Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tamoxifen increases endometrial cell proliferation and the incidence of endometrial cancer in postmenopausal women. The purpose of this study was to evaluate apoptosis and apoptosis-related factors in endometrium in relation to tamoxifen exposure. We analyzed benign postmenopausal endometrium from breast cancer patients receiving tamoxifen (n = 35) and from controls (n = 24), and endometrial cancer tissue from tamoxifen-treated breast cancer patients (n = 15) and endometrial cancer from women without tamoxifen exposure (n = 51). Apoptosis was examined morphologically, and the percentage of apoptotic epithelial cells was defined as the apoptotic index. In the benign samples, the presence of apoptotic cells was also evaluated immunohistochemically by the expression of caspase-3 and the monoclonal antibody M30. The expression of Fas, FasL, and Bcl-2 was analyzed in all tissue samples. No differences were observed in the mean apoptotic index in benign endometrium in tamoxifen users (0.17%) versus controls (0.08%), or in tamoxifen-exposed (2.46%) versus nonexposed endometrial cancer (2.28%). However, the ratio of the apoptotic index with the previously reported proliferation index was lower in benign endometrium from tamoxifen users than in controls (0.02 +/- 0.026 vs. 0.05 +/- 0.03, Mann-Whitney U <0.005). In benign endometrium FasL was more frequently expressed in tamoxifen-users than in controls (chi(2) <0.05). We conclude that the apoptosis/proliferation ratio in benign endometrium from tamoxifen users is lower than in controls, indicating that the tamoxifen-induced higher proliferation is not compensated for by increased apoptosis. An imbalance between cell proliferation and apoptosis, and possibly suppression of the antitumor immune response by FasL overexpression in tamoxifen-exposed endometrium might play a role in the development of endometrial cancer in tamoxifen users.
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PMID:Apoptosis and apoptosis-associated parameters in relation to tamoxifen exposure in postmenopausal endometrium. 1273 25

Luteinizing hormone-releasing hormone (LHRH) and its receptor are frequently expressed in human ovarian and endometrial cancers and are part of an autocrine mechanism of growth control. We have previously shown that the LHRH analog Triptorelin induces activation of nucleus factor kappa B (NFkappaB) and reduces apoptosis induced by doxorubicin in human ovarian cancer cells EFO-21 and EFO-27. The present study was performed to investigate the anti-apoptotic effects of LHRH analogs on apoptosis induced by doxorubicin, UV-light and ligation of CD95 in human endometrial and ovarian cancer cells. We further investigated the interaction of the LHRH system with the apoptotic pathway focusing on the effector-protease caspase 3. Doxorubicin (100 nM) induced apoptosis in the LHRH-receptor-positive human endometrial cancer cell line Ishikawa and in the human ovarian cancer cell lines EFO-21 and NIH:OVCAR-3. Pretreatment for 24 h with native LHRH, the LHRH agonist Triptorelin or the LHRH antagonist Cetrorelix (100 nM) significantly reduced apoptosis induced by doxorubicin in these cells. In EFO-21 cells pretreatment with 100 nM Triptorelin also reduced UV-light-induced apoptosis from 76% to 62.7% (p<0.01). EFO-21 cells express CD95. Cross-linking of CD95 with monoclonal antibody anti-APO-1 (500 ng/ml) increased apoptosis from spontaneous rate to 10.3% to 38.3% in EFO-21 cells (p<0.001). Pre-treatment with Triptorelin did not reduce CD95-mediated apoptosis in these cells. LHRH analogs protect human endometrial and ovarian cancer cells from DNA-replication-dependent cytotoxic agent and UV-light-induced apoptosis, but not from CD95-mediated apoptosis.
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PMID:Luteinizing hormone-releasing hormone (LHRH) inhibits apoptosis induced by cytotoxic agent and UV-light but not apoptosis mediated through CD95 in human ovarian and endometrial cancer cells. 1527 47

Cyr61 (CCN1) is a member of the CCN protein family; these secreted proteins are involved in diverse biological processes such as cell adhesion, angiogenesis, apoptosis, and either growth arrest or growth stimulation depending on the cellular context. We studied the role of Cyr61 in endometrial tumorigenesis. Levels of Cyr61 were decreased in endometrial tumors compared with normal endometrium. Knockdown of Cyr61 expression by RNA interference in a well differentiated endometrial adenocarcinoma cell line (Ishikawa) stimulated its cellular growth. Conversely, overexpression of the protein in the undifferentiated AN3CA endometrial cancer cell line decreased their growth concurrently with increased apoptosis in liquid culture. These same cells had decreased clonogenic capacity and a nearly complete loss of tumorigenicity in vivo. Furthermore, partially purified Cyr61 suppressed growth of endometrial cancer cells. The increased apoptosis in these endometrial cancer cells with forced overexpression of Cyr61 was associated with elevated expression of the pro-apoptotic proteins Bax, Bad, and TRAIL (tumor necrosis factor receptor-associated ligand). Cyr61-induced caspase-3 activation and depolarization of mitochondrial membrane. In summary, endometrial cancer cells have decreased expression of Cyr61 compared with normal endometrium, and this lowered expression may provide the transformed cells a growth advantage over their normal counterpart.
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PMID:Cyr61 suppresses growth of human endometrial cancer cells. 1547 75

