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)

Cowden disease is an autosomal dominant inherited cancer syndrome characterized by the occurrence of multiple hamartomas, tumors or hyperplastic lesions that may develop in any organ. The disease is related to germline mutation of the PTEN gene, a recently cloned tumor suppressor gene involved in the pathogenesis of sporadic glioblastoma and endometrial carcinoma. It has been shown that the PTEN gene product was a phosphatase able for dephosphorylating a lipid substrate: the phosphatidylinositol (3,4,5)-triphosphate (PIP3). So PTEN appears to negatively control the PI3K-AKT signaling pathway implicated in regulation of cell growth and survival.
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PMID:[Cowden disease and the PTEN gene: a successfully clinical and biological combined approach]. 1179 8

Staurosporine is a potent apoptosis inducer, but its mechanism remains to be clarified. We investigated the involvement of PTEN in staurosporine-induced apoptosis. Ishikawa cells, from an endometrial carcinoma cell line, expressed a high amount of PTEN mRNA but did not express the PTEN protein because of protein truncations. We isolated clones expressing the steady-state level of the PTEN protein from PTEN-null Ishikawa cells by transfection. The obtained clones showed reduced proliferative activity and reduced anchorage-independent cell growth with the augmented p27(Kip1). These cell lines were sensitized to apoptosis by staurosporine. A low concentration of UCN-01 did not affect apoptosis, but a high concentration augmented apoptosis in the PTEN-expressing clone. Alpha-sphingosine and H-7 did not affect apoptosis in these cell lines. PI3K inhibition augmented staurosporine-induced apoptosis in the parental cell line, but not in the PTEN-expressing clone. In the clone, phosho-Akt/PKB and phospho-Bad (Ser-136) were downregulated. Staurosporine reduced the levels of phospho-Akt/PKB and phospho-Bad (Ser-136) in all the cell lines, but the reduction was most significant in the PTEN-expressing clone. These results suggest that inhibition of the PI3K/Akt/PKB signaling pathway might be associated with staurosporine-induced apoptosis in Ishikawa cells.
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PMID:PTEN augments staurosporine-induced apoptosis in PTEN-null Ishikawa cells by downregulating PI3K/Akt signaling pathway. 1196 94

PTEN and the PI3K/Akt pathway are involved in the development and/or progression of endometrial carcinoma. To clarify the impact of the pathway-related molecules on prognosis, we analyzed PTEN, phosphorylated-Akt (p-Akt), and Ki-67 expression by immunohistochemistry in 99 patients with advanced endometrial carcinoma. PTEN-negative or PTEN-mixed staining was found in 66% of tumors. Positive staining of p-Akt was found in 40% of tumors. Loss of PTEN expression (negative or mixed) was significantly associated with positive p-Akt expression. The patients with PTEN-positive and p-Akt-negative expression clearly showed a higher survival rate than patients in the other groups. Subsequent multivariate analysis revealed that the combination of PTEN/Akt expression was an independent prognostic factor. Examining the relationship between p-Akt expression and Ki-67 labeling index (LI), we found that negative p-Akt was related to a decrease in Ki-67 LI. Additionally, the patients with low Ki-67 LI, as determined by p-Akt-expression status, had a better prognosis. In the present study, we demonstrated that PTEN-positive and p-Akt-negative expression was a predictor of survival for patients with advanced endometrial carcinoma. This study suggests the clinical significance of PTEN and p-Akt expression analysis in treatment decisions for patients with advanced endometrial carcinoma.
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PMID:PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma. 1601 20

Mutations of RAS, RAF, and PTEN, all important members of the RAS/MAPK and PI3K/AKT cascades, are reported in a variety of human tumors, including melanomas and endometrial cancer. In endometrial cancer, mutually exclusive mutations of PTEN and KRAS have been reported. On the other hand, mutation of BRAF is highly frequent, and mutually exclusive mutations of BRAF and NRAS have also been reported in melanomas. In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades. Twelve cell lines, six melanoma and six endometrial cancer, were analyzed; 4 (67%) of the 6 melanomas had gene mutations in the RAS/MAPK cascade, and a decrease or loss of PTEN expression was also observed. These results suggested that simultaneous up-regulations in these two cascades play important roles in carcinogenesis of melanocytes. However, no activation of AKT by phosphorylation was observed. On the other hand, 4 (67%) of the 6 endometrial cancer cell lines had mutually exclusive up-regulations in these cascades. However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6. These results suggest that simultaneous up-regulation of RAS/MAPK and PI3K/AKT cascades are crucial events in the pathogenesis of melanocytes, whereas up-regulation of either the RAS/MAPK or PI3K/AKT cascade is crucial for the majority of endometrial cancers.
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PMID:Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade. 1627 42

