Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We also compared the effect of a B-Raf small inhibitory RNA construct and the B-Raf kinase inhibitor AAL881 on both B-Raf wild-type and mutant thyroid carcinoma cell lines. We found a high prevalence of the T1799A (V600E) mutation in papillary and anaplastic carcinoma specimens and cell lines. There was no difference in patient age, B-Raf expression, Ki67 immunostaining, or clinical stage at presentation between wild-type and BRAF(V600E) specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAF(V600E) patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-Raf(V600E) induced a comparable reduction of viability in both wild-type and BRAF(V600E) mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAF(V600E)-harboring cells than wild-type ones, possibly because of better inhibitory activity against B-Raf(V600E). We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-Raf(V600E) may provide clinical benefit for patients with thyroid cancer.
Mol Cancer Ther 2007 Mar
PMID:Targeting BRAFV600E in thyroid carcinoma: therapeutic implications. 1736

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO'90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor-induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation.
Mol Cancer Ther 2007 Apr
PMID:Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer. 1743 Nov 11

16alpha-Hydroxy-dehydroepiandrosterone (16alpha-OH-DHEA) belongs to the products of extensive DHEA metabolism in mammalian tissues. It is a precursor of 16alpha-hydroxylated estrogens, increased levels of which are associated with autoimmune disorders. A highly specific radioimmunoassay of unconjugated 16alpha-OH-DHEA was developed and evaluated. Polyclonal rabbit antisera were raised against 3beta,16alpha-dihydroxy-17,19-dione-19-O-(carboxymethyloxime) and 3beta,16alpha-dihydroxy-7,17-dione-7-O-(carboxymethyloxime) BSA conjugates. Two methods were used for preparation of the conjugates. Homologous radioiodinated derivatives with tyrosine methyl ester were prepared as tracers. While antisera to 7-CMO cross-reacted with DHEA as much as by 58%, the cross-reaction of the chosen antiserum prepared via 19-oxogroup by micellar conjugation technique with 16beta-OH-DHEA was only 0.13% and with all other structurally related steroids, including DHEA were lower than 0.01%. The detection limit was 0.017 pmol (5.7 pg)/tube, the average intra- and inter-assay coefficients of variation were 8.2 and 11.4%, respectively. Mean recovery of serum spiked with 16alpha-OH-DHEA varied between 80 and 110%, the results were independent on sample dilution. 16alpha-OH-DHEA concentrations in 18 randomly selected sera, including 6 samples from patients with thyroid cancer were compared with results obtained by earlier GC-MS method. Physiological levels of 16alpha-OH-DHEA in 316 sera (184 females and 132 males) analyzed so far varied between 0.0 and 1.86 nmol/l.
J Steroid Biochem Mol Biol 2007 May
PMID:A novel radioimmunoassay of 16alpha-hydroxy-dehydroepiandrosterone and its physiological levels. 1746 80

The molecular mechanism responsible for cadmium-induced cell death in thyroid cancer cells (FRO) is unknown. We demonstrated that apoptosis of FRO cells induced by cadmium was concentration and time dependent. Cadmium caused the rapid elevation of intracellular calcium and induced phosphorylation of Akt, p53, JNK, ERK and p38. Inhibition of PI3K/Akt attenuated the cadmium-induced apoptosis, but the inhibition of JNK inhibitor, ERK or p38 aggravated it, indicating that activation of PI3K/Akt was a pro-apoptosis signal in response to cadmium treatment, whereas the activation of stress-activated protein kinase JNK, ERK and p38 functioned as survival signals to counteract the cadmium-induced apoptosis. Buffering of the calcium response attenuated mitochondrial impairment, recovered the cadmium-activated Akt, p53, JNK, ERK and p38, and subsequently blocked the apoptosis. These results suggested that apoptosis induced by cadmium in FRO cells was initiated by the rapid elevation of intracellular calcium, followed by calcium-mediated activation of PI3K/Akt and mitochondrial impairment.
Cell Mol Life Sci 2007 Jun
PMID:Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells. 1751 53

