock proteins HSP27 and HSP70 and the protooncogenes Fos, Jun and EGFR were investigated in human lung carcinomas and matched normal tissues. We found that the mRNA expression of Topo II and TS were elevated in tumor tissue versus corresponding normal tissue. Additionally Topo II and TS correlated with the proliferating activity determined by expression of histone 3. P170, MRP, HSP70 and also EGFR mRNA were elevated in some tumor probes, but not GST-pi, GPX, MGMT and HSP27 mRNA. Additionally, we determined various values of Fos and Jun mRNA expression but there was no uniform pattern. The finding that some proteins were abnormally expressed in lung tumors compared to the adjacent normal tissue is an important finding for further investigations on the development of individualized chemotherapy but more samples should be examined to extend these observations.
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PMID:Comparison of the mRNA expression of factors related to drug resistance in lung tumors and adjacent normal tissue. 2154 93

To validate established cutoff levels of thymidylate synthase (TS) and excision repair cross-complementing (ERCC-1) intratumoral mRNA expressions in tumor samples from metastatic colorectal cancer (mCRC) patients treated with PTK787/ZK222584 (PTK/ZK). From 122 samples of patients with mCRC enrolled in CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) or CONFIRM-2, mRNA was isolated of microdissected formalin-fixed paraffin-embedded samples and quantitated using TaqMan-based technology. Existing TS and ERCC-1 cutoff levels were tested for their prognostic value in first-line and second-line therapy. TS expression was associated with overall survival (OS) in first-line, but not second-line therapy. ERCC-1 was associated with OS in patients treated with first-line and second-line FOLFOX4. In first-line FOLFOX4, combination of high TS and/or high ERCC-1 was associated with shorter OS. A correlation was observed between ERCC-1 expression and benefit from PTK/ZK+FOLFOX4 treatment. TS and ERCC-1 expression is associated with clinical outcome in mCRC. Baseline TS and ERCC-1 levels may allow the selection of patients who benefit from FOLFOX4 chemotherapy.
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PMID:TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials. 2178 64


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