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)

Protein kinase C-related kinases are regulated by phosphatidylinositol-3-kinase and Rho family GTPases. The isoform PRK1 has been characterized in detail in prostate cancer, but not in other carcinomas. We analyzed our prior microarray data for PRK1 gene expression in 175 carcinomas and evaluated tissue microarrays for protein expression in 251 carcinomas and a comprehensive group of normal tissues. We also used immunoblotting to determine the levels and phosphoactivation status of PRK1, PRK2, and PDK1 in 12 ovarian serous carcinomas, SKOV3 cells, and 3 samples of normal ovarian surface epithelium (OSE). The highest average level of PRK1 messenger RNA was observed in ovarian serous carcinomas compared with all other carcinomas, including those of the prostate, bladder/ureter, breast, colon, stomach/esophagus, kidney, liver, pancreas, and lung (P = .05). By immunohistochemistry, PRK1 was observed in selected normal cells, including epithelium from the gynecologic tract and hematolymphoid elements. All serous ovarian and endometrial endometrioid adenocarcinomas and mesotheliomas were immunoreactive for PRK1. The findings in nonserous ovarian and most carcinomas from the prostate, breast, and pancreas were also positive but less consistently so. In comparison with OSE, the serous carcinomas typically had greater pPRK1/total PRK1 (P = .02) as well as greater pPDK/total PDK (P = .01). The relative phosphorylation status of these 2 kinases correlated within each sample. In summary, PRK1 is present in various malignancies, but especially in serous carcinomas, where the increased activation status of PRK1 and its upstream regulator, PDK, as compared with normal OSE suggests a role in ovarian cancer development or progression.
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PMID:PRK1 distribution in normal tissues and carcinomas: overexpression and activation in ovarian serous carcinoma. 1942 17

Ovarian cancer is known to be highly invasive. The poor prognosis of advanced ovarian cancer comes from increased invasiveness of human ovarian cancer cells. The lysophosphatidic acid (LPA)/Rho/Rho-associated kinase (ROCK) pathway is intimately involved in the course of ovarian cancer progression, and the inhibition of this pathway attenuates ovarian cancer invasiveness. Fasudil (1-[5-isoquinolinesulfonyl]-homopiperazine; HA-1077) is a drug that has been in clinical use in Japan for the prevention of vasospasm after subarachnoid hemorrhage and is known to be a potent ROCK-specific inhibitor. In this study, we examined the effect of fasudil on LPA-induced invasiveness of human ovarian cancer cells to explore the potential of fasudil as an anticancer agent against ovarian cancer. Fasudil induced changes in cell morphology but not in cell viability. Fasudil significantly inhibited LPA-induced invasion and motility of human ovarian cancer cells in a dose-dependent manner. Furthermore, fasudil caused the loss of intracellular cytoskeletal rearrangement, which is necessary for cell motility, such as stress fiber formation and focal adhesion assembly. Fasudil suppressed LPA-induced tyrosine phosphorylation of paxillin, a representative focal adhesion protein, and serine phosphorylation of myosin light chain, which are essential for the process for cell migration. These findings showed that fasudil attenuated the invasiveness of human ovarian cancer cells via inhibition of the LPA/Rho/ROCK pathway. In SKOV-3ip1 ovarian cancer xenografts, intraperitoneal treatment with fasudil significantly reduced tumor burden and ascites formation. Our findings suggest that fasudil might be useful to prevent the progression of ovarian cancer in clinical settings.
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PMID:Fasudil inhibits lysophosphatidic acid-induced invasiveness of human ovarian cancer cells. 1995 21

