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)

A novel pentacyclic acridine, 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4), has been identified as a potent inhibitor of telomerase in the cell-free telomeric repeat amplification protocol (TRAP). Modeling and biophysical studies suggest that RHPS4 inhibits telomerase through stabilization of four-stranded G-quadruplex structures formed by single-stranded telomeric DNA. In contrast to G-quadruplex interactive telomerase inhibitors described previously, RHPS4 inhibited telomerase at submicromolar levels (50% inhibition in the TRAP assay at 0.33 +/- 0.13 microM). Moreover, RHPS4 exhibited a wide differential between this potent inhibition of telomerase and acute cellular cytotoxicity (mean IC(50) value of 7.02 microM in 4-day growth inhibition assay). RHPS4, when added to 21NT breast cancer cells at nonacute cytotoxic concentrations (200 nM) every 3 to 4 days, induced a marked cessation in cell growth after 15 days. Similar effects were observed using another cell line possessing relatively short telomeres, A431 human vulval carcinoma cells, but not in a human ovarian carcinoma cell line (SKOV-3) possessing relatively long telomeres. In 21NT cells, growth cessation was accompanied by an increase in cells in the G(2)/M phase of the cell cycle, a reduction in cellular telomerase activity, and a lower expression of the hTERT gene. These effects occurred in the absence of a detectable reduction in telomere length as measured by slot blotting. RHPS4 also induced a cessation of growth of GM847 cells that maintain telomeres by a nontelomerase alternative mechanism for lengthening telomeres (ALT) after 15 days. RHPS4 represents a promising G-quadruplex interactive small molecule that is a potent cell-free inhibitor of human telomerase and induces growth inhibitory effects in human tumor cell lines after prolonged (2-week) exposure to nonacute cytotoxic drug concentrations.
Mol Pharmacol 2001 Nov
PMID:Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. 1164 26

Experimental evidence suggests that attachment of ovarian carcinoma cells to the peritoneal mesothelium involves the interaction between CD44 on ovarian carcinoma cells and hyaluronic acid on mesothelial surfaces. The authors therefore evaluated local and disseminated ovarian serous carcinomas for the expression of standard CD44 and CD44 splice variants CD44v5, CD44v6, and CD44v7/8. The relative amount of hyaluronic acid (HA) in stroma surrounding tumor nests also was studied. Using immunohistochemistry and archival tissue, 14 serous ovarian carcinomas confined to the ovary (stage I) and 14 serous ovarian carcinomas with peritoneal implants and positive peritoneal fluid (stage III) were stained with antibodies to standard CD44, CD44v5, CD44v6, and CD44v7/8. All tissues also were analyzed for HA using a HA binding peptide. Immunostaining was classified as focal or diffuse and graded from 1 to 4 based on intensity. Immunoreactivity for standard CD44 was seen in 5 of 14 (36%) stage I tumors and 10 of 14 (71%) stage III tumors. Similarly, immunoreactivity with CD44v5 was seen in 2 of 14 (14%) stage I tumors and 9 of 14 stage III tumors (64%). Hyaluronic acid was present in the stroma surrounding all stage I and III tumors, but was more intense in the stroma adjacent to metastatic implants from stage III carcinomas. Tumor cells were uniformly negative for intracellular HA. These results suggest that CD44S and CD44v5 are differentially expressed in early (stage I) and advanced (stage III) ovarian serous carcinomas and support previous studies that suggest a role for CD44 and stromal HA in the dissemination of ovarian epithelial cancer.
Appl Immunohistochem Mol Morphol 2001 Dec
PMID:Expression of CD44S and CD44v5 is more common in stage III than in stage I serous ovarian carcinomas. 1175 56

