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)

Tamoxifen (TAM), a nonsteroidal antiestrogen, is used in the adjuvant treatment of breast cancer. Previous studies, however, have indicated that some human breast and endometrial tumors are stimulated to grow with TAM in the athymic mouse. One such TAM-stimulated tumor is the EnCa101 human endometrial adenocarcinoma. Our aim was to evaluate the ability of different doses of TAM or other nonsteroidal antiestrogens to stimulate the growth of EnCa101 tumors in athymic mice. Additionally we have evaluated less estrogenic antiestrogens (two steroidal antiestrogens, RU 39,411 and ICI 164,384, and two nonsteroidal antiestrogens, keoxifene and MER-25) for their ability to inhibit TAM-stimulated growth. All experiments were done in ovariectomized athymic mice transplanted in the axillary mammary fat with 1-mm3 pieces of EnCa101 tumor. Sustained release preparations (0.5-2.0-cm Silastic capsule or 5-mg TAM cholesterol pellet) of TAM caused similar tumor growth. The growth rate was not altered by an additional daily i.p. injection of 1 mg TAM in 0.1 ml peanut oil. A 3-mg TAM daily dose was toxic. Four weeks of treatment (100-micrograms s.c. injections, every other day) with nonsteroidal antiestrogens, trioxifene mesylate, enclomiphene, or nafoxidine stimulated tumor growth. However, keoxifene stimulated this tumor to a lesser degree than TAM and partially inhibited TAM-stimulated growth. ICI 164,384 showed no stimulatory activity (1-mg s.c. injections every other day) alone compared to controls but inhibited TAM-stimulated (0.25-cm Silastic capsule) growth. In a parallel experiment, RU 39,411 (1-mg s.c. injections every other day) stimulated EnCa101 to grow. In contrast when RU 39,411 was administered in a sustained release preparation (2.0-cm Silastic capsule) there was no stimulatory growth compared to controls. Additionally RU 39,411 inhibited TAM-stimulated growth, but the low-potency antiestrogen, MER-25, was less effective in this regard. These data suggest that less "estrogenic" antiestrogens can inhibit TAM-stimulated tumor growth in vivo. Thus these compounds or derivatives may prove useful as a second-line endocrine therapy should TAM-stimulated tumor growth occur in the clinic.
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PMID:Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. 233 15

Animals of the BDII inbred rat strain are known to be genetically predisposed to endometrial adenocarcinoma (EAC). Using them as models of human EACs, we studied tumors arising in F1 and F2 progeny from BDII animals crossed to animals from two other inbred strains, in which EACs were quite rare. In order to identify chromosomal regions exhibiting DNA copy number changes, comparative genomic hybridization (CGH) was applied in a series corresponding to 27 different solid tumors, most of which were classified as EACs, from these animals. The main findings from the study were that, although many different chromosomes were involved in copy number variation, some of the changes detected were recurrent and quite specific. Among specific changes found were gains in rat chromosome (RNO) regions 4q12 approximately q22, 6q14 approximately q16, and whole chromosome arms in some of the small metacentric chromosomes (e.g., RNO14, 16, and 18). RNO10 was involved in gain in the terminal and proximal regions. Each of these regions contains previously identified cancer-related genes representing possible candidates to be involved in the development of EAC. Furthermore, it was observed that there were clear differences in the pattern of copy number changes between tumors occurring in the two different crosses, and also between solid tumors and cell cultures. Endometrial cancer is the most common human gynecological cancer, but not much is known about specific genetic changes influencing this disease. Two genetic alterations that have been reported from human endometrial cancer are amplification of the ERBB2 gene and mutations in the 12 codon of the KRAS gene. One case of Erbb2 amplification was found but there were no Kras mutations in the rat material studied. We conclude that molecular genetic analysis of the rat BDII model will provide important new information about EAC in mammals.
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PMID:Analysis of genetic changes in rat endometrial carcinomas by means of comparative genomic hybridization. 1142 50

