UMLS:C0476089 - FACTA Search

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Query: UMLS:C0476089 (endometrial cancer)
11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous studies have demonstrated the anticancer activity of the tomato carotenoid, lycopene. However, the molecular mechanism of this action remains unknown. Lycopene inhibition of human breast and endometrial cancer cell growth is associated with inhibition of cell cycle progression at the G(1) phase. In this study we determined the lycopene-mediated changes in the cell cycle machinery. Cells synchronized in the G(1) phase by serum deprivation were treated with lycopene or vehicle and restimulated with 5% serum. Lycopene treatment decreased serum-induced phosphorylation of the retinoblastoma protein and related pocket proteins. This effect was associated with reduced cyclin-dependent kinase (cdk4 and cdk2) activities with no alterations in CDK protein levels. Lycopene caused a decrease in cyclin D1 and D3 levels whereas cyclin E levels did not change. The CDK inhibitor p21(Cip1/Waf1) abundance was reduced while p27(Kip1) levels were unaltered in comparison to control cells. Serum stimulation of control cells resulted in reduction in the p27 content in the cyclin E--cdk2 complex and its accumulation in the cyclin D1--cdk4 complex. This change in distribution was largely prevented by lycopene treatment. These results suggest that lycopene inhibits cell cycle progression via reduction of the cyclin D level and retention of p27 in cyclin E--cdk2, thus leading to inhibition of G(1) CDK activities.
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PMID:Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27(Kip1) in the cyclin E-cdk2 complexes. 1142 93

Basic transcription element binding (BTEB, also designated BTEB1) protein is a member of the Sp-family of GC-box binding transcription factors that exhibit distinct patterns of expression in many cell types and tissues. A role for BTEB1 in the regulation of cell growth and gene transcription has been invoked, but little is known about the molecular mechanisms underlying these activities. The present study examined the functional consequences of high and low BTEB1 expression in the human endometrial carcinoma cell line Hec-1-A, by deriving stable clonal lines that expressed sense (S) and anti-sense (As) rat BTEB1 constructs. Clonal S lines, with BTEB1 mRNA and protein levels higher than in corresponding parent (N) and As lines, displayed enhanced DNA synthesis upon 3[H]-thymidine incorporation, in serum-containing but not in serum-free medium, and increased cell cycle kinetics, concomitant with the induction in expression of the genes for the cell cycle-associated components cyclin D1, PCNA, cyclin-dependent kinase (Cdk) inhibitor p21, and Cdk2. Compared to N and As lines, S lines also had diminished ability to grow in multi-layers and exhibited increased mRNA levels for plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte protease inhibitor (SLPI), and tissue inhibitor of metalloproteinases (TIMP)-2. In serum-free medium, S, but not N nor As lines, had enhanced DNA synthesis with transforming growth factor (TGF)-beta1, albeit all lines demonstrated similar responses to insulin-like growth factor-I and to epidermal growth factor, respectively. The higher DNA synthesis in S relative to N and As, lines upon exogenous TGF-beta1 addition, was observed in concert with increased expression of cyclins D1 and E and p21, genes. Moreover, S and As lines had increased mRNA levels for TIMP-1, TIMP-2, PAI-1, and beta-catenin, and diminished SLPI, and to a lesser extent, Cdk4 mRNA levels, with TGF-beta1 treatment. These results suggest that BTEB1 may mediate cell growth, in part, by modulating gene expression levels of distinct cell cycle and growth-associated proteins. The correlation between serum- and TGF-beta1 induction of DNA synthesis with increased BTEB1 expression further suggests that BTEB1 may constitute an important downstream regulatory component of various signaling pathways utilized by serum-associated and other growth factors in endometrial epithelial cells.
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PMID:Increased expression of the Zn-finger transcription factor BTEB1 in human endometrial cells is correlated with distinct cell phenotype, gene expression patterns, and proliferative responsiveness to serum and TGF-beta1. 1147 43