c-Ets1 controls the expression of some genes involved in extracellular matrix remodeling. To elucidate the involvement of c-Ets1 in epithelial ovarian carcinogenesis, we investigated the role of the proto-oncogene c-ets1 in the regulation of physiological processes such as cell proliferation, differentiation, and tumor invasion. Using fluorescent immunohistochemistry, we analyzed serial frozen sections for c-Ets1 protein expression in 26 patients with ovarian epithelial carcinoma, 10 patients with benign cystadenoma of the ovary, and 10 premenopausal patients with normal ovaries. We analyzed the relationship between the percentage of c-Ets1 stained cells in a patient and characteristics of the patient including histological classification, clinical stage, histological grade, and clinical outcome. c-Ets1 was not detected in any cases of benign ovarian cystadenoma. Most of the c-Ets1 proteins were found in the cytoplasm and some in the nucleus of epithelial ovarian cancer tissues. Moreover, c-Ets1 was strongly expressed in the head portion of papillary cancer tissues that had invaded the stroma. c-Ets1 expression was significantly associated with clinical stage (p<0.01), histological grade (p<0.01), and clinical outcome (p<0.01). Survival data were available for all patients and univariate Cox regression analysis showed that c-Ets1 expression was significantly associated with a poor prognosis (p<0.05). Our results demonstrate that c-Ets1 expression in epithelial ovarian cancer correlates to the malignant potential of the tumor.
Int J Mol Med 2002 Mar
PMID:c-Ets1 is a promising marker in epithelial ovarian cancer. 1183 35

Ovarian surface epithelial cells have been implicated in the genesis of common ovarian cancers. The integrity of DNA of ovarian surface epithelial cells contiguous with the ovulatory stigma becomes compromised during the rupture process; most cells degenerate by apoptosis, however some, bearing sublethal lesions, persist along the margins of ovulated follicles. Clonal expansion of a genetically-damaged surface epithelial cell (i.e. with unrepaired DNA, but not committed to death) can presumably give rise to ovarian carcinoma. It was hypothesized that estradiol and progesterone regulate ovarian surface epithelial cell-cycle dynamics associated with folliculo-luteal transitions and ovulatory wound repair/remodeling. Progesterone up-regulated the tumor suppressor p53 and inhibited baseline and estradiol-stimulated proliferation of cultured sheep ovarian surface epithelial cells. Anti/mitotic responses to steroid hormones were transcriptionally- and receptor-dependent. Rates of apoptosis (DNA fragmentation) were unaffected by progesterone. High concentrations of estradiol, via a nongenomic (perhaps antioxidant) mechanism, suppressed basal and H(2)O(2)-induced apoptosis. We suggest that, progesterone serves to inhibit proliferation of ovarian surface epithelial cells throughout the luteal phase--providing the time (growth arrest) required to correct any metabolic disturbances to DNA that are perpetrated as an inevitable by-product of the ovulatory process. With luteolysis and dominance of an estrogenic preovulatory follicle the ovarian surface epithelium is then regenerated. Thus, it is conceivable that perturbations to the steroid hormonal milieu of ovarian cycles could be a predisposing factor for cancerous transformation of an ovarian surface epithelial cell.
Mol Cell Endocrinol 2002 Jan 15
PMID:Steroid hormonal regulation of proliferative, p53 tumor suppressor, and apoptotic responses of sheep ovarian surface epithelial cells. 1185 Jan 22

Endothelin-1 (ET-1) is a powerful mitogenic peptide produced by different tumors. In ovarian carcinoma cells, ET-1 acts as an autocrine growth factor, selectively through ET(A) receptor (ET(A)R), which is predominantly expressed in tumor cells. The aim of this study was to examine whether ET-1 plays a role in the sensitivity of three ovarian carcinoma cell lines (OVCA 433, HEY, and SK-OV-3) to apoptosis induced by two different stimuli. Our results demonstrated that the addition of ET-1 markedly inhibited serum withdrawal and paclitaxel-induced apoptosis in a concentration-dependent manner, as demonstrated by Annexin-V assay, sub-G(1) peak in DNA content histograms, internucleosomal DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling method. Pretreatment of the cells with an ET(A)R antagonist, BQ 123, reversed the ET-1-induced protective effect. Paclitaxel-induced apoptosis resulted in the phosphorylation of Bcl-2 that was suppressed by the addition of ET-1. Further analysis of the signaling pathway demonstrated that ET-1 stimulated Akt activation. The phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin blocked ET-1-induced Akt phosphorylation. Inhibition of ET-1-stimulated mitogen-activated protein kinase activity did not affect ET-1 protection from paclitaxel-mediated apoptosis. Moreover, BQ 123 blocked the Akt-mediated pathway activated by ET-1, sensitizing ovarian carcinoma cells to paclitaxel treatment. These results establish a novel role for ET-1 in determining protection of ovarian carcinoma cells against paclitaxel-induced apoptosis through Bcl-2-dependent and PI3-K-mediated Akt pathways and suggest that ET-1 and ET(A)R could represent important targets for anticancer therapy.
Mol Pharmacol 2002 Mar
PMID:Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. 1185 32

