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)

Small-cell lung cancer (SCLC) cells may express somatostatin receptors [14]. Receptor-positive tissue can be visualised in vivo by scintigraphy with radiolabelled somatostatin analogues. In a prospective study we examined 18 patients with histologically proven SCLC for the diagnostic value of somatostatin receptor scintigraphy using indium-111 pentetreotide. Planar whole body scanning was performed 4 and 24 hours after administration. Additional SPECT imaging of the thorax and the abdomen was done at 24 hours. The results were compared with conventional staging procedures: ultrasound, x-ray, computed tomography and bone scintigraphy. In all 18 patients the primary tumour was correctly identified. Out of 13 patients with mediastinal lymphoma formation 10 patients showed positive SRS. In 2 more patients SRS showed mediastinal uptake while CT scanning was negative. The detection of distant metastases in patients with extensive disease was true positive in 8 cases (OSS, HEP, BRA), false negative in 4 cases (PLE, ADR, HEP), corresponding to a sensitivity of 67%. In 2 patients cerebral metastases were no longer detectable by SRS after previous local irradiation. Even though the method is limited in respect of revealing distant metastases in the upper abdominal area due to physiological uptake in liver, spleen and kidneys, differentiation between limited disease (LD) and extensive disease (ED) was possible in all cases. We conclude that [111In]pentetreotide scintigraphy is a suitable method for the detection of SCLC primary tumours and a substantial tool for differentiation between LD and ED if combined with ultrasonography of the upper abdomen.
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PMID:[Diagnostic value of somatostatin receptor scintigraphy with indium-111 pentetreotide in small-cell bronchial carcinoma]. 955 59

Urinary trypsin inhibitor (UTI), a Kunitz-type protease inhibitor, interacts with cells as a negative modulator of the invasive cells. Human ovarian cancer cell line, HRA, was treated with phorbol ester (PMA) to evaluate the effect on expression of urokinase-type plasminogen activator (uPA), since the action of uPA has been implicated in matrix degradation and cell motility. Preincubation of the cells with UTI reduced the ability of PMA to trigger the uPA expression at the gene level and at the protein level. UTI-induced down-regulation of PMA-stimulated uPA expression is irreversible and is independent of a cytotoxic effect. Down-regulation of uPA by UTI is mediated by its binding to the cells. We next asked whether the mechanism of inhibition of uPA expression by UTI was due to interference with the protein kinase C second messenger system. An assay for PKC activity demonstrated that UTI does not directly inhibit the catalytic activity of PKC and that PMA translocation of PKC from cytosol to membrane was inhibited by UTI, indicating that UTI inhibits the activation cascade of PKC. PMA could also activate a signaling pathway involving MEK1/ERK2/c-Jun-dependent uPA expression. When cells were preincubated with UTI, we could detect suppression of phosphorylation of these proteins. Like several types of PKC inhibitor, UTI inhibited PMA-stimulated invasiveness. We conclude that UTI markedly suppresses the cell motility possibly through negative regulation of PKC- and MEK/ERK/c-Jun-dependent mechanisms, and that these changes in behavior are correlated with a coordinated down-regulation of uPA which is likely to contribute to the cell invasion processes.
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PMID:Suppression of urokinase expression and invasiveness by urinary trypsin inhibitor is mediated through inhibition of protein kinase C- and MEK/ERK/c-Jun-dependent signaling pathways. 1105 91

