Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BRCA1 tumor suppressor gene has previously been implicated in induction of high levels of apoptosis in osteocarcinoma cell lines. Overexpression of BRCA1 was shown to induce an apoptotic signaling pathway involving the c-Jun N-terminal kinase (JNK), but the signaling steps upstream and downstream of JNK were not delineated. To better understand the role of BRCA1 in apoptosis, we examined the effect of wild-type and C-terminal-truncated dominant negative BRCA1 on breast and ovarian cancer cell lines subjected to a number of different pro-apoptotic stimuli, including growth factor withdrawal, substratum detachment, ionizing radiation, and treatment with anticancer agents. All of these treatments were found to induce substantial levels of apoptosis in the presence of wild-type BRCA1, whereas dominant negative BRCA1 truncation mutants diminished the apoptotic response. Subsequent mapping of the apoptotic pathway induced by growth factor withdrawal demonstrated that BRCA1 enhanced signaling through a pathway that sequentially involved H-Ras, MEKK4, JNK, Fas ligand/Fas interactions, and caspase-9 activation. In addition, the pathway functioned independently of the p53 tumor suppressor. These data suggest that BRCA1 is an important modulator of the response to cellular stress and that loss of this apoptotic potential due to BRCA1 mutations may contribute to tumor development.
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PMID:BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines. 1093 85

We found that a short synthetic peptide corresponding to the "antisense homology box" of Fas ligand induced apoptotic cell death of Fas-expressing human ovarian cancer cell lines. The peptide was deduced from residues 256-265 of human Fas ligand, based on the hypothesis that it should contain a specific binding site to the corresponding Fas. Interestingly, the ovarian cancer cell line NOS4, which was sensitive to anti-Fas antibody induced apoptosis, was not affected by the peptide, whereas another cell line, SKOV-3, which was insensitive to anti-Fas antibody, was killed by the peptide. Thus, this short peptide was shown to have a unique activity to induce apoptosis in human ovarian cancer cells in a manner different from anti-Fas antibody.
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PMID:A short peptide derived from the antisense homology box of Fas ligand induces apoptosis in anti-Fas antibody-insensitive human ovarian cancer cells. 1122 89

The efficacy of cisplatin in cancer chemotherapy is limited by the development of resistance. Although the molecular mechanisms involved in chemoresistance are poorly understood, cellular response to cisplatin is known to involve activation of MAPK and other signal transduction pathways. An understanding of early signal transduction events in the response to cisplatin could be valuable for improving the efficacy of cancer therapy. We compared cisplatin-induced activation of three MAPKs, JNK, p38, and ERK, in a cisplatin-sensitive human ovarian carcinoma cell line (2008) and its resistant subclone (2008C13). The JNK and p38 pathways were activated differentially in response to cisplatin, with the cisplatin-sensitive cells showing prolonged activation (8-12 h) and the cisplatin-resistant cells showing only transient activation (1-3 h) of JNK and p38. In the sensitive cells, inhibition of cisplatin-induced JNK and p38 activation blocked cisplatin-induced apoptosis; persistent activation of JNK resulted in hyperphosphorylation of the c-Jun transcription factor, which in turn stimulated the transcription of an immediate downstream target, the death inducer Fas ligand (FasL). Sequestration of FasL by incubation with a neutralizing anti-FasL antibody inhibited cisplatin-induced apoptosis. In contrast, chemoresistance in 2008C13 cells was associated with failure to up-regulate FasL. Moreover, in these cells, selective stimulation of the JNK/p38 MAPK pathways by adenovirus-mediated delivery of recombinant MKK7 or MKK3 led to sensitization to apoptosis through reactivating FasL expression. Thus, the JNK > c-Jun > FasL > Fas pathway plays an important role in mediating cisplatin-induced apoptosis in ovarian cancer cells, and the duration of JNK activation is critical in determining whether cells survive or undergo apoptosis.
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PMID:Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells. 1263 5

The Fas/Fas ligand (FasL) system has been suggested to play an important role in the establishment of an immune privilege status of the tumor by inducing Fas-mediated apoptosis in tumor-specific lymphocytes. However, the role of cell surface-expressed FasL in tumor cell protection has recently become controversial. In this study, we have demonstrated that ascites-derived epithelial ovarian cancer cells lack membranal FasL but constitutively secrete whole, intracellular FasL (37 kDa) via the release of microvesicles. In contrast, normal ovarian surface epithelial cells express, but do not secrete, FasL. We have also identified a heavily glycosylated form of secreted FasL (48 kDa), associated with microvesicles isolated directly from the ascites fluid of patients with ovarian cancer. Following the disruption of the microvesicle membrane, both the 37-kDa and 48-kDa forms of secreted FasL were able to trigger Fas-mediated apoptosis in Jurkat T cells. These results suggest that the release of secreted FasL, and not the membrane form, may provide a mechanism by which tumors might counterattack Fas-bearing immune cells, thus facilitating their escape from immune surveillance and promoting tumor cell survival.
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PMID:Epithelial ovarian cancer cells secrete functional Fas ligand. 1450 Mar 97