Anaplastic thyroid carcinoma (ATC) remains one of the most lethal human cancers. We hypothesized that sorafenib, a multikinase inhibitor of the BRaf, vascular endothelial growth factor receptor-2, and platelet-derived growth factor receptor-beta kinase, would decrease tumor growth and angiogenesis in an orthotopic model of ATC. The in vitro antiproliferative and proapoptotic effects of sorafenib on ATC cell lines were examined. To study the in vivo effects of sorafenib on orthotopic ATC tumors in nude mice, sorafenib was given p.o. at 40 or 80 mg/kg daily. Intratumoral effects were studied using immunohistochemical analysis. The effect of sorafenib on survival of the mice was also studied. Sorafenib inhibited the in vitro proliferation of ATC cell lines. Sorafenib also significantly inhibited tumor angiogenesis via the induction of endothelial apoptosis in an orthotopic model of thyroid cancer. As result, the growth of orthotopic ATC xenografts was reduced and the survival of the test animals was improved. Sorafenib exerts significant antitumor activity in an orthotopic xenograft model of ATC via a potent antiangiogenic effect. The antiangiogenic effects of sorafenib suggest that its use in clinical setting may not depend on the BRAF mutational status of thyroid tumors. Given the lack of curative options for patients with ATC, sorafenib warrants further study as a therapeutic agent against ATC.
Mol Cancer Ther 2007 Jun
PMID:Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. 1757 7

Among the group of bioactive sphingolipids, sphingosylphosphorylcholine (SPC) has been known to induce both antiproliferative and proliferative effects depending on cell type. In the present investigation we show that SPC (1-10 microM) reduced the proliferation of FRO cells (an anaplastic thyroid carcinoma cell line) in a concentration dependent manner. The effect was pertussis toxin insensitive, and independent of phospholipase C, protein kinase C, p38 kinase, or jun kinase. In addition to inhibiting the migration of FRO cells, application of SPC induced a rapid (<10 min) rounding of the cells, which was dependent on extracellular sodium. However, DAPI staining and caspase-3 analysis could not reveal any apoptotic effects of SPC. Furthermore, when cells treated with SPC for 24h were washed and replated, they continued to grow, albeit somewhat slower than control cells. Flow cytometry analysis revealed a significant increase in the population of cells in the G2-M phase, and a reduction in S phase. SPC reduced the phosphorylation of Akt with about 50% and evoked a substantial decrease in the amount of phosphorylated mitogen-activated protein (MAP) kinase. In cells treated with the PI3 kinase inhibitor wortmannin, both migration and proliferation were inhibited, as well as the amount of phosphorylated MAP kinase. Treatment of the cells with either SPC or wortmannin increased the levels of p21, but decreased that of cyclin B1 and Cdc2. Taken together, SPC is an effective suppressor of thyroid cancer cell proliferation and migration, and this effect is, in part, mediated by inhibition of both the PI3K-Akt and the MAP kinase signalling pathways.
Mol Cell Endocrinol 2007 Aug 15
PMID:Antiproliferative effect of sphingosylphosphorylcholine in thyroid FRO cancer cells mediated by cell cycle arrest in the G2/M phase. 1760 21

Iodine-124 is a positron-emitting iodine isotope, enabling measurement of iodine uptake using positron emission tomography (PET). There is a number of situations where the use of (124)I-PET/computed tomography (CT) can improve the current clinical practice in the diagnosis and treatment of thyroid cancer. Firstly, (124)I-PET/CT can aid in the staging of patients, because of better detection of metastatic disease and measurement of metabolic tumour volume, and thus separate low-risk from high risk patients. Secondly, the much higher sensitivity and spatial resolution of PET compared to gamma scintigraphy can also improve detection of recurrent disease. Furthermore, (124)I-PET can be used for patient-specific radioiodine therapy radiation dosimetry. Simultaneous administration of the therapeutic dose of (131)I and a tracer dose of (124)I allows for accurate measurement of iodine uptake during therapy. The decay scheme of (124)I, with few positrons and many gamma rays emitted per decay, often simultaneously, poses a challenge to quantitative PET imaging. Improved correction methods and the use of last-generation PET/CT scanners with faster electronics and better energy resolution can overcome this.
Q J Nucl Med Mol Imaging 2008 Mar
PMID:The role of (124)I-PET in diagnosis and treatment of thyroid carcinoma. 1765 2

