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

This paper investigates the effects of tumor vaccines on T cell proliferation induced by 12-0 tetradecanoylphorbol-13-acetate (TPA). Viral oncolysate (VO) tumor vaccines containing inactivated influenza virus A significantly inhibited TPA-induced T cell proliferation. In contrast, a control tumor vaccine (CO) that contained the same cellular components as VO but lacked influenza virus did not affect the TPA-induced proliferation. These effects were also observed with peripheral blood mononuclear cells (PBMC) from ovarian cancer patients, although VO and CO each induced significant and similar levels of proliferation in these cells in the absence of TPA. Protein kinase C (PKC) is a pivotal enzyme in signal transduction pathways that control cell proliferation, and TPA is a specific activator of PKC. VO and CO showed differential effects on the inhibition of purified protein kinase C (PKC). These studies demonstrate the antagonistic effects of different tumor vaccines on T lymphocyte proliferation and suggest that influenza virus A or virus-modified cellular components may interfere with signal transduction in the immune cells of the recipient of the tumor vaccine.
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PMID:Immunological effects of tumor vaccines: III. Influenza virus oncolysates inhibit the TPA induced activation of peripheral blood mononuclear cells. 193 17

The ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and D,L-buthionine-S,R-sulphoximine (BSO) to modulate cis-diamminedichloroplatinum(II) (CDDP) sensitivity was investigated in human ovarian cancer cell lines sensitive (KF) or with intrinsic resistance (KK and MH) to CDDP. The KK and MH cell lines were derived from ascites of patients with clear-cell carcinoma and serous cystadenocarcinoma of the ovary who both showed clinical resistance to CDDP. The CDDP IC50 value of KK and MH cells was about 4.6- and 10.2-fold higher than that of KF cells. PKC activities in the cytosol and membrane of KK and MH cells were also about 4- to 5-fold higher than those of KF cells. Proliferation of KF, KK and MH cells was inhibited in a dose-dependent manner by TPA. The membrane PKC activities in the KF cells were rapidly activated and down-regulated 24 hr after exposure to TPA, while those in the KK and MH cells were not down-regulated even after exposure to TPA for 24 hr, suggesting that the membrane form of PKC may be involved in the intrinsic resistance. Continuous exposure to 10 nM TPA for 5 days significantly reduced the CDDP sensitivity of KF and KK cells, while exposure to 10 nM TPA for 1 hr significantly elevated that of KK and MH cells. Interestingly, 1-hr exposure to 1 microM TPA induced CDDP-resistance in KK cells. Such changes in CDDP sensitivity by TPA seemed to be linked with those of cellular PKC activity, i.e., when the CDDP sensitivity was reduced by TPA, the cellular PKC rose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of sensitivity of human ovarian cancer cells to cis-diamminedichloroplatinum(II) by 12-O-tetradecanoylphorbol-13-acetate and D,L-buthionine-S,R-sulphoximine. 837 36

We recently demonstrated a correlation between the expression levels of the PKC eta isozyme and the MDR1 or MRP genes in blasts from AML patients, and in primary breast cancers. In order to extend these findings we analysed ovarian cancer cells from 14 ascites aspirates from 8 patients using a cDNA-PCR approach. 5 patients were examined in follow up studies. 4 out of these 5 patients received continuous chemotherapy. The relative increases in MDR1, MRP, LRP or PKC eta mRNA expression levels were monitored. In one of these patients combined significant increase in MDR1, MRP, LRP and PKC was seen. One follow up sample was obtained after chemotherapy was discontinued. In this case significant relative decreases of MDR1, LRP and PKC eta mRNA expression levels were found. Furthermore, a significant positive correlation was determined for the relative mRNA expression levels of MRP and PKC eta. These results point to a multifactorial emergence of MDR in this type of tumor with a possible involvement of the PKC eta isozyme.
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PMID:Expression analysis of protein kinase C isozymes and multidrug resistance associated genes in ovarian cancer cells. 961 8

Protein kinase C (PKC) signaling pathways play an important role in cell survival and anticancer drug-induced apoptosis. We observed in clonogenicity assays of BG-1 human ovarian cancer cells that gemcitabine cytotoxicity was increased synergistically when drug treatment was followed or preceded by a 24-h exposure to 10 nM 12-O-tetradecanoylphorbol-13-acetate (TPA). Coincubation of 10 nM TPA with pharmacological inhibitors of PKC abrogated the synergism of TPA and gemcitabine. These observations prompted further investigation of PKC signaling events linked to TPA and gemcitabine cytotoxicity in BG-1 cells. Because PKC isoforms are differentially expressed in various cell types, we determined that BG-1 cells express the alpha, beta, delta, epsilon, and zeta isoforms of PKC. In addition, 1-h exposures to 10 microM gemcitabine triggered cytosol to membrane translocation of PKC isoforms alpha, delta, and epsilon, indicating these isoforms were activated by gemcitabine. We also explored the PKC mechanism(s) responsible for the synergism of TPA and gemcitabine, and determined that treatment with 10 nM TPA for 24 h in BG-1 cells: 1) downregulated PKCdelta and PKCalpha, without affecting PKCepsilon, 2) did not affect cell cycle distribution into S phase. 3) increased extracellular signal-regulated kinase signaling, and 4) increased intracellular alkaline phosphatase activity, a biochemical marker of cellular differentiation. Chronic exposure (24 h) to TPA enhanced gemcitabine cytotoxicity, perhaps by inducing cellular differentiation pathways in BG-1 cells. Therefore, the use of differentiating agents in combination with gemcitabine may improve its clinical efficacy.
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PMID:The effects of gemcitabine and TPA on PKC signaling in BG-1 human ovarian cancer cells. 1006 71