The goal of this study was to examine the effect of ursolic acid, a pentacyclic triterpenoid compound, on growth of the endometrial cancer cell line SNG-II. We found that ursolic acid strongly inhibited the growth of SNG-II cells in a dose- and time-dependent manner. Morpholgical changes characteristic of apoptosis were observed in treated cells, such as the presence of apoptotic bodies and fragmentation of DNA into oligonucleosomal-sized fragments. We also investigated the active forms of caspase-3, -8 and -9 in ursolic acid-treated SNG-II cells. At 25 and 50 microM strength, ursolic acid induced marked increases in caspase-3 activity to approximately 5-fold that of control cells. Levels of cleaved caspase-3 increased in a time- and dose-dependent manner. Activation of caspases also led to the cleavage of target proteins, such as PARP. Ursolic acid treatment also resulted in a cleavage of poly (ADP-ribose) polymerase in a dose-dependent manner. Testing whether caspase-3 activation and DNA polymerase activity were inhibited by addition of Ac-DEDV-HCO during ursolic acid treatment showed that 50 microM Ac-DEDV-HCO inhibited caspase-3 activity in treated cells. Although DNA fragmentation was observed after ursolic acid treatment, DNA fragmentation did not occur in SNG II cells treated with both Ac-DEDV-HCO and ursolic acid. Because some researchers have suggested that mitochondrial pathways are involved in ursolic acid-induced apoptosis secondary to induction of mitochondrial cytochrome c release, we studied mitochondrial events in ursolic acid-induced apoptosis in these cell lines. After ursolic acid treatment, the anti-apoptotic Bcl-2 protein decreased and Bax expression was enhanced. Our results indicated that ursolic acid induced apoptotic processes in the endometrial cancer SNG-II cell line through mechanisms involving mitochondrial pathways and Bcl-2 family proteins.
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PMID:Ursolic acid induces Bax-dependent apoptosis through the caspase-3 pathway in endometrial cancer SNG-II cells. 1558 1

The extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway plays a critical role in the anticancer action in vitro. ERK1/2 activation or phosphorylation is responsible for increased cyclooxygenase-2 (COX-2) protein expression in some cancer cells treated with selective COX-2 inhibitor NS398. We determined the effect of NS398 on ERK signaling and the synergistic effect of combined treatment with NS398 and a specific MEK inhibitor U0126 on three human endometrial cancer cell lines: Ishikawa, HEC-1A and AN3CA cells. Results showed that NS398 and U0126 individually, and especially the combination of both exhibited profound anti-proliferation of all three cell lines in a time- and concentration-dependent manner by [3-(4, 5)-dimethylthiazol-z-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay. The phosphorylated ERK1/2 was up-regulated in HEC-1A and AN3CA cells, but the COX-2 protein expression was unchanged in the three cancer cell lines treated with NS398 alone. However, both phosphorylated ERK1/2 and COX-2 protein expression were concentration-dependently decreased in all three cell types by combined treatment with NS398 and U0126 assessed by western blot analysis. Simultaneously, the combination of NS398 and U0126 resulted in 2-fold increase in apoptosis of all three lines over that by the individual alone, and enhanced G0/G1 phase arrest of Ishikawa and HEC-1A cells induced by U0126 treatment determined by flow cytometry. The synergistic and complementary effects of combining NS398 and U0126 were found to be associated with activation of caspase-3, alterations of Bcl-2 family proteins and cell cycle regulatory proteins detected by western blot analysis. Taken together, these findings correlate with blocking MEK-ERK signaling cascade and down-regulating COX-2 protein expression in endometrial cancer cells with combination treatment of NS398 and U0126, suggesting that the combinatory use of NS398 and specific MEK inhibitors may be valuable for chemotherapy or chemoprevention of human endometrial cancer.
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PMID:Significant anti-proliferation of human endometrial cancer cells by combined treatment with a selective COX-2 inhibitor NS398 and specific MEK inhibitor U0126. 1570 31

Under normal conditions, in human endometrium, apoptotic and antiapoptotic factors play an important role in tissue homeostasis. Abnormalities of apoptosis, a process implicated in several events in the reproductive organs, may contribute to neoplastic transformation. The present study aimed to investigate the involvement of both the receptorial and the mitochondrial pathways of apoptosis in normal endometrium and in endometrial carcinoma, by measuring caspase-3 and caspase-8 activities and cytosolic cytochrome c levels. Twelve endometrial carcinomas and nine normal endometrial specimens (four in mild proliferative phase, five in late secretory phase) were included in this study. Cytosolic fractions, obtained by differential centrifugation of tissue homogenates, were analyzed for caspase-3 and caspase-8 activities, as well as for cytochrome c content. Caspase-8 activity in normal secretory phase endometrium was higher than that in the proliferative phase and in the endometrial carcinoma. Moreover, higher cytochrome c levels were detected in endometrial carcinoma with respect to normal secretive endometrium. No significant differences were found in caspase-3 activity between normal and pathologic endometrium. The results obtained suggest that in normal endometrium, apoptosis takes place through the activation of both receptorial and mitochondrial pathways. Defects in both these pathways may contribute to the development of endometrial carcinoma.
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PMID:Receptorial and mitochondrial apoptotic pathways in normal and neoplastic human endometrium. 1588 80

