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)

Medullary thyroid carcinoma in both sporadic and familial forms is a curable disease if detected early and treated by the proper surgery. The advent of genetic screening for the RET protooncogene portends great promise in the earlier diagnosis and treatment of familial forms of MTC. New chemotherapy protocols have produced some tumor regression in patients with metastatic MTC. Improved use of Adriamycin and hyper-fractionated radiotherapy combined with debulking procedures has prolonged survival in anaplastic thyroid cancer. Thyroid gland lymphoma, if diagnosed early and treated by combined chemoradiotherapy, carries a good prognosis for survival. The best treatment for thyroid sarcomas and SCC of the thyroid is early diagnosis and aggressive surgery combined with radiotherapy.
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PMID:Thyroid cancers. II. Medullary, anaplastic, lymphoma, sarcoma, squamous cell. 884 33

Recently we demonstrated that several flavonoids can inhibit the proliferation of certain human thyroid cancer cell lines. Among the flavonoids tested, apigenin and luteolin are the most effective inhibitors of these tumor cell lines. In the present study, we investigated the signal transduction mechanism associated with the growth inhibitory effect of apigenin, using a human anaplastic thyroid carcinoma cell line, ARO (UCLA RO-81-A-1). Using Western blot method, it was shown that the inhibitory effect of apigenin on ARO cell proliferation is associated with an inhibition of both EGFR tyrosine autophosphorylation and phosphorylation of its downstream effector mitogen activated protein (MAP) kinase. Protein levels of these signaling molecules were not affected. The inhibitor of phosphorylation by apigenin occurred within 30 min and continued for 4 h. A dose-dependent inhibition was demonstrable ranging from 12.5 microM to 50 microM. The level of phosphorylated c-Myc, a nuclear substrate for MAPK, was depressed from 16-48 h after apigenin treatment, finally leading to a programmed cell death involving DNA fragmentation. Furthermore, treatment with apigenin resulted in the inhibition of both anchorage-dependent and anchorage-independent thyroid cancer cell growth. In summary, apigenin is a promising inhibitor of signal transduction pathways that regulate the growth (anchorage-dependent and independent) and survival of human anaplastic thyroid cancer cells. Apigenin may provide a new approach for the treatment of human anaplastic thyroid carcinoma for which no effective therapy is presently available.
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PMID:Signal pathways involved in apigenin inhibition of growth and induction of apoptosis of human anaplastic thyroid cancer cells (ARO). 1062 90

Anaplastic thyroid carcinomas (ATCs) are highly aggressive, extremely lethal human cancers with poor therapeutic response. Chemokines are a superfamily of small cytokine-like proteins that induce, through their interaction with G protein-coupled receptors, cytoskeletal rearrangement, firm adhesion to endothelial cells, and directional migration. In this study, we characterized the expression of CXC chemokine receptor 4 (CXCR4) and analyzed its functions in ARO cells, a human ATC cell. The normal primary cultured thyroid cells and ATC cell lines expressed CXCR4 and stromal cell-derived factor (SDF)-1 alpha transcripts, detected by RT-PCR. Fluorescence activated cell sorting analysis of CXCR4 expression in normal and ATC cells showed that ARO cells expressed significant levels of CXCR4. FRO, NPA, and normal thyroid cells did not express membrane CXCR4, as determined by fluorescence activated cell sorting analysis. To identify the functional role of CXCR4 in ARO cells, we treated ARO cells with SDF-1 alpha and analyzed the signaling pathways, cellular migration, and proliferation. SDF-1alpha enhanced the migration but did not affect the proliferation of ARO cells or activate the Janus kinase/signal transducer and activator of transcription signaling pathways. However, SDF-1 alpha/CXCR4 activation resulted in phosphorylation of the p70S6 kinase and its target protein, ribosomal S6 protein, and also activation of the ERK1/ERK2 signaling pathways. Furthermore, SDF-1 alpha/CXCR4- mediated activation of the p70S6 kinase and phosphorylation of the S6 protein were inhibited by treatment with an mTOR/FRAP inhibitor. The specificity of the CXCR4-mediated migration of ARO cells was demonstrated by the dose-dependent inhibition of migration by neutralizing anti-CXCR4. The ATC cells, FRO and NPA, which do not express CXCR4, did not demonstrate significant SDF-1 alpha-mediated migration in vitro. In addition, the CXCR4-mediated migration of ARO cells was inhibited by treatment with pertussis toxin (a Gi-protein inhibitor) and PD 98059 (a mitogen-activated ERK kinase inhibitor) but not by LY294002 and wortmanin, phosphatidylinositol 3-kinase inhibitors. These findings suggest that a subset of ATC cells expresses functional CXCR4, which may be important in tumor cell migration and local tumor invasion.
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PMID:CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells. 1251 84