Cisplatin is among the most effective chemotherapeutic agents in the treatment of human ovarian cancer. The cytotoxicity of cisplatin results primarily from its ability to bind covalently to DNA and prevent DNA replication and transcription. The ubiquitin-proteasome pathway plays important roles in a broad array of basic cellular processes. Lactacystin is a selective inhibitor of the proteasome that can inhibit the ubiquitin pathway. However, the effect of lactacystin on DNA repair and the antitumor activity of cisplatin in ovarian cancer have not been evaluated. We report in this work that lactacystin, at concentrations that do not appear harmful, increased cisplatin toxicity in three resistant human ovarian carcinoma cell lines. In addition, lactacystin significantly enhanced DNA platination and decreased DNA repair of cisplatin-DNA adducts in these cell lines, as measured by atomic absorption spectrometry. Furthermore, Northem blot analysis and in vitro nuclear transcript elongation assay demonstrated that lactacystin dramatically reduced the steady-state mRNA expression and the rate of transcription of the DNA repair gene ERCC-1 in these cells. These observations indicate that proteasome inhibition has impact on nucleotide excision repair in several ways: i/ the normal ERCC-1 message upregulation is suppressed; ii/ cisplatin-DNA adduct repair is inhibited, and iii/ DNA platination, as well as cisplatin cytotoxicity, is enhanced.
Cell Mol Biol (Noisy-le-grand) 2001
PMID:Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC-1 expression. 1193 75

The objective of this study was to analyze the correlation between matrix metalloproteinases (MMPs) and angiogenic genes and survival in advanced-stage ovarian carcinomas. Primary and metastatic ovarian carcinomas from patients diagnosed with FIGO stage III-IV disease and followed up to 20 years were studied using mRNA in situ hybridization (ISH). Expression of MMP-2, MMP-9, membrane-type 1-MMP (MT1-MMP), the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (bFGF) was studied. MMP-2, MMP-9 and TIMP-2 mRNA was detected in both tumor and stromal cells, while MT1-MMP was largely confined to tumor cells. In univariate analysis of primary tumors, TIMP-2 and MMP-9 mRNA expression correlated with poor outcome. In metastatic lesions, mRNA expression of TIMP-2, MMP-2, and MT1-MMP correlated with poor survival. In a multivariate analysis of primary tumors, TIMP-2 expression in stromal cells (P=0.006) and MMP-9 expression in tumor cells (P=0.011) retained their predictive value. Intense expression of bFGF mRNA and weak expression of IL-8 mRNA was detected in both stromal and tumor cells in most cases, while VEGF mRNA expression was limited to a few cases. Angiogenic mRNA expression showed no correlation with disease outcome in survival analysis (P>0.05). We conclude that bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.
Mol Cell Endocrinol 2002 Feb 22
PMID:The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma. 1198 10

We have used human ovarian carcinoma BG-1 cells to determine which steps in the pathway of estrogen signaling are disrupted by the aryl hydrocarbon receptor (AhR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We report that inhibition of estrogen signaling occurs between 7 and 18 h after TCDD treatment and that this effect is not caused by a decrease in estradiol concentration. TCDD decreased estrogen receptor (ER) levels in cells grown in standard medium; however, in estrogen-stripped medium, ER (but not AhR) levels were dramatically reduced (approximately 7-fold) but were not decreased further by TCDD. Because the absolute level of estradiol inducibility and inhibition by TCDD was similar in either medium, decreases in ER are not responsible for the antiestrogenic effect. The AhR also did not bind to the estrogen-responsive element (ERE) in vitro, and ERE binding by nuclear ER complexes was not decreased by TCDD, indicating that the effect of TCDD does not involve direct competition between the AhR and ER for DNA binding. However, inhibition of protein synthesis by cycloheximide blocked the TCDD-induced inhibition of ER-dependent gene expression. Overall, our results are consistent with the action of a TCDD-induced protein at a step(s) after ER-DNA binding, most likely at the level of gene transcription.
Mol Pharmacol 2002 Jun
PMID:Analysis of the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human ovarian carcinoma BG-1 cells. 1202 1

