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)

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

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.
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PMID:Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. 1503 19

Activated oncogenes have been detected in a variety of malignant tumors and altered expressions of certain genes are known to play a functional role in the cancer process. The chemical carcinogen, BP, and the insertion of c-Ha-ras, induced characteristics of transformed phenotypes in a suitable human breast epithelial cell line. Carcinogen-treated and Ha-ras-transfected cells showed a progression of changes in the morphology, anchorage independent growth, invasiveness and tumorigenicity in SCID mice. Tumor growth occurs after a series of molecular events that parallel morphological changes. The aim of this work was to determine the neoplastic phenotypes following treatment with benzo(a)pyrene (BP) and transfection with c-Ha-ras oncogene changes and PCNA, Neu, ErbB-3 and Cytokeratin 18 protein expression in MCF-10F cells, a spontaneously immortalized human breast epithelial cell line. Protein expression was determined by immunofluorescent staining coupled with confocal microscopy. An increased oncoprotein expression in comparison to MCF-10F cells was observed in PCNA, Neu, ErbB-3 and Cytokeratin 18 protein expression in breast epithelial cells transformed with a chemical carcinogen and/or oncogene transfected that are not present in the MCF-10F. This in vitro cancer model can be used as a valuable model in the study of breast carcinogenesis.
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PMID:Oncoprotein expression and morphological phenotypes of human breast epithelial cells transformed by the c-Ha-ras oncogene. 1614 47

Aberrant expression of the epidermal growth factor receptor family has been implicated in the pathogenesis and progression of breast cancer and associated with poor prognosis. To evaluate the prognostic impact of the ErbB receptors expression profile, we analyzed a well-characterized series of 145 primary breast carcinomas for the simultaneous expression of epidermal growth factor receptor (EGFR/HER-1), ErbB-2 (HER-2), ErbB-3 (HER-3), and ErbB-4 (HER-4), using immunohistochemistry. Tumors were considered negative or positive for each marker when less than or more than 25% of the cancer cells were immunopositive. Expression of EGFR, ErbB-2, ErbB-3, and ErbB-4 was observed in 31 (21.4%), 65 (44.8%), 72 (49.7%), and 81 (55.9%) of the cases, respectively. There were significant associations between EGFR expression and pT status (P = 0.01), and between ErbB-3 expression and pN (P = 0.003), menopausal (P = 0.01) and PR (P < 0.001) status. The majority of the cases co-expressed two or more receptors. ErbB-3 resulted positive in 51/81 (63.0%) of the ErbB-4 positive cases and ErbB-3/ErbB-4 co-expression was statistically significant (P = 0.0003). As expected, ErbB-2 expression was associated with reduced overall survival at 15 years of follow-up (P = 0.04), even after adjusting for a series of other prognostic factors (P = 0.05). Moreover, cumulative analysis of ErbB-2/3/4 expression showed a strong positive association between higher total ErbB-2/3/4 expression score and worse prognosis (P = 0.002). The simultaneous expression in cancer cells of more than one ErbB receptor identifies a subset of breast cancer patients at high risk for poor survival.
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PMID:ErbB-receptors expression and survival in breast carcinoma: a 15-year follow-up study. 1624 16

Inhibition of the epidermal growth factor receptor (EGFR) represents one of the most important avenues for research and development in the field of cancer therapy. The EGFR is a member of the ErbB receptor tyrosine kinase (TK) family, which also includes ErbB-2 (HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). Current EGFR therapies available for use include monoclonal antibodies, such as cetuximab, and small-molecule EGFR TK inhibition by agents such as erlotinib. Side effects of these agents include dermatologic manifestations without the bone marrow suppressive properties of chemotherapy. Understanding of rash and how it relates to EGFR inhibitor toxicity and, perhaps more importantly, EGFR inhibitor response must be more clearly defined with clinical trials. The optimum management of rash in patients receiving anti-EGFR therapy remains somewhat controversial; this is secondary to imprecise classification of rash as well as the lack of clinical trials to determine the most appropriate treatment algorithm for these patients. We propose a treatment strategy to help aggressively treat dermatologic side effects allowing patients to continue receiving therapy without dose interruption or drug discontinuation.
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PMID:Management of rash and other toxicities in patients treated with epidermal growth factor receptor-targeted agents. 1633 49