Understanding the detailed mechanisms of a chemotherapeutic agent action on cancer cells is essential for planning the clinical applications because drug effects are often tissue and cell type specific. This study set out to elucidate the molecular pathways of Taxol effects in human anaplastic thyroid cancer cells using as an experimental model four cell lines, ARO, KTC-2, KTC-3 (anaplastic thyroid cancer), and FRO (undifferentiated follicular cancer), and primary thyrocytes. All cell lines were sensitive to Taxol, although to different extent. In primary thyrocytes the drug displayed substantially lower cytotoxicity. In thyroid cancer cells, Taxol-induced changes characteristic to apoptosis such as poly (ADP-ribose) polymerase and procaspase cleavage and alteration of membrane asymmetry only within a narrow concentration range, from 6 to 50 nm. At higher concentration, other form(s) of cell death perhaps associated with mitochondrial collapse was observed. Low doses of Taxol enhanced Bcl2 phosphorylation and led to its degradation observed on the background of a sustained or increasing Bax level and accumulation of survivin and X-chromosome-linked inhibitor of apoptosis. c-jun-NH(2) terminal kinase activation was essential for the apoptosis in anaplastic thyroid cancer cells, whereas Raf/MAPK kinase/ERK and phosphatidylinositol-3-OH kinase/Akt were likely to comprise main survival mechanisms. Our results suggest an importance of cautious interpreting of biological effects of Taxol in laboratory studies and for determining optimal doses of Taxol to achieve the desired therapeutic effect in anaplastic thyroid cancers.
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PMID:Molecular mechanisms of the effects of low concentrations of taxol in anaplastic thyroid cancer cells. 1504 68

Thyroid carcinomas represent only 1% of all human malignancies, but more than 90% of endocrine tumors. It can be histologically divided into papillary, follicular, anaplastic or medullary thyroid carcinomas. Here we report the genetic causes of the development of these tumors. For papillary thyroid carcinoma formation of fused genes of tyrosine kinases (RET proto-oncogene, NTRK1 proto-oncogene and met proto-oncogene) with other genes is typical. They can activate these kinases and induce mutation in BRAF gene. The presence of PAX8/PPARgamma fused gene and ras mutations are important in the development of follicular thyroid carcinoma. Anaplastic thyroid carcinoma derives from the dedifferentiation of papillary and follicular carcinomas as a consequence of mutation or loss of heterozygozity in p53 gene. Medullary thyroid carcinoma comes from parafollicular C-cells, where point somatic and germ-line mutations (in familial form of medullary thyroid carcinoma or in multiple endocrine neoplasia type 2) in the RET proto-oncogene determine its development. Identification of these specific genetic alternations for each type of carcinoma can contribute to precision of the diagnosis, explanation of the origin of carcinomas, establishment of prognosis of the disease or in future as a tool for the target gene therapy.
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PMID:[Genetic causes of the thyroid carcinomas]. 1558 14

Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.
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PMID:BRAF mutation in thyroid cancer. 1594