The mechanism of action of fenretinide, a synthetic retinoid currently undergoing testing as a chemopreventive and chemotherapeutic agent, is incompletely understood. In the present study, fenretinide caused apoptotic changes, including DNA fragmentation and cleavage of caspase substrates, in six low-passage ovarian cancer cell lines. However, the caspase activation pathway used by this agent varied. Transient transfection of cDNA-encoding cytokine response modifier A (CrmA), a caspase-8 inhibitor, diminished fenretinide-induced death in OV177 cells. Likewise, IETD(OMe)-fluoromethylketone (fmk) inhibited fenretinide-induced apoptosis by >80% in OV177 or OV266 cells and by approximately 50% in OV17, OV167, or OV207 cells. Further analysis demonstrated that inhibition of Fas ligand, tumor necrosis factor-alpha, or TRAIL signaling with blocking reagents did not affect fenretinide-induced apoptosis, raising the possibility that fenretinide activates caspase-8 in a death receptor-independent manner. In contrast, CrmA transfection or IETD(OMe)-fmk treatment did not inhibit fenretinide-induced apoptosis in OV202 cells. These divergent behaviors did not correlate with increased levels of procaspase-10, which is relatively resistant to CrmA and IETD(OMe)-fmk, nor with the expression of procaspase-8 and -9, apoptotic protease activating factor-1, or cellular FLICE-like inhibitory protein. Similarly, fenretinide treatment increased ceramide levels equally in cells that do (OV177) and do not (OV202) rely on caspase-8 to initiate apoptosis. These results indicate that synthetic retinoids can use caspase-8 as an initiating caspase, but they also indicate unexpected heterogeneity in caspase activation pathways among closely related cell lines.
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PMID:Heterogeneous role of caspase-8 in fenretinide-induced apoptosis in epithelial ovarian carcinoma cell lines. 1464 74

The Forkhead family transcription factor FKHRL1 is an inducer of apoptosis in its unphosphorylated form and was recently reported to be a substrate of Akt kinase. We studied the roles of FKHRL1 in both cisplatin-resistant Caov-3 (a papillary adenocarcinoma cell line) and cisplatin-sensitive A2780 human ovarian cancer cell lines. Treatment of Caov-3 cells but not A2780 cells with cisplatin transiently stimulated the phosphorylation of FKHRL1. Transfection experiments revealed that a kinase inactive-mutant of Akt or a triple mutant (TM) of FKHRL1, in which all three of the putative Akt phosphorylation sites were converted to alanine, was unable to phosphorylate the FKHRL1 protein in cells treated with cisplatin. Because the phosphorylated form of FKHRL1 is known to be localized in the cytoplasm, we examined whether cisplatin-induced phosphorylation of FKHRL1 might have an effect on the subcellular distribution of FKHRL1. Cisplatin induced the localization of FKHRL1 in the cytoplasm in Caov-3 cells but not in A2790 cells. Moreover, cisplatin induced the association of 14-3-3 protein with phosphorylated-FKHRL1 in Caov-3 cells but not in A2790 cells. Because the unphosphorylated form of FKHRL1 binds the Fas ligand promoter, thereby inducing apoptosis, we further examined the effect of the phosphorylation status of FKHRL1 on the activity of the Fas ligand promoter in the presence of cisplatin. Transfection with the kinase-inactive mutant of Akt or TM of FKHRL1 induced the activity of the Fas ligand promoter in Caov-3 cells. Moreover, exogenous expression of TM of FKHRL1 in Caov-3 cells decreased the cell viability after treatment with cisplatin. Our findings suggest that cisplatin causes the phosphorylation of FKHRL1 via a phosphatidylinositol 3-kinase/Akt cascade, and inhibition of this cascade sensitizes ovarian cancer cells to cisplatin.
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PMID:Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin. 1470 73