p21-Activated kinases (PAKs) are regulators of cell motility and proliferation. PAK activity is regulated in part by phosphoinositide-dependent kinase 1 (PDK1). We hypothesized that reduced PAK activity was involved in the effects of 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a previously characterized PDK1 inhibitor derived from celecoxib. In three human thyroid cancer cell lines, OSU-03012 inhibited cell proliferation with reduced AKT phosphorylation by PDK1. OSU-03012 unexpectedly inhibited PAK phosphorylation at lower concentrations than PDK1-dependent AKT phosphorylation in two of the three lines. In cell-free kinase assays, OSU-03012 was shown to inhibit PAK activity and compete with ATP binding. In addition, computer modeling predicted a docking site for OSU-03012 in the ATP binding motif of PAK1. Finally, overexpression of constitutively activated PAK1 partially rescued the ability of motile NPA thyroid cancer cells to migrate during OSU-03012 treatment, suggesting that inhibition of PAK may be involved in the cellular effects of OSU-03012 in these cells. In summary, OSU-03012 is a direct inhibitor of PAK, and inhibition of PAK, either directly or indirectly, may be involved in its biological effects in vitro.
Mol Pharmacol 2007 Nov
PMID:2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a celecoxib derivative, directly targets p21-activated kinase. 1767 71

One form of functional proteomics entails profiling of genuine activities, as opposed to surrogates of activity or active "states," in a complex biological matrix: for example, tracking enzyme-catalyzed changes, in real time, ranging from simple modifications to complex anabolic or catabolic reactions. Here we present a test to compare defined exoprotease activities within individual proteomes of two or more groups of biological samples. It tracks degradation of artificial substrates, under strictly controlled conditions, using semiautomated MALDI-TOF mass spectrometric analysis of the resulting patterns. Each fragment is quantitated by comparison with double labeled, non-degradable internal standards (all-d-amino acid peptides) spiked into the samples at the same time as the substrates to reflect adsorptive and processing-related losses. The full array of metabolites is then quantitated (coefficients of variation of 6.3-14.3% over five replicates) and subjected to multivariate statistical analysis. Using this approach, we tested serum samples of 48 metastatic thyroid cancer patients and 48 healthy controls, with selected peptide substrates taken from earlier standard peptidomics screens (i.e. the "discovery" phase), and obtained class predictions with 94% sensitivity and 90% specificity without prior feature selection (24 features). The test all but eliminates reproducibility problems related to sample collection, storage, and handling as well as to possible variability in endogenous peptide precursor levels because of hemostatic alterations in cancer patients.
Mol Cell Proteomics 2008 Mar
PMID:A sequence-specific exopeptidase activity test (SSEAT) for "functional" biomarker discovery. 1798 38

Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases. The most frequent type of thyroid malignancy is papillary carcinoma, which constitutes approximately 80% of all cases. Papillary carcinomas frequently have genetic alterations leading to the activation of the MAPK signal pathway. Those include RET/PTC rearrangement and point mutations of the BRAF and RAS genes. Mutations in these genes are found in over 70% of papillary carcinomas and they rarely overlap in the same tumor. Frequent genetic alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPAR gamma rearrangement. RET point mutations are crucial for the development of medullary thyroid carcinomas. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. Detection of these genetic alterations using molecular techniques is important for preoperative fine-needle aspiration diagnosis, prognosis and treatment of thyroid cancer.
Expert Rev Mol Diagn 2008 Jan
PMID:Molecular genetics of thyroid cancer: implications for diagnosis, treatment and prognosis. 1808 33


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