Phytochemicals bind to and regulate the human estrogen receptors (ERalpha and ERbeta), mimicking actions of the endogenous estrogen, 17beta-estradiol, and known antiestrogens such as ICI 182,780. Recently, however, some of these estrogenic phytochemicals have been shown to affect other signal transduction pathways, such as receptor tyrosine kinases and mitogen-activated protein kinases (MAPK). Previously, we found that certain phytochemicals, such as flavone, apigenin, kaempferide and chalcone, have potent antiestrogenic activity. However, the antiestrogenicity of these compounds does not correlate with their ER binding capacity, suggesting alternative signaling as a mechanism for their antagonistic effects. In this study, we examined the effects of these compounds on the transcription factor activator protein-1 (AP-1). Using AP-1-luciferase stable human endometrial adenocarcinoma Ishikawa and human embryonic kidney (HEK) 293 cells, chalcone, flavone and apigenin all stimulated AP-1 activity. Additionally, we determined the effects of the phytochemicals on transcription factors that are downstream targets of various MAPK pathways. To test this, we used HEK 293 cells stably cointegrated with GAL4 transcriptional activation systems of Elk-1, c-Jun or C/EBP homologous protein (CHOP). Chalcone was the only phytochemical that activated all three transcription factors [Elk-1, 2.7-fold (P < 0.001); c-Jun, 2.7-fold (P = 0.025); CHOP, 3.0-fold (P = 0.002)], whereas apigenin stimulated CHOP (3.9-fold; P < 0.001), but inhibited phorbol myristoyl acetate-induced c-Jun activity (71%;P = 0.006). This work suggests that phytochemicals affect multiple signaling pathways that converge at the level of transcriptional regulation. The ability of flavonoids to regulate MAPK-responsive pathways in a selective manner indicates a mechanism by which phytochemicals may influence human health and disease.
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PMID:Flavonoid phytochemicals regulate activator protein-1 signal transduction pathways in endometrial and kidney stable cell lines. 1209 58

Estrogen 17beta-estradiol (E2) rapidly modulates several signaling pathways related to cell growth, preservation, and differentiation. The physiological role of these nongenomic effects with regard to downstream outcomes, and the relationship with transcriptional estrogen activity are unclear. Furthermore, the ability of selective estrogen receptor modulators (SERMs) to trigger nongenomic actions is largely unknown. To determine whether estrogen receptor (ER) ligands exert nongenomic activity in endometrial adenocarcinoma cells, and whether this activity affects transcription and DNA synthesis, we challenged human Ishikawa cells with E2 or partial ER agonists 4-hydroxytamoxifen (OHT) and raloxifene (ral). Serum-starved Ishikawa cells exposed for 5 min to 0.1 nM E2 showed induced phosphorylation of MAPK (ERK1/2). Ral and 4-OHT each at 1 nM also stimulated ERK in a rapid transient manner. E2 and 4-OHT induced proto-oncogene c-fos mRNA expression in Ishikawa cells within 30 min, but ral had no effect. In contrast to nongenomic action, only E2 stimulated expression of an estrogen response element (ERE)-driven luciferase (LUC) reporter gene. To examine DNA synthesis, [(3)H]-thymidine incorporation was measured in serum-starved cultures exposed to E2 or partial agonists for 2 d. E2 at 1 nM stimulated thymidine uptake in an ERK-dependent manner, but 1 nM 4-OHT, 1 nM ral, and 0.1-nM concentrations of E2 had no significant effects. Taken together, these data indicate that both nongenomic and direct transcriptional ER effects are likely required to promote DNA synthesis.
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PMID:Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands are not sufficient to promote deoxyribonucleic acid synthesis in human endometrial adenocarcinoma cells. 1248 37