The role of the NKG2D immunoreceptor and its ligands in antitumor immune response is incompletely understood. Here, we report that effector immune cells infiltrating ovarian carcinoma are mostly CD8+ lymphocytes lacking CD28 but expressing the NKG2D costimulatory receptor. Human ovarian carcinoma expresses the novel NKG2D ligand lymphocyte effector cell toxicity-activating ligand (Letal). Letal was found to be an independent prognosticator of improved survival in advanced ovarian cancer. Higher levels of tumor-derived Letal were associated with stronger lymphocyte infiltration. Letal exerted marked costimulatory effects and induced type-1 polarization in CD8+CD28- tumor-infiltrating lymphocytes ex vivo. Letal engagement increased the expression of the glucose transporter Glut-1, enhanced glucose up-take, and protected CD8+ lymphocytes from cisplatin-induced killing. Letal also down-regulated the expression of Fas in CD8+ cells and rendered them resistant to Fas ligand-induced apoptosis. Our results indicate that Letal promotes tumor immune surveillance by promoting the survival and intratumoral expansion of antitumor cytotoxic lymphocytes. We propose that Letal could be used for the ex vivo expansion of apoptosis-resistant tumor-reactive cytotoxic lymphocytes for adoptive transfer.
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PMID:Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28- antitumor T cells. 1502 60

A novel caspase-3-specific inhibitory peptide and an agonistic peptide that binds to the Fas molecule were discovered using our computer screening strategy called the amino acid complement wave (ACW) method, which is based on the complementarities of interacting amino acids between comprehensive testing peptides and a target protein surface pocket. The precise binding configurations of the designed peptides on the three-dimensional (3D) structure of the target protein and the prediction of binding affinities (DeltaG) are determined by the molecular docking program. A designed novel tetrapeptide inhibitor of caspase-3, Ac-DNLD-CHO, was revealed to have potent and specific inhibitory activity. When a designed Fas ligand mimic peptide (Fas reactive peptide-4, FRAP-4) was multimerized by carboxyl terminal linkages of polylysine branches (MAP), the octamer (FRAP-4)(8)-MAP effectively induced apoptosis of human ovarian cancer cell line NOS4 cells. Thus the ACW method for structure-based design of optimized small peptides can be used to further develop small peptidomimetic and nonpeptidic organic forms into a new generation of effective pharmaceuticals.
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PMID:Genomic drug discovery for apoptosis regulation using a new computer screening amino acid complement wave method. 1525 24

The expression and functions of IL-12 receptor (IL-12R) in human ovarian carcinoma cell lines have been investigated. Ovarian carcinoma cells express both the IL-12Rbeta1 and the IL-12Rbeta2 subunits. IL-12R crosslinking resulted in phosphorylation of Tyk2, p44 (ERK1) and Akt kinases and activation of STATs 2, 3, 4 and 5. IL-12 induced substantial upregulation of Fas ligand (FasL) surface expression in ovarian carcinoma cells paralleled by an increased ability to induce apoptosis in Jurkat cells and PHA-activated lymphocytes. The induction of surface expression of FasL by IL-12 was not due to upregulation of FasL gene expression, but resulted from downregulation of matrix metalloproteinases (MMPs)-3 and -7 and consequently reduced cleavage of FasL from the cell surface. These findings bring new insights into the significance of IL-12-mediated effects in nonlymphoid cancer cells that might be of importance for improving the design of IL-12-based therapies for ovarian cancer.
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PMID:IL-12 receptor-mediated upregulation of FasL in human ovarian carcinoma cells. 1538 42

Drug resistance in ovarian cancer treatment urges the exploration of new targets for drugs against this malignancy. Fas is a cell membrane receptor which, after engagement with Fas ligand (FasL), triggers apoptotic death. In this study Fas and FasL levels in cyst fluids and sera of patients with benign, borderline and malignant ovarian tumors and in corresponding tumors are determined. Fas and FasL were determinded by ELISA and immunohistochemistry in 30 patients with benign, 5 patients with borderline and 24 patients with malignant epithelial ovarian tumors. In serum there were no differences in median Fas levels, while median FasL levels were higher in healthy women (p=0.02). In malignant cyst fluids, median Fas levels where higher compared to benign cyst fluids (p<0.01). FasL immunostaining was more frequent in malignant ovarian tumors (p=0.002). In conclusion, serum Fas or FasL levels do not seem useful markers. Elevated Fas and equal FasL levels in malignant cyst fluids, suggest an increased production of Fas, and not of FasL by malignant cells. High expression of both Fas and FasL, in malignant ovarian tumors present Fas/FasL as an interesting route to explore for innovative cancer therapy.
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PMID:Fas and Fas ligand in cyst fluids, serum and tumors of patients with benign and (borderline) malignant ovarian tumors. 1564 22


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