The inappropriate activation of one or more members of the ErbB family of receptor tyrosine kinases [ErbB-1 (EGFR), ErbB-2, ErbB-3, ErbB-4] has been linked with oncogenesis. ErbB-2 is frequently coexpressed with ErbB-3 in breast cancer cells and in the presence of the ligand heregulin (HRG) the ErbB-2/ErbB-3 receptors form a signaling heterodimer that can affect cell proliferation and apoptosis. The major goal of the present study was to determine whether endogenous HRG causes autocrine/paracrine activation of ErbB-2/ErbB-3 and contributes to the proliferation of mammary epithelial tumor cells. Tyrosine-phosphorylated (activated) ErbB-2 and ErbB-3 receptors were detected in the majority of extracts from tumors that had formed spontaneously or as a result of oncogene expression. HRG-1 transcripts and protein were found in the epithelial cells of most of these mouse mammary tumors. Various mouse mammary cell lines also contained activated ErbB-2/ErbB-3 and HRG transcripts. A approximately 50 kDa C-terminal fragment of pro-HRG was detected, which indicates that the HRG-1 precursor is readily processed by these cells. It is likely that the secreted mature HRG activated the ErbB-2/3 receptors. Addition of an antiserum against HRG to the mammary epithelial tumor cell line TM-6 reduced ErbB-3 Tyr-phosphorylation. Treatment with HRG-1 siRNA oligonucleotides or infection with a retroviral construct to stably express HRG siRNA effectively reduced HRG protein levels, ErbB-2/ErbB-3 activation, and the rate of proliferation, which could be reversed by the addition of HRG. The cumulative findings from these experiments show that coexpression of the HRG ligand contributes to activation of ErbB-2/Erb-3 in mouse mammary tumor cells in an autocrine or paracrine fashion.
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PMID:Expression of heregulin by mouse mammary tumor cells: role in activation of ErbB receptors. 1648 17

EGFR is frequently mutated and amplified in lung adenocarcinomas sensitive to EGFR inhibitors gefitinib and erlotinib. A secondary mutation, T790M, has been associated with acquired resistance but has not been shown to be sufficient to render EGFR mutant/amplified lung cancers resistant to EGFR inhibitors. We created a model for studying acquired resistance to gefitinib by prolonged exposure of a gefitinib-sensitive lung carcinoma cell line (H3255; EGFR mutated and amplified) to gefitinib in vitro. The resulting resistant cell line acquired a T790M mutation in a small fraction of the amplified alleles that was undetected by direct sequencing and identified only by a highly sensitive HPLC-based technique. In gefitinib-sensitive lung cancer cells with EGFR mutations and amplifications, exogenous introduction of EGFR T790M effectively conferred resistance to gefitinib and continued ErbB-3/PI3K/Akt signaling when in cis to an activating mutation. Moreover, continued activation of PI3K signaling by the PIK3CA oncogenic mutant, p110alpha E545K, was sufficient to abrogate gefitinib-induced apoptosis. These findings suggest that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in cancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib.
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PMID:Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. 1690 27

Numerous dietary and pharmacological agents have been proposed as alternative strategies for treatment and prevention of colorectal cancer. Curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and treatment of colorectal cancer. EGF-R related protein (ERRP), a recently identified pan-erbB inhibitor, is a potential therapeutic agent for colorectal cancer. Here we examine whether curcumin together with ERRP will cause a greater inhibition of growth of colon cancer cells than either agent alone and the mechanisms of this inhibition. Human colon cancer HCT-116 or HT-29 cells were incubated with increasing doses of curcumin (up to 10 microM) or ERRP (up to 5 microg/ml), or a combination of both for 48 h. We observed that the cell growth inhibition and stimulation of apoptosis in response to the combinatorial treatment was significantly greater than that caused by either agent alone. These changes were associated with decreased activation (tyrosine phosphorylation) of EGFR, ErbB-2, ErbB-3, and/or IGF-1R. Whereas curcumin inhibited constitutive activation of both EGFR and IGF-1R, ERRP decreased activation of EGFR, ErbB-2, and ErbB-3 but had no effect on IGF-1R. Further, the combination therapy caused a greater attenuation of downstream effectors such as NF-kappaB, Akt and BAD activation, and down-regulation of procaspase-3 than that noted with either agent alone. The superior effects of the combinatorial treatment could partly be attributed to inhibition of constitutive activation of EGFRs and IGF-1R signaling pathways.
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PMID:Mechanisms of curcumin- and EGF-receptor related protein (ERRP)-dependent growth inhibition of colon cancer cells. 1704 74