3,3'-Diindolylmethane (DIM), a major in vivo product of indole-3-carbinol (I3C), is a promising anticancer agent derived from vegetables of the Brassica genus including broccoli, Brussels sprouts and cabbage. We report here that DIM has a potent cytostatic effect in cultured human Ishikawa endometrial cancer cells. A combination of northern blot and quantitative PCR analyses revealed that DIM induced the level of TGF-alpha transcripts by approximately 4-fold within 24 h of indole treatment. DIM also induced a 4-fold increase in the activity of the estrogen response marker, alkaline phosphatase (AP). Co-treatment of cells with the estrogen receptor (ER) antagonist ICI, or with the inhibitor of PKA-mediated activation of the ER, H89, ablated the DIM induction of both TGF-alpha expression and AP activity. Furthermore, DIM increased the maximum stimulatory effect of estrogen on TGF-alpha expression. Co-treatment with the protein synthesis inhibitor, cycloheximide, abolished the inductive effects of DIM, indicating differences in the mechanistic requirements of DIM and estrogen. DIM treatment also stimulated levels of secreted TGF-alpha protein by >10-fold. The ectopic addition of TGF-alpha inhibited the growth of Ishikawa cells, whereas incubation with a TGF-alpha antibody partially reversed the growth inhibitory effects of DIM. Taken together, these results extend our previous findings of the ligand independent estrogen receptor agonist activity of DIM, and uncover an essential role for the stimulation in TGF-alpha expression and the TGF-alpha activated signal transduction pathway in the potent cytostatic effects of DIM in endometrial cancer cells.
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PMID:Cytostatic effects of 3,3'-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression. 1169 43

The expression of GnRH 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 breast, ovary and endometrium. Dose-dependent antiproliferative effects of GnRH agonists in cell lines derived from these cancers have been observed by various investigators. GnRH antagonists also have marked antiproliferative activity in most breast, ovarian and endometrial cancer cell lines tested, indicating that the dichotomy of GnRH agonists and antagonists might not apply to the GnRH system in cancer cells. 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 cancer cells. Rather, the GnRH receptor 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 nuclear factor kappaB and protects the cancer cells from apoptosis. Furthermore, GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (AP-1) pathway independent of the known AP-1 activators, protein kinase or mitogen activated protein kinase.
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PMID:Biology of the gonadotropin-releasing hormone system in gynecological cancers. 1175 Oct 60

Progesterone is a critical steroid hormone that controls cell proliferation and differentiation in the female reproductive tract. Progesterone acts through two nuclear receptor isoforms, progesterone receptors A and B (PRA and PRB, respectively), each with unique cellular effects. Loss of PRB has recently been linked to the development of poorly differentiated endometrial tumors, a lethal form of cancer. To study the molecular effects of progesterone, progesterone receptors were introduced into Hec50co endometrial cancer cells by adenoviral vectors encoding either PRA or PRB. Progesterone induced the cyclin-dependent kinase inhibitors p21 and p27, thereby significantly reducing the percentage of proliferating cells. Cancer cell invasion was also markedly inhibited as measured by Matrigel invasion studies. Similarly, a differentiated, secretory phenotype was induced by progesterone in cells expressing PRB. However, replicative senescence was induced by progesterone only in cells expressing PRA. Expression array analysis followed by confirmatory semiquantitative reverse transcription-PCR experiments demonstrated a significant progesterone-dependent inhibition of expression of a cadre of cellular adhesion molecules, including fibronectin, integrin alpha3, integrin beta1, integrin beta3, and cadherin 6. The level of down-regulation of adhesion molecule expression was significantly greater in the presence of the B isoform, demonstrating that progesterone acts principally through B receptors to inhibit cancer cell invasiveness modulated by adhesion molecules.
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PMID:Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. 1183 May 47

The PTEN tumor suppressor gene encodes a phosphatidylinositol 3'-phosphatase that is inactivated in a high percentage of human tumors, particularly glioblastoma, melanoma, and prostate and endometrial carcinoma. Previous studies showed that PTEN is a seryl phosphoprotein and a substrate of protein kinase CK2 (CK2). However, the sites in PTEN that are phosphorylated in vivo have not been identified directly, nor has the effect of phosphorylation on PTEN catalytic activity been reported. We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). Following transient over-expression, a fraction of CK2 and PTEN co-immunoprecipitate. Moreover, pharmacological inhibition of CK2 activity leads to decreased Akt activation in PTEN+/+ but not PTEN-/- fibroblasts. Our results contrast with previous assignments of PTEN phosphorylation sites based solely on mutagenesis approaches, suggest that CK2 is a physiologically relevant PTEN kinase, and raise the possibility that CK2-mediated inhibition of PTEN plays a role in oncogenesis.
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PMID:Direct identification of PTEN phosphorylation sites. 1229 95

In the human endometrial carcinoma cell line HEC1B, the overexpression of Bcl-2 leads to a G2/M cell cycle arrest. The experiments presented in this work suggest a direct interaction between the antiapoptotic protein Bcl-2 and the cyclin-dependent kinase Cdk-2 and suggest that such interaction is cell cycle dependent. While further experiments are currently under way in our laboratory to elucidate the significance of Cdk-2/Bcl-2 complexes in PCD and cell cycle regulation, we demonstrate also a specific inhibitory function of Bcl-2 on the activity of the coprecipitated kinase.
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PMID:Association of Bcl-2 with cyclin a/Cdk-2 complex and its effects on Cdk-2 activity. 1248 75

Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is a multifunctional protein kinase expressed abundantly in the central nervous system. Because changes in intracellular Ca2+ concentrations affect progression through the mitotic cell cycle, enhanced expression of CaMKIV has been reported in small cell lung carcinoma and hepatocellular carcinoma. To elucidate the involvement of CaMKIV in endometrial carcinogenesis, we analyzed serial frozen sections from 31 patients with endometrial carcinoma and 20 patients with normal endometria for CaMKIV protein expression, using fluorescent immunohistochemistry. We analyzed the relationship between the percentages of CaMKIV stained cells and the patient characteristics, including clinical stage, histological grade, myometrial invasion, and clinical outcome. In the normal endometria, CaMKIV was detected in none of the cases examined. Most of the CaMKIV proteins were found in the nucleus of endometrial carcinoma tissue. CaMKIV expression was significantly associated with clinical stage (stage I and II versus stage III and IV; p<0.01), myometrial invasion (no myometrial invasion versus the presence of invasion to greater than one-half the myometrium; p=0.02), and clinical outcome (no evidence of disease versus died of disease; p=0.04). Scoring on the basis of the percentage of positive cells indicated that CaMKIV expression was significantly associated with PCNA-labeling index (p=0.02). Our results demonstrate that CaMKIV expression in endometrial carcinoma correlates with the malignant potential of this tumor.
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PMID:CaMKIV expression is associated with clinical stage and PCNA-labeling index in endometrial carcinoma. 1252 74

Endometrial cancer (EC) is a hormone-dependent cancer that currently represents the most frequent malignancy of the female reproductive tract. The involvement of steroid hormones in its etiology and progression has been reported. The possibility that even gonadotropins (GT) could play a role in the genesis and establishment of EC is supported by the fact that specific receptors for the GT luteinizing hormone/human chorionic GT (LH/hCG) have been detected in a high percentage of ECs, and their expression is apparently related to the cancer grading. However, the precise mechanisms by which GTs might exert their effect on EC is still obscure. The aim of this study was to determine the effects of LH/hCG on the invasion potential of EC cell lines and primary human EC cells. Human recombinant (hr) LH (and hCG) induced a significant increase in cell invasiveness through Matrigel-coated porous membranes in an EC human cell line Hec1A, which expresses the LH/hCG receptor. This effect turned out to depend on hrLH binding to its specific receptors and to the subsequent activation of protein kinase A (PKA). Moreover the hrLH-induced increase in Hec1A invasiveness relied upon a PKA-dependent functional activation of beta(1) integrin receptors, as well as the subsequent induction of matrix metalloproteinase-2 secretion in its active form. The same mechanisms were also found to be operative in primary EC cells. In fact, a significant percentage of primary ECs expressed the LH/hCG receptor, and hrLH addition to primary EC cells, which expressed the specific receptors produced an increase in cell invasiveness only in those tumor cells possessing the specific receptors. This effect was also dependent on PKA activity. We conclude that LH/hCG can regulate EC cells invasiveness, and this result provides a rationale for the use of inhibitors of LH secretion such as GnRH analogues in the treatment of EC.
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PMID:Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A. 1287 38

We investigated the mechanism of ligand-independent activation of the estrogen receptor (ER) by 3,3'-diindolylmethane (DIM), a promising anticancer agent derived from vegetables of the Brassica genus, in Ishikawa and HEC-1B human endometrial cancer cells. DIM stimulated the activity of an ER-responsive reporter by over 40-fold, equivalent to the maximum induction produced by estradiol (E2), whereas cotreatment of cells with the ER antagonist, ICI-182,780 (ICI), abolished the stimulatory effect of DIM. DIM also induced the expressions of the endogenous genes, TGF-alpha, alkaline phosphatase, and progesterone receptor similar to levels induced by E2. Induction of gene expression by DIM was inhibited by the protein synthesis inhibitor, cycloheximide. In addition, cotreatment of cells with the protein kinase A (PKA) inhibitor, H89, or the MAPK inhibitor, PD98059, reduced DIM activation of the ER by 75% and 50%, respectively. Simultaneous treatment of cells with both inhibitors completely abolished the effect of DIM. DIM stimulated MAPK activity and induced phosphorylation of the endogenous PKA target, cAMP response element binding protein (CREB), in a PKA-dependent manner. Expression of MCREB, a nonphosphorylatable CREB mutant, partially abolished activation of the ER by DIM. These results demonstrate that DIM is a mechanistically novel activator of the ER that requires PKA-dependent phosphorylation of CREB.
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PMID:Potent ligand-independent estrogen receptor activation by 3,3'-diindolylmethane is mediated by cross talk between the protein kinase A and mitogen-activated protein kinase signaling pathways. 1464 98

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