A radiation etiology is well known in thyroid carcinogenesis. RET oncogene rearrangement is the most common oncogenic alteration in Chernobyl-related papillary thyroid cancer (PTC). To find the characteristic alteration associated with RET rearrangements in radiation-induced thyroid cancers, we analyzed the RET oncogene by fluorescence in situ hybridization. The fluorescence in situ hybridization technique has the possibility of detecting RET rearrangements at a single-cell level regardless of the specific fusion partner involved and directly reveals RET copy number on a per-cell basis. Our study demonstrated RET amplification in all 3 cases of radiation-associated thyroid cancers but not in sporadic well-differentiated PTC (n = 11). Furthermore, RET amplification was observed in all 6 cases of sporadic anaplastic thyroid cancers (ATCs). The frequency of RET amplification-positive cells was higher in ATC (7.2%-24.1%) than in PTC (1.5%-2.7%). The highest frequency of RET amplification-positive cells was observed among ATC cases with a strong p53 immunoreactivity. In conclusion, we found RET amplification, which is a rare oncogenic aberration, in thyroid cancer. This report is the first one to suggest the presence of RET amplification in PTC and ATC. RET amplification was correlated with radiation-associated, high-grade malignant potency, and p53 accumulation, suggesting genomic instability. RET amplification might be induced by a high level of genomic instability in connection with progression of thyroid carcinogenesis and, subsequently, be associated with radiation-induced and/or high-grade malignant cases.
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PMID:RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy. 1727 Feb 45

The incidence of thyroid cancer is rapidly increasing in the United States. A large number of incidentalomas are found during routine head and neck evaluations. The diagnostic workup still revolves around fine needle aspiration biopsy. Ultrasound guided fine needle aspiration biopsy is likely to yield the best results. Surgical resection offers the best treatment choice. Controversy continues in relation to total versus less than total thyroidectomy. The incidence of complications is inversely proportional to the extent of surgery and obviously related to the experience of the operating surgeon. The decision regarding the extent of thyroidectomy should be based on prognostic factors and risk groups. Prognostic factors are well defined, such as age, grade of the tumor, extrathyroidal extension, size, distant metastasis, and histology. Nodal metastasis has minimal implications. Based on prognostic factors, thyroid cancer can be divided into low, intermediate and high risk groups. In the high risk group and in selected intermediate risk patients, radioactive iodine dosimetry and ablation should be considered after total thyroidectomy. PET scanning and the use of recombinant TSH have been major advances in follow-up care for patients with thyroid cancer. Thyroglobulin appears to be a very good tumor marker for follow-up. No major breakthrough is noted in the management of anaplastic thyroid cancer, however, identification of RET mutation has been extremely helpful in evaluating the family members of the patient with medullary thyroid cancer with strong consideration given to total thyroidectomy.
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PMID:Advances in the management of thyroid cancer. 1746 86

Molecular mechanism of thyroid carcinogenesis has been well studied through the discovery of genetic abnormalities such as RET/PTC rearrangement and BRAF mutation, both of which constitutively activate MAP kinase pathway and are frequently found in papillary thyroid cancer. The TP53 mutation is thought to play a critical role in transformation of differentiated thyroid cancer into anaplastic thyroid cancer. Besides these genetic alterations, cancer stem cell theory has recently been applied to thyroid field. A better understanding of thyroid cancer stem cell may not only ameliorate our comprehension of thyroid cancer biology, but also open the possibility of innovative diagnostic procedures and development of novel targeted therapies. In this article, we mainly review thyroid carcinogenesis based on the evidence of radiation-induced cancer and cancer stem cell hypothesis.
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PMID:[Molecular mechanism of thyroid carcinogenesis]. 1801 55

In this study, we evaluated the activity of two novel pyrazolopyrimidine derivatives (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concentrations of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 microM Si 34 determined a decrease of cell counts by approximately 25% and approximately 75% compared with those of control cells respectively. Similar findings were observed using Si 35. Treatment with both Si 34 and Si 35 at 10 microM increased cell mortality also ( approximately 29% and approximately 18% respectively). At these concentrations, a decrease in cyclin D1 levels was observed. To improve the biopharmaceutical properties, a liposome formulation was prepared. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 microM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were associated with weak apoptotic death. Inhibition of epidermal growth factor-stimulated src and ERK phosphorylation, as well as reduction of migration properties of ARO cells was also observed. Moreover, the growth of tumor xenografts induced in severe combined immunodeficiency (SCID) mice was inhibited by i.v. administration of 25-50 mg/kg of the drug liposomal formulation. In conclusion, the liposomal preparation of this novel pyrazolopyrimidine derivative appears to be a promising tool for the treatment of anaplasic thyroid cancer.
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PMID:Cytotoxic effects of a novel pyrazolopyrimidine derivative entrapped in liposomes in anaplastic thyroid cancer cells in vitro and in xenograft tumors in vivo. 1850 2


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