Protein kinase C (PKC) is an attractive target in cancer therapy. It is overexpressed in a variety of cancers, and nonspecific inhibitors of PKC have demonstrated antitumor activity. Antisense oligonucleotides targeted against PKC-alpha, which have high specificity, can inhibit mRNA and protein expression as well as the growth of tumors in vitro and in vivo. This Phase I study sought to characterize the safety profile and to determine the maximum tolerated dose of antisense to PKC-alpha when administered by continuous infusion in patients. Patients with incurable malignancies received ISIS 3521, a 20-length phosphorothioate oligodeoxynucleotide specific for PKC-alpha. Treatment was delivered over a period of 21 days by continuous i.v. infusion followed by a 7-day rest period. Doses were increased from 0.5 to 3.0 mg/kg/day. Patients continued on the study until evidence of disease progression or unacceptable toxicity was detected. Between August 1996 and September 1997, 21 patients were treated in five patient cohorts. The maximum tolerated dose was 2.0 mg/kg/day. The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0 mg/kg/day. Pharmacokinetic measurements showed rapid plasma clearance and dose-dependent steady-state concentrations of ISIS 3521. Evidence of tumor response lasting up to 11 months was observed in three of four patients with ovarian cancer. The recommended dose of ISIS 3521 for Phase II studies is 2.0 mg/kg/day when given over a period of 21 days. Side effects are modest and consist of thrombocytopenia and fatigue. Evidence of antitumor activity provides the rationale for Phase II studies in ovarian cancer and other malignancies.
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PMID:Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. 1058 45

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

Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, P1-3 kinase inhibitors, Wortmannin and LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast, a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that both the MEK1 inhibitor and the P13-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells. Taken together, our results suggest that activation of dual signaling pathways, MEKI-MAPK and P13K-Akt, is required for the FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic target for cancer.
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PMID:Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells. 1146 75

The 70 kDa ribosomal S6 kinase (p70S6K) is important for cell growth and survival. Activation of p70S6K requires sequential phosphorylation of multiple serine and threonine sites often triggered by growth factors and hormones. Here, we report that paclitaxel, a microtubule-damaging agent, induces phosphorylation of p70S6K at threonine 421 and serine 424 (T421/S424) in a concentration- and time-dependent manner in multiple breast and ovarian cancer cell lines demonstrated by a T421/S424 phospho-p70S6K antibody. Phosphoamino-acid analysis and Western blot analysis by serine-/threonine-specific antibodies further confirms that both serine and threonine residues are phosphorylated in p70S6K following treatment with paclitaxel. Paclitaxel-induced p70S6K(T421/S424) phosphorylation requires both de novo RNA and protein synthesis via multiple signaling pathways including ERK1/2 MAP kinase, JNK, PKC, Ca(++), PI3K, and mammalian target of rapamycin (mTOR). Despite phosphorylation of p70S6K(T421/S424), paclitaxel inactivates this kinase in a concentration- and time-dependent manner as illustrated by in vitro kinase assay. Inhibitors of mTOR, PI3K, and Ca(++) impair p70S6K activity, whereas inhibitors of JNK and PKC stimulate p70S6K activity. Inhibition of PKC and JNK prevents paclitaxel-induced p70S6K inactivation. Moreover, the paclitaxel-induced phosphorylation and low activity of p70S6K mainly occurs during mitosis. In summary, paclitaxel is able to induce p70S6K(T421/S424) phosphorylation and decrease its activity in mitotic cells via multiple signaling pathways. Our data suggest that paclitaxel-induced p70S6K(T421/S424) phosphorylation and kinase inactivation are differentially regulated. Our data also indicate that paclitaxel may exert its antitumor effect, at least in part, via inhibition of p70S6K.
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PMID:Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis. 1255 62

The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in these cancer cells. The GnRH receptor rather interacts with the mitogenic signal transduction of growth-factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in downregulation of cancer cell proliferation. In addition GnRH activates nucleus factor kappaB (NFkappaB) and protects the cancer cells from apoptosis. Furthermore GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK). Recently it was shown that human ovarian cancer cells express a putative second GnRH receptor specific for GnRH type II (GnRH-II). The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists. In previous studies we have demonstrated that in ovarian cancer cell lines except for the EFO-27 cell line GnRH-I antagonist Cetrorelix has comparable antiproliferative effects as GnRH-I agonists indicating that the dichotomy of GnRH-I agonists and antagonists might not apply to the GnRH-I system in cancer cells. After GnRH-I receptor knock down the antiproliferative effects of GnRH-I agonist Triptorelin were abrogated while the effects of GnRH-I antagonist Cetrorelix and GnRH-II were still existing. In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found. These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.
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PMID:Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer. 1459 54

We show that atypical PKCiota, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCiota protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCiota DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKCiota proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCiota protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCiota as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCiota is a novel target for therapy.
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PMID:Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. 1611 79


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