Members of the receptor tyrosine kinase family, that include EGFR, ErbB-2/HER-2, ErbB-3/HER-3 and ErbB-4/HER-4, are frequently implicated in experimental models of epithelial cell neoplasia as well as in human cancers. Therefore, interference with the activation of these growth factor receptors represents a promising strategy for development of novel and selective anticancer therapies. Indeed, a number of inhibitors that target either EGFR or HER-2, with the exception of a few that target both; have been developed for treatment of epithelial cancers. Since most solid tumors express different ErbB receptors and/or their ligands, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. Here we describe the significance of an ErbB family of receptors in epithelial cancers, and summarize different available therapeutics targeting these receptors. It also emphasizes the need to develop pan-ErbB inhibitors and discusses EGF-Receptor Related Protein, a recently isolated negative regulator of EGFR as a potential pan-ErbB therapeutic for a wide variety of epithelial cancers.
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PMID:Emerging therapies in gastrointestinal cancers. 1716 31

The HER2/neu oncogene is an important diagnostic and prognostic factor and therapeutic target in breast and other cancers. We developed and characterized a breast cancer cell line (Bam1a) that overexpresses the activated HER2/neu and ErbB-3 and has a gene expression profile consistent with the ErbB-2 genetic signature. We evaluated the effects of the epidermal growth factor receptor (EGFR)/HER2 inhibitor, gefitinib, on this breast tumor line in vitro and in vivo. We characterized the effects of gefitinib on EGFR, HER2, and ErbB-3 phosphorylation by Western blot and determined the effects on downstream signaling through growth, survival, and stress pathways and the effect on proliferation, cell cycle, and apoptosis. Gefitinib treatment diminished phosphorylation of the ErbB-3 > EGFR > HER2/neu and signal transducers and activators of transcriptions in a dose-dependent fashion. Downstream mitogenic signaling through mitogen-activated protein (MAP)/extracellular signal regulated kinase kinase, p44/42 MAP kinase (MAPK) and stress signaling through c-Jun-NH(2)-kinase (JNK) 1 and c-Jun was impaired (1 micromol/L, 4-24 h), leading to cytostasis and cell cycle arrest within 24 h by decreased cyclin D1, cyclin B1, and p(Ser795)Rb and increased p27. Proliferation and colony formation were inhibited at 0.5 and 1 micromol/L, respectively, and correlated with altered gene expression profiles. Diminished survival signaling through Akt, induction of bim, loss of connexin43, and decreased production of vascular endothelial growth factor-D preceded caspase-3 and poly(ADP)ribose polymerase (PARP) cleavage and apoptosis (>50% 2 micromol/L, 48 h). Oral administration of gefitinib was able to prevent the outgrowth of Bam1a tumor cells from palpable lesions, shrink established tumors, eliminate HER2 and HER3 phosphorylation, and decrease MAPK and Akt signaling in vivo. A variant of the Bam1a cell line, IR-5, with acquired ability to grow in 5 micromol/L gefitinib was developed and characterized. IR-5 bears a novel point mutation in the HER2/neu that corresponds to a L726I in the ATP-binding pocket and correlates with a log decrease in sensitivity to gefitinib, increased heterodimerization with EGFR and HER3, and impaired down-regulation. Gene expression profiling of IR-5 showed increased expression of EMP-1, NOTCH-1, FLT-1, PDGFB, and several other genes that may contribute to the resistant phenotype and sustain signaling through MAPK and Akt. This model will be useful in understanding the differences between intrinsic drug sensitivity and acquired resistance in the context of therapeutic strategies that target oncogene addicted diseases.
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PMID:Breast cancer expressing the activated HER2/neu is sensitive to gefitinib in vitro and in vivo and acquires resistance through a novel point mutation in the HER2/neu. 1763 94


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