GnRH has been implicated as an important local autocrine and paracrine factor in regulating ovarian function. However, to date, the transcriptional regulation of GnRH receptor (GnRHR) gene in human ovary remains poorly understood. Here we report the characterization of a new upstream promoter for the GnRHR gene in human granulosa-luteal cells. Using progressive deletion analysis, a region between nucleotide -1300 and -1018 (relative to the translation start site) was shown to exhibit the highest promoter activities in two immortalized human granulosa-luteal cell lines, SVOG-4o and SVOG-4m. Two putative CCAAT/enhancer binding protein (C/EBP) motifs and one GATA motif were identified within this region. Mutational studies showed that these three motifs cooperated synergistically to regulate GnRHR gene transcription in the granulosa cells but not in other cell types including human ovarian carcinoma OVCAR-3, human embryonic kidney-293 (HEK-293) and mouse pituitary gonadotrope-derived alphaT3-1 cells. Surprisingly, by competitive EMSAs, we found that an Oct-1 consensus sequence was able to inhibit protein complex formation with the distal C/EBP motif, suggesting a possible cross-talk between the Oct-1 transcription factor and this C/EBP motif. Taken together, our results strongly indicate a role of the C/EBP and GATA motifs in regulating GnRHR gene transcription in human granulosa-luteal cells and further suggest that tissue-specific expression of human GnRHR gene is mediated by differential promoter usage.
Mol Endocrinol 2002 Jul
PMID:Characterization of a new upstream GnRH receptor promoter in human ovarian granulosa-luteal cells. 1208 50

We previously reported the identification of three minimal regions of deletion on the short arm of chromosome 3 (3p) in epithelial ovarian tumor specimens, suggesting that the inactivation of tumor-suppressor genes in these regions may be important in terms of ovarian tumorigenesis. Another previous study of ovarian cancer observed that allele loss of chromosome 179 was frequently found in ovarian tumors that also showed loss of heterozygosity (LOH) of chromosomes 3p, 13q, 17p, and Xp. In an independent study, we also reported a high frequency of LOH for selected chromosome 17 loci in high-grade and late-stage ovarian tumors. We have extended our LOH analysis of chromosome 3p to include 102 ovarian tumor specimens (29 and 73 samples were previously examined for LOH of chromosome 3p and 17 markers, respectively), using additional polymorphic markers, to assess the coordinate LOH of loci representing the three chromosome 3p minimal regions of deletions [von Hippel-Lindau syndrome (VHL), thyroid hormone receptor beta, and fragile histidine triad (FHIT)] and LOH of other important loci [tumor protein 53 (TP53), breast cancer 1 early onset (BRCA1), breast cancer 2 early onset, retinoblastoma 1, ornithine carbamoyltransferase, and androgen receptor] or somatic mutations in TP53. There was a significant association between LOH of any chromosome 3p marker and LOH of any chromosome 17 marker (P = 0.026). The frequency of LOH at the TP53 locus was higher in the group of samples that displayed LOH of a 3p marker (P = 0.019), as was the frequency of LOH at the BRCA1 locus (P = 0.014). LOH of chromosome 3p was noted in four specimens that did not display LOH of either the BRCA1 or the TP53 locus, indicating that LOH of these loci need not precede LOH of the chromosome 3p loci. We found a significant association between LOH of the VHL (3p25) locus and LOH of any chromosome 17 marker (P = 0.005), suggesting that there may be an important relationship, in the tumorigenesis of epithelial ovarian cancer, between a gene at 3p25 and a gene located on chromosome 17. Our results indicate that inactivation of p53 by somatic mutation is unlikely to be a prerequisite to chromosome 3p LOH, because we found no significant association between mutations in TP53 and LOH of the three chromosome 3p loci. The frequency of LOH at the FHIT locus at 3p14 increased significantly with advancing age at diagnosis (P = 0.018), as did the frequency of somatic TP53 mutations (P = 0.008).
Mol Carcinog 2002 Jun
PMID:Comparative analysis of loss of heterozygosity of specific chromosome 3, 13, 17, and X loci and TP53 mutations in human epithelial ovarian cancer. 1211 14


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