We studied the effect of ursolic acid, a pentacyclic triterpene acid, on the growth of poorly differentiated type endometrial cancer HEC108 cells in vitro. Ursolic acid strongly inhibited the growth of HEC108 cells in a dose- and time-dependent manner. Morphological changes characteristic of apoptosis were observed in ursolic acid-treated cells, such as the presence of apoptotic bodies and fragmentation of DNA to oligonucleosomal-sized fragments. Investigation of caspase activity in ursolic acid-treated HEC108 cells showed that exposure at 50, 75 or 100 microM induced marked increases in caspase-3 activity (after 24 h) to 5.00, 11.76 or 12.75 times that of control levels, while cleaved caspase-3 levels increased in dose-dependent manner after 24 h. Activation of caspase was shown to lead to the cleavage of target proteins such as PARP. Ursolic acid treatment also resulted in a cleavage of poly(ADP-ribose) polymerase in a dose-dependent manner. Testing whether caspase-3 activation and DNA polymerase activity were inhibited by the addition of Ac-DEDV-HOC during ursolic acid treatment showed that 50 microM Ac-DEDV-HOC inhibited caspase-3 activity in treated cells. A mitochondrial pathway has been suggested to be involved in ursolic acid-induced apoptosis because the treatment induces mitochondria cytochrome c release. Experimentally, we found that anti-apoptotic Bcl-2 protein levels decreased after ursolic acid treatment, while Bax expression increased. Our results indicated that ursolic acid induced apoptotic processes in these poorly differentiated endometrial cancer cells occurs through mechanisms involving mitochondrial pathways and Bcl-2 family proteins.
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PMID:Molecular mechanism of ursolic acid induced apoptosis in poorly differentiated endometrial cancer HEC108 cells. 1601 38

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11

In several recent studies, we have shown that P-LAP can be a poor prognostic factor and a factor of chemoresistance in endometrial carcinoma, especially in the advanced patients. In our study, we investigated whether P-LAP alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We transfected P-LAP cDNA into A-MEC cells (endometrial adenocarcinoma cell line), and A-MEC-LAP cells displayed a 1.8-fold, 2.0-fold and 1.7-fold increase in IC(50) against paclitaxel, carboplatin and cisplatin respectively. Translational downregulation by siRNA2 to P-LAP on A-MEC-LAP cells demonstrated 60%, 51% and 58% decrease in IC(50). To investigate the mechanism of P-LAP-induced chemoresistance, we also assessed whether P-LAP transfection had an effect on carboplatin-induced apoptotic death of A-MEC cells. A-MEC and A-MEC-pc (transfected with vector alone) cells exhibited a strong apoptotic response to carboplatin, while A-MEC-LAP cells exhibited a weak apoptotic response. In an attempt to identify the mechanism of the inhibitory effect on apoptotic response to carboplatin, we next assessed the expression of cleaved caspases and PARP cleavage. While treatment of A-MEC-pc cells with carboplatin exhibited increased levels of cleaved caspase 3, caspase 7 and caspase 9 compared to that after no treatment, A-MEC-LAP cells did not show any expression of these caspases. These results suggest that P-LAP reduces sensitivity to anticancer drugs via inhibition of mitochondria-mediated apoptosis, and may be a molecular target for conquering anticancer drug resistance.
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PMID:A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells. 1618 79

Human endometrial epithelial cells undergo apoptosis immediately before the menstrual period. Apoptotic signalling was analysed using human endometrial tissue and a human endometrial carcinoma cell line (HHUA). Activity levels of caspase-3, -8, and -9 were elevated in human endometrium during the late secretory phase and in HHUA cells incubated with an anti-Fas monoclonal antibody (mAb). Fas-mediated apoptosis of HHUA cells was blocked by prior exposure to inhibitors of caspase-9, -8 and -3. In HHUA cells treated with anti-Fas mAb, a release of cytochrome c was detected in the cytosolic fraction, in addition a full-length Bid was degraded. Full-length FLIP(L) (p55) was degraded during apoptosis, and p29 (regarded as the product of p55 cleavage) appeared instead of FLIP(L). In normal human endometrial tissue, Bid degradation was also observed in a cyclic manner with a peak during the early secretory phase of the menstrual cycle. Furthermore, the release of cytochrome c was seen in the early secretory phase. However, expression of FLIP(S) was only observed during the menstrual cycle in normal endometrial tissue. We concluded that the main apoptotic signalling in both normal human endometrial tissue and HHUA cells exposed to anti-Fas mAb is the mitochondrial pathway via Bid degradation. Although the function of FLIP is still unknown on normal endometrial tissue, it may be regulated by FLIP(L) expression on HHUA cells derived from human endometrial carcinoma.
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PMID:Caspase cascade of Fas-mediated apoptosis in human normal endometrium and endometrial carcinoma cells. 1687 Sep 53


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