Bikunin (bik, also known as urinary trypsin inhibitor [UTI]), a Kunitz-type protease inhibitor, interacts with cells as a negative modulator of the invasive cells. Human ovarian cancer cell line, HRA, was treated with phorbol ester (PMA) in order to evaluate the effect on expression of urokinase-type plasminogen activator (uPA). Preincubation of the cells with bik reduced the ability of PMA to trigger the uPA expression at the gene level and at the protein level. We next asked whether the mechanism of inhibition of uPA expression by bik is due to interference with MAP kinase, since PMA could also activate a signaling pathway involving MEK/ERK/c-Jun-dependent uPA expression. When cells were preincubated with bik, we could detect suppression of phosphorylation of these proteins, demonstrating that bik markedly suppresses the cell motility possibly through negative regulation of MEK/ERK/c-Jun-dependent mechanisms, and that these changes in behavior are correlated with a coordinated down-regulation of uPA which is likely to contribute to the cell invasion processes. To clarify the role of bik on tumor metastasis, HRA cells were transfected with an expression vector harboring a cDNA encoding for human bik. Transfection of HRA with the bik cDNA resulted in five variants stably expressing functional bik and significantly reduced invasion, but not proliferation, adhesion, or migration relative to the parental cells. Animals with bik* transfectants induced reduced peritoneal dissemination and long term survival. These results suggest that transfection with the bik gene induces the suppression of tumor cell invasion and peritoneal dissemination, and can prolong survival. This pre-clinical animal model offers the possibility to explore gene therapy as a new treatment modality for ovarian cancer.
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PMID:Suppression of urokinase expression and tumor metastasis by bikunin overexpression [mini-review]. 1177 42

Bikunin is a Kunitz-type protease inhibitor, acting at the level of tumor invasion and metastasis. The goal of this study was to investigate the effect of bikunin-dependent signal transduction involved in the expression of a plasminogen activator (PA) system and invasion. We report here the following. 1) The human ovarian cancer cell line HRA produced secreted and cell-associated urokinase-type PA (uPA) and PA inhibitor type 1 (PAI-1). The plasma membrane of the cells showed enzymatically active uPA even in the presence of high level of PAI-1, as measured by zymography, Western blot, chromogenic assay, enzyme-linked immunosorbent assay, and Northern blot. 2) HRA cells leading to invasion are induced through up-regulation of uPA expression. 3) HRA cells specifically released transforming growth factor-beta type 1 (TGF-beta1) participating in an autocrine/paracrine regulation of cell invasion. 4) Elimination of endogenous TGF-beta1 could induce change in uPA/PAI-1 expression, which could in turn modify the invasive behavior of the cells. 5) The constitutive expression of TGF-beta1 as well as up-regulation of the PA system observed in HRA cells was inhibited by preinoculation of the cells with bikunin or calcium channel blocker SK&F 96365 but not with nifedipine or verapamil, with an IC(50) of approximately 100 nm for bikunin or approximately 30 microm for SK&F 96365, respectively, as measured by enzyme-linked immunosorbent assay. Bikunin showed no additive effect on SK&F 96365-mediated suppression of TGF-beta1 expression. 6) The ability of TGF-beta1 to elevate free intracellular Ca(2+), followed by activation of Src and ERK, was reduced by preincubation of the cells with bikunin. In conclusion, bikunin could inhibit the constitutive expression of TGF-beta1 and TGF-beta1-mediated, Src- and ERK-dependent, PA system signaling cascade, at least in part, through inhibition of a non-voltage-sensitive calcium channel.
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PMID:A Kunitz-type protease inhibitor, bikunin, inhibits ovarian cancer cell invasion by blocking the calcium-dependent transforming growth factor-beta 1 signaling cascade. 1249 70

We provided evidence previously that bikunin, a Kunitz-type protease inhibitor, can disrupt dimerization of CD44 proteins, which may result in suppression of receptor-mediated MAP kinase signaling. However, to what extent dimerization may alter ligand-induced signaling has not been documented. Given the recent recognition that some growth factor receptors can form heterodimers with CD44, the present study was undertaken to determine whether the CD44 and growth factor receptors (e.g., EGFR, FGFR, HGFR, VEGFR, TGF-betaRI, or TGF-betaRII) can form heterodimers in cancer cells and, if so, to investigate the potential functional consequences of such heterodimerization. We also examined whether bikunin can abrogate these heterodimerizations and inhibit CD44/growth factor-dependent signaling. Here, we show direct evidence for heterodimerization of CD44-FGFR and CD44-TGF-betaRI in human chondrosarcoma HCS-2/8 cells, CD44-EGFR complex in human glioma U87MG cells, and CD44-TGF-betaRI heterodimer in human ovarian cancer HRA cells. Coupling of CD44 and growth factor receptor may be selective, depending on a cell type. Bikunin does not alter the ligand binding, whereas functionally reduces heterodimerization between CD44 and growth factor receptors. The disruption of heterodimerization substantially reduces receptor-induced tyrosine phosphorylation and ERK1/2 activation. Taken together, our data suggest that bikunin-mediated suppression of heterodimerization between CD44 and growth factors may inhibit the agonist-promoted activation of the signaling pathway.
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PMID:Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling. 1559 42