Gonadotropin-releasing hormone (GnRH) receptor expression is often elevated in ovarian cancer, but its potential role in ovarian cancer metastasis has just begun to be revealed. Cadherin switching is a crucial step during tumorigenesis, particularly in metastasis. Here, we showed that GnRH is an inducer of E- to P-cadherin switching, which is reminiscent of that seen during ovarian tumor progression. Overexpression of P-cadherin significantly enhanced, whereas knockdown of P-cadherin reduced migration and invasion regardless of E-cadherin expression, suggesting that inappropriate expression of P-cadherin contributes to the invasive phenotype. These effects of P-cadherin were mediated by activation of the Rho GTPases, Rac1, and Cdc42, through accumulation of p120 catenin (p120(ctn)) in the cytoplasm. The use of p120(ctn) small interfering RNA or chimeric cadherin construct to inhibit p120(ctn) expression and cytoplasmic localization, respectively, resulted in significant inhibition of cell migration and invasion, with a concomitant reduction in Rac1 and Cdc42 activation, confirming that the effect was p120(ctn) specific. Similarly, the migratory/invasive phenotype could be reversed by expression of dominant-negative Rac1 and Cdc42. These results identify for the first time cadherin switching and p120(ctn) signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer.
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PMID:Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer. 2011 84

Small GTPases, particularly the Rho family, are key regulators of cell motility and migration. Dock180 was well known for the main target of signal adaptor protein Crk and acted as a guanine-nucleotide exchange factor for small GTPase Rac1. In the present study, Dock180 was found to combine primarily with CrkI other than CrkII, and its association with Elmo1 was also demonstrated in ovarian cancer cell SKOV3. To evaluate the role of Dock180 in human ovarian cancer cell, we performed RNAi-mediated knockdown of Dock180 in SKOV3 cells using small interfering RNA expression vector. In Dock180 knockdown cells, we found that Elmo1 expression and Rac1 activity were decreased simultaneously. By contrast, the expressions of both another Crk-combining molecule C3G and Rap1 activity were observed to increase obviously. Accordingly, all Dock180 knockdown cells present with evident change in cell morphology, reduced cell proliferation, and attenuated cell migration. Taken together, these results suggest that signal transfer of Crk/Dock180/Rac1 is implicated in actin cytoskeleton reorganization and thus in the cell proliferation, motility, invasion, and of human ovarian cancer cell line SKOV3.
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PMID:The role of Crk/Dock180/Rac1 pathway in the malignant behavior of human ovarian cancer cell SKOV3. 2023 2

Geranylgeranylacetone (GGA), an isoprenoid compound, is a widely used antiulcer drug developed in Japan. GGA is structurally similar to plaunotol and geranylgeraniol, another isoprenoid reported to exert strong anticancer effects. In an earlier study, GGA was shown to inhibit ovarian cancer invasion by attenuating not only Rho activation, but also Ras-MAPK activation. In this study, we aimed to test whether GGA could have a therapeutic effect on colon cancer cells. As a result, we found that GGA induced a dose-dependent decrease in the proliferative activity through induction of cell apoptosis and cell cycle arrest in the G1 phase. The induction of apoptosis was mediated by the activation of both caspase-8 and caspase-9 pathways. The induction of G1 arrest was mediated by the increase of p21 and p27, and also the decrease of phosphorylated retinoblastoma protein levels. This study showed the potential anticancer activity of GGA. As this drug is already available in Japan for clinical use as an antiulcer/antigastritis agent, clinical trials will be designed to confirm its potential usefulness for cancer patients.
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PMID:Isoprenoid geranylgeranylacetone inhibits human colon cancer cells through induction of apoptosis and cell cycle arrest. 2072 17

BRCA2 germline mutations account for the majority of heredity breast and ovarian cancer. Besides its role in DNA damage repair, BRCA2 also plays an important role in cytokinesis, transcription regulation, and cancer cell proliferation. Recently, we reported that BRCA2 localizes to centrosomes as well as nuclei and the dysfunction of BRCA2 in a centrosome causes abnormalities in cell division. Here, we identified a nucleolar phosphoprotein, nucleophosmin (NPM), as a novel BRCA2-associated protein. We also detected the binding of BRCA2 to ROCK2, an effector of Rho small GTPase. Because it is known that ROCK2 binds to NPM at centrosomes, these 3 proteins may form a complex. NPM-binding region was within amino acids 639-1,000 of BRCA2. Exogenous expression of this BRCA2 region resulted in aberrant centrosome amplification and a high frequency of multinucleated cells. Our results suggested that a complex consisting of BRCA2, NPM, and ROCK2 maintains the numerical integrity of centrosomes and accurate cell division and that dysfunction of this regulation might be involved in the tumorigenesis of breast cancer.
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PMID:BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. 2108 79

Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70(S6K)), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70(S6K) is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70(S6K) acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70(S6K) in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70(S6K) was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70(S6K) colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70(S6K) did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70(S6K) stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70(S6K) expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70(S6K) specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70(S6K) in tumor progression.
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PMID:p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells. 2125 6

Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.
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PMID:Ovarian cancer: Stat3, RhoA and IGF-IR as therapeutic targets. 2212 Jun 72

Previous studies described functional roles for Rho GDP dissociation inhibitor 2 (RhoGDI2) in bladder, gastric and breast cancers. However, only limited expression and no functional analyses have been done for RhoGDI2 in ovarian cancer. We determined RhoGDI2 protein expression and function in ovarian cancer. First, protein gel blot analysis was performed to determine the expression levels of RhoGDI2 in ovarian cells lines. RhoGDI2 but not RhoGDI1 protein expression levels varied widely in ovarian carcinoma cell lines, with elevated levels seen in Ras-transformed ovarian epithelial cells. Next, immunohistochemistry was performed to detect RhoGDI2 expression in patient samples of ovarian cysts and ovarian cancer with known histological subtype, stage, grade and outcome. RhoGDI2 protein was significantly overexpressed in high-grade compared with low-grade ovarian cancers, correlated with histological subtype, and did not correlate with stage of ovarian cancer nor between carcinomas and benign cysts. Unexpectedly, stable suppression of RhoGDI2 protein expression in HeyA8 ovarian cancer cells increased anchorage-independent growth and Matrigel invasion in vitro and in tail-vein lung colony metastatic growth in vivo. Finally, we found that RhoGDI2 stably-associated preferentially with Rac1 and suppression of RhoGDI2 expression resulted in decreased Rac1 activity and Rac-associated JNK and p38 mitogenactivated protein kinase signaling. RhoGDI2 antagonizes the invasive and metastatic phenotype of HeyA8 ovarian cancer cells. In summary, our results suggest significant cell context differences in RhoGDI2 function in cancer cell growth.
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PMID:RhoGDI2 antagonizes ovarian carcinoma growth, invasion and metastasis. 2214 92

The Rho-associated serine-threonine protein kinase (ROCK) is a downstream effector of Rho GTPases that is frequently activated in the epithelial to mesenchymal transition (EMT) of human ovarian cancer cells. On the other hand, endothelin-1 (ET-1) and its receptor endothelin A receptor (ET(A)R) are overexpressed in primary and metastatic ovarian carcinoma, which suggests that ET-1 promotes tumor dissemination. Hence, two human ovarian carcinoma cell lines, SK-OV-3 and CaOV3, were chosen to study the effects of ET-1/ET(A)R and ROCK in promoting EMT of ovarian cancer cells. We found that ET-1 exposure induced EMT of SK-OV-3 and CaOV3 by monitoring cells morphology, enhanced fibronectin, and reduced E-cadherin protein. At the same time, ET-1/ET(A)R enhanced the level of transcription of SLUG a transcriptional repressor of E-cadherin. More importantly, a constitutively active mutant of ROCK enhanced the transcription of SLUG by stimulating SLUG promoter activity. Furthermore, ROCK inhibitor Y27632 reversed the increase in fibronectin induced by ET-1/ET(A)R. Our data suggest that ROCK cooperated with ET-1/ET(A)R to promote EMT of human ovarian carcinoma cells through upregulation of SLUG mRNA.
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PMID:ROCK cooperated with ET-1 to induce epithelial to mesenchymal transition through SLUG in human ovarian cancer cells. 2223 46


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