Cellular response to oestradiol stimuli is mediated both by oestrogen receptor (ER) binding to oestrogen response elements (EREs) and by non-nuclear actions like activation of mitogen-activated protein kinase (MAPK) signal transduction. Therefore, oestradiol stimuli might be able to interfere with the action of antitumoral substances directed against receptor tyrosine kinase signalling. We investigated the effect of oestradiol on the inhibition of HER2 signalling by trastuzumab (Herceptin) in two human endometrial adenocarcinoma cell lines. Activation of the extracellular signal-regulated kinase (ERK-1/2), a major mediator of HER2 signalling, was measured by means of western blotting experiments and ERE activation was determined in transient reporter-gene assays. In endometrial Ishikawa and HEC-1A adenocarcinoma cells, HER2 signalling was inhibited by trastuzumab only in the absence of oestradiol. We were able to demonstrate that oestradiol counteracted the inhibitory effects of trastuzumab by rapid phosphorylation of ERK-1/2, a kinase downstream of the HER2 receptor. The pure anti-oestrogen ICI 182,780 was able to restore both the trastuzumab-triggered inhibition of the ERK-1/2 pathway and the antiproliferative action of this substance in Ishikawa cells. Our data suggest that combinations of trastuzumab with anti-oestrogens may be effective in the treatment of endometrial cancers with a positive ER and HER2 receptor status.
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PMID:The activation of an extracellular signal-regulated kinase by oestradiol interferes with the effects of trastuzumab on HER2 signalling in endometrial adenocarcinoma cell lines. 1276 21

Keratinocyte growth factor receptor (KGFR), also known as FGFR2 IIIb, is a splice variant of FGFR-2. KGFR is expressed in many types of epithelial cell and is activated with four known ligands [FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10] that are predominantly synthesized by mesenchymal cells. KGFR is highly expressed in the late-proliferative phase of a normal endometrium and in endometrial adenocarcinoma. In the present study, we attempted to determine the expression and localization of KGFR in human cervical cancer cell lines and cervical cancer tissues. The KGFR protein was detected in CaSki and HeLa cells, but not in ME-180 cells of cervical cancer cell lines. In non-cancer cervical tissues, KGFR immunoreactivity was weakly expressed in the surface of squamous epithelial cells and vascular smooth muscle cells. Immunohistochemically, the KGFR protein was detected in squamous cell carcinoma in 36 of 42 (86%) cervical cancer patients. In cervical cancer tissues, KGFR was detected in 17 of 18 (94%) of patients with the keratinizing type and 19 of 24 (79%) of patients with the non-keratinizing type of cervical cancer. Furthermore, KGFR was prominently localized in proliferating reserve cells and squamous metaplastic reserve cells adjacent to cancer cells. In contrast, KGFR was not detected in cervical ductal cells in cancer or non-cancer cervical tissues. These findings may indicate that KGFR mediates the growth and differentiation of reserve cells and squamous cell carcinoma in the cervix.
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PMID:Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in human uterine cervical cancer. 1506 36

CD109 is a cell surface protein, a member of the alpha(2) macroglobulin/C3,C4,C5 family of thioester-containing proteins. The authors have recently reported that high expression of the CD109 gene was detected in approximately half of the examined lung and esophageal squamous cell carcinomas as well as in the testis, and that CD109 has the characteristics of a cancer-testis antigen. In the present study CD109 expression in cervical squamous cell carcinoma was compared with that in endometrial adenocarcinoma by reverse transcription polymerase chain reaction (RT-PCR). The result demonstrated that CD109 expression is significantly higher in cervical squamous cell carcinomas than in endometrial adenocarcinomas and normal cervix and endometrium. In contrast, when expression of RET finger protein (RFP) and bromodomain testis-specific (BRDT) genes, which are also known to be highly expressed in the testis, was examined, no significant difference in their expression levels was observed between squamous cell carcinomas and adenocarcinomas. These findings suggest that CD109 may become a molecular target for the development of new therapeutics for squamous cell carcinoma of various tissue origins.
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PMID:CD109 expression in squamous cell carcinoma of the uterine cervix. 1582 42