A soybean Kunitz trypsin inhibitor (KTI) interacts with cells as a negative modulator of the invasive cells. Using complementary pharmacological and genetic approaches, we provide novel findings regarding mechanisms by which KTI inhibits signaling pathways in ovarian cancer cells leading to invasion. Transforming growth factor-beta1 (TGF-beta1) directly activates Src kinase, which in turn activates ERK-phosphatidylinositol 3-kinase/Akt, the downstream targets of Src, for urokinase-type plasminogen activator (uPA) up-regulation in human ovarian cancer HRA cells. Preincubation of the HRA cells with KTI reduced the ability of TGF-beta1 to trigger the uPA expression at the gene level and at the protein level. To further elucidate the mechanism of the KTI-dependent suppressive effect of TGF-beta1-induced uPA expression and invasion, we investigated which signaling pathway transduced by KTI is responsible for this inhibitory effect. Here, we show that 1) KTI suppressed TGF-beta1-induced phosphorylation of Src, ERK1/2, and Akt by 40-60%; 2) KTI was insensitive to suppress the phosphorylation of ERK1/2 and Akt in the constitutively active (CA)-c-Src (Y529F) cells; 3) uPA expression was up-regulated in TGF-beta1-stimulated HRA cells and in unstimulated Y529F cells; 4) the addition of KTI reduced the TGF-beta1-induced increase of uPA gene and protein expression in the wild-type c-Src-transfected cells (in contrast, KTI could not inhibit uPA expression in the Y529F cells); and 5) CA-c-Src transfection resulted in a 2-fold increase in invasiveness, whereas KTI did not reduce invasion of the Y529F cells. Using additional complementary genetic approaches (CA-MEK1, CA-Akt, or kinase-dead-Akt), we conclude that KTI may suppress uPA expression and promotion of invasion possibly through one or more upstream targets of Src.
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PMID:Suppression of urokinase expression and invasion by a soybean Kunitz trypsin inhibitor are mediated through inhibition of Src-dependent signaling pathways. 1600 10

The human colorectal epithelium is maintained by multipotent stem cells that give rise to absorptive, mucous, and endocrine lineages. Recent evidence suggests that human colorectal cancers are likewise maintained by a minority population of so-called cancer stem cells. We have previously established a human colorectal cancer cell line with multipotent characteristics (HRA-19) and developed a serum-free medium that induces endocrine, mucous and absorptive lineage commitment by HRA-19 cells in vitro. In this study, we investigate the role of the beta1 integrin family of cell surface extracellular matrix receptors in multilineage differentiation by these multipotent human colorectal cancer cells. We show that endocrine and mucous lineage commitment is blocked in the presence of function-blocking antibodies to beta1 integrin. Function-blocking antibodies to alpha2 integrin also blocked both HRA-19 endocrine lineage commitment and enterocytic differentiation by Caco-2 human colon cancer cells; both effects being abrogated by the MEK inhibitor, PD98059, suggesting a role for ERK signaling in alpha2-mediated regulation of colorectal cancer cell differentiation. To further explore the role of alpha2 integrin in multilineage differentiation, we established multipotent cells expressing high levels of wild-type alpha2 integrin or a non-signaling chimeric alpha2 integrin. Overexpression of wild-type alpha2 integrin in HRA-19 cells significantly enhanced endocrine and mucous lineage commitment, while cells expressing the non-signaling chimeric alpha2 integrin had negligible ability for either endocrine or mucous lineage commitment. This study indicates that the collagen receptor alpha2beta1 integrin is a regulator of cell fate in human multipotent colorectal cancer cells.
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PMID:Alpha2beta1 integrin regulates lineage commitment in multipotent human colorectal cancer cells. 1866 72

A 68-year-old man was referred to our hospital because of an abnormal chest shadow. Adenocarcinoma was detected using percutaneous needle aspiration cytology from the left supraclavicular lymph node. The patient was diagnosed as having primary adenocarcinoma of the lung(cT1bN3M1b: BRA OSS). Exon 18G 719X and exon 20 T790M mutations of the EGFR gene were detected in the same specimen. For first-line chemotherapy, four courses of cisplatin plus docetaxel were used. The primary lesion and a brain metastasis were reduced after the first-line chemotherapy. About four months later, he developed a recurrent brain metastasis and leptomeningeal carcinomatosis. He was treated with erlotinib(150mg/day)after wholebrain irradiation. The leptomeningeal carcinomatosis findings on a head CT image and the patient's consciousness disorder improved after treatment. EGFR-TKI therapy was effective in a case with leptomeningeal carcinomatosis, and coexisting EGFRsensitive and EGFR-resistant mutations.
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PMID:[A case of lung adenocarcinoma with coexisting G719X and T790M EGFR mutations in which erlotinib was effective for the treatment of leptomeningeal carcinomatosis]. 2350 2

Aim: The aim of the present study was to explore the associations between the economic, political, sociocultural and physical environments in kindergartens, along with the frequency and variety of vegetables served, and the amount of vegetables eaten. Method: The BRA Study collected data through two paper-based questionnaires answered by the kindergarten leader and pedagogical leader of each selected kindergarten, and a five-day vegetable diary from kindergartens (n = 73) in Vestfold and Buskerud Counties, Norway. The questionnaires assessed environmental factors, and the frequency and variety of vegetables served. The non-parametric Mann-Whitney U and Kruskal-Wallis tests were used to explore the associations between factors in the kindergarten environments and vegetables served and eaten. Results: Kindergartens that included expenditures for food and beverages in the parental fees served a larger variety of vegetables (p = 0.046). A higher frequency of served vegetables (p = 0.014) and a larger amount (p = 0.027) of vegetables eaten were found in kindergartens where parents paid a monthly fee of 251 NOK or more. Similarly, the amount of vegetables eaten was higher (p = 0.017) in kindergartens where the employees paid a monthly fee to eat at work. Furthermore, a larger amount (p = 0.046) of vegetables was eaten in kindergartens that had written guidelines for food and beverages that were offered. Conclusions: This study indicates that the economic environment in a kindergarten seems to be positively associated with the vegetables served and eaten there. This is of high relevance for public health policy as vegetable consumption is an important factor in reducing the risk of non-communicable diseases.
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PMID:Is the environment in kindergarten associated with the vegetables served and eaten? The BRA Study. 2943 Oct 28

Background: Chromosomal instability (CIN) and microsatellite instability (MSI) account for the major causes of colorectal cancer (CRC). As an important component of the CIN pathway, PIK3CA mutation is a negative prognostic factor in CRC. However, the relationship between PIK3CA mutation and mismatch repair (MMR) status has not been well clarified. Methods: MMR status was determined by immunohistochemical assay. KRAS, NRAS, BRAF, PIK3CA and TP53 mutations were comparatively analyzed in 424 MMR-proficient (pMMR) and 104 MMR-deficient (dMMR) CRC tumors using next-generation sequencing (NGS). Results: PIK3CA mutation was more commonly mutated in dMMR tumors. PIK3CA mutation less commonly coexisted with KRAS/NRAS/BRAF and TP53 mutations, but more likely coexisted with HER2 and PTCH1 mutations in dMMR tumors compared with pMMR tumors. In tumors with concurrent RAS/BRAF and PIK3CA mutations, PIK3CA and RAS/BRAF mutant allele frequencies (MAFs) were highly concordant in dMMR tumors, whereas PIK3CA MAFs were significantly lower than the corresponding RAS/BRAF MAFs in pMMR tumors, implying that PIK3CA mutation may occur in the early stage of dMMR CRC. Conclusions: The molecular pathogenesis is different between dMMR and pMMR tumors with PIK3CA mutation in CRC. PIK3CA mutation may act as a clonally dominant truncal mutation in dMMR CRC. Thus, combination of PIK3CA mutation and MMR status might determine a specific group of CRC to select treatment or elevate prognosis.
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PMID:Prevalence and characteristics of PIK3CA mutation in mismatch repair-deficient colorectal cancer. 3232 87


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