Prostaglandin (PG) F(2alpha) is a potent bioactive lipid in the female reproductive tract, and exerts its function after coupling with its heptahelical G-protein-coupled receptor [F-series-prostanoid (FP) receptor] to initiate cell signaling and target gene transcription. In the present study, we found elevated expression of fibroblast growth factor (FGF) 2, FGF receptor 1 (FGFR1), and FP receptor, colocalized within the neoplastic epithelial cells of endometrial adenocarcinomas. We investigated a role for PGF(2alpha)-FP receptor interaction in modulating FGF2 expression and signaling using an endometrial adenocarcinoma cell line stably expressing the FP receptor to the levels detected in endometrial adenocarcinomas (FPS cells) and endometrial adenocarcinoma tissue explants. PGF(2alpha)-FP receptor activation rapidly induced FGF2 mRNA expression, and elevated FGF2 protein expression and secretion into the culture medium in FPS cells and endometrial adenocarcinoma explants. The effect of PGF(2alpha) on the expression and secretion of FGF2 could be abolished by treatment of FPS cells and endometrial tissues with an FP receptor antagonist (AL8810) and inhibitor of ERK (PD98059). Furthermore, we have shown that FGF2 can promote the expression of FGF2 and cyclooxygenase-2, and enhance proliferation of endometrial adenocarcinoma cells via the FGFR1 and ERK pathways, thereby establishing a positive feedback loop to regulate neoplastic epithelial cell function in endometrial adenocarcinomas.
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PMID:F-prostanoid receptor regulation of fibroblast growth factor 2 signaling in endometrial adenocarcinoma cells. 1747 53

Gastrointestinal stromal tumors (GIST) are rare in the vermiform appendix. Only 5 cases have been reported so far, all being 14 mm or less, and they have yet not been investigated at the molecular level. Here, we report 2 appendiceal gastrointestinal stromal tumors in a 78-year-old woman and a 72-year-old man with a history of endometrial adenocarcinoma and urinary bladder carcinoma, respectively. The first patient had a history of pelvic irradiation. Both gastrointestinal stromal tumors were incidental findings at surgery for appendicitis-like symptoms and on follow-up for bladder carcinoma, respectively. Tumors were 5 and 25 mm and were located in the mid portion and the tip, respectively. The larger gastrointestinal stromal tumor was pedunculated. Both revealed a spindle cell histology with variable stromal hyalinization and occasional skeinoid fibers in 1 case. Immunohistochemistry showed reactivity for CD117 and CD34 and loss of p16 in both. Case 2 overexpressed the catalytic subunit of the human telomerase reverse transcriptase immunohistochemically. Molecular analysis of KIT revealed a missense mutation K558R in case 1 and an in-frame deletion I571_R588 in case 2, both in the juxtamembrane domain (exon 11). Comparative genomic hybridization was successful in case 2 (larger lesion) and revealed no chromosomal imbalance. We suggest that the molecular pathogenesis of appendiceal gastrointestinal stromal tumors beyond initiating KIT mutations might be different from their gastric and intestinal counterparts. The coincidence of loss of p16 and overexpression of human telomerase reverse transcriptase seems to be in contradiction to the small size, the benign nature, and the limited growth potential of appendiceal gastrointestinal stromal tumors.
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PMID:Gastrointestinal stromal tumors of the vermiform appendix: clinicopathologic, immunohistochemical, and molecular study of 2 cases with literature review. 1854 14

We evaluated whether inhibition of heat shock protein 90 (hsp90) function by novobiocin derivatives could induce the degradation of signal transducers that drive cancer cell growth and thereby promote apoptosis. Removal of the noviose moiety in novobiocin and introduction of a tosyl substituent at C-4 or C-7 coumarin nucleus provided derivatives 4TCNA and 7TCNA which compared favourably with novobiocin in MCF-7 breast cancer cells. Here we extend the antiproliferative and apoptotic properties of these analogues to a panel of cancer cell lines. Destabilization of hsp90 client proteins Raf-1, HER2, and cdk4 suggests inhibition of hsp90 chaperoning function. In HT29 colon and IGROV1 ovarian cancer cells, the growth inhibiting effect of 4TCNA and 7TCNA was consistent with the stimulation of cell death as assessed by the processing and activation of caspase 9, 8, 7 and 3 and the subsequent cleavage of poly(ADP-ribose) polymerase (PARP). In Ishikawa endometrial adenocarcinoma cells, 4TCNA also promoted apoptosis and the processing of PARP. These derivatives impacting multiple pathways involved in the neoplastic process may represent promising drugs for cancer therapy.
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PMID:Antiproliferative and apoptotic activities of tosylcyclonovobiocic acids as potent heat shock protein 90 inhibitors in human cancer cells. 1884 35


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