The PTEN tumor suppressor is a central negative regulator of the PI3K/AKT signaling cascade that influences multiple cellular functions including cell growth, survival, proliferation and migration in a context-dependent manner. Dysregulation of this signaling pathway contributes to many cancers in man. PTEN is the most commonly altered component of the PI3K pathway in human malignancies. Mutations occur in both heritable and sporadic settings, with high frequency in sporadic glioblastoma, prostate and endometrial cancer. Data from human tumors and animal models support the concept that the effects of PTEN inactivation are tissue-specific. Elucidation of the mechanisms regulating activation of unique downstream effectors that mediate distinct outcomes of PTEN loss will augment our understanding of tumorigenesis and ultimately lead to novel therapeutic options.
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PMID:PTEN function in normal and neoplastic growth. 1641 71

The fact that the genetic alterations of PTEN are frequently found in hormone-dependent cancers, such as endometrial, breast, and prostate cancers, might suggest the involvement of PTEN in the hormone-dependent cell growth of such tumors. Estrogen promotes the cell growth of the tumors by inducing peptide growth factors in part. We analyzed the possible involvement of PTEN in peptide-growth factor-dependent cell growth in endometrial carcinoma cells. PTEN-null Ishikawa cells were efficiently infected with recombinant adenovirus at 20 MOI (multiplicity of infection) to express PTEN protein. In PTEN-IK cells, phospho-Akt/PKB was down-regulated regardless of the consistent expression of Akt/PKB. The cell growth of parental IK cells was significantly stimulated by EGF and IGF-I, and PTEN-IK cells were further sensitized to the EGF-or IGF-I-growth stimulation. EGFR antibody could completely compromise the stimulatory effects of EGF in both cell lines. Wortmannin, a PI3K inhibitor, or UO126, a MAPK inhibitor, partly suppressed EGF-mediated cell growth stimulation in both cell lines. EGF augmented the level of phospho-Akt/PKB of PTEN-IK cells more effectively than that of parental IK cells. These results imply that the dysfunction of PTEN leads cells into a less-sensitive phenotype to peptide growth factors by constitutive activation of the PI3K/Akt/PKB signaling pathway in endometrial carcinoma.
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PMID:PTEN sensitizes epidermal growth factor-mediated proliferation in endometrial carcinoma cells. 1652 71

Cellular response to estrogen is mediated both by estrogen receptor (ER) binding to estrogen response element (ERE) and by non-nuclear actions like activation of signal transducing pathways. The main aims are to study if PI3K/Akt signaling pathway can be activated by 17beta-estradiol (E2) via non-nuclear action and to investigate the relationship of the action of E2 and ER in endometrial cancer cells expressing with different status of ER. The levels of phosphorylated Akt (Ser473) (P-Akt) and total Akt were examined by western blot and Akt kinase activity was measured in cells after stimulation with 1 microM E2 at different time points. Inhibitory role of LY294002 on activation of Akt induced by E2 and its estrogen antagonist, ICI182780 were also tested. P-Akt/Akt was used as a measure of activation of Akt. We found that maximum P-Akt/Akt and Akt kinase activity took place at 30 min in Ishikawa cells and 15 min in HEC-1A cells and the activation persisted for at least 2 h after stimulation with 1 microM E2. The activation of Akt elicited gradually with increasing doses of E2. PI3K inhibitor, LY294002, stopped the activating Akt in a dose-dependent manner and 50 microM LY294002 completely blocked the activation of Akt induced by E2. ICI182780 could block the activation of PI3K/Akt in ER-positive Ishikawa cells but not in HEC-1A cells with poor-expressed ER. This study demonstrated that E2 is able to promptly activate PI3K/Akt signal pathway in Ishikawa cells in an ER-dependent manner and ER-independent in HEC-1A cells. Blockage of PI3K/Akt cascade may become a potential and effective way to control endometrial carcinoma, especially in ER-negative cancers, which show no response to endocrinal therapy.
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PMID:17 beta-estradiol activates PI3K/Akt signaling pathway by estrogen receptor (ER)-dependent and ER-independent mechanisms in endometrial cancer cells. 1656 92

The phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway and the mitogen activated protein kinase (MAPK) pathway are important in the development and proliferation of various human cancers. It has been found recently that ursolic acid treatment affects growth and apoptosis in cancer cells. We sought to determine whether prominent signaling pathways, including the PI3K-Akt pathway and the MAPK (JNK, P38, and P44/42) pathway mediate these effects. Endometrial cancer cells often have high levels of phosphorylated Akt seen in conjunction with a PTEN mutation or deletion. Elevation in Akt protects the cancer cell from apoptosis. Ursolic acid treatment moderately decreased PI3K levels in SNG-II cells. Treatment also decreased phospho-Akt and phospho-P44/42 in a dose- and time-dependent fashion, dramatically in SNG-II cells and moderately in HEC108 cells. This effect was most pronounced following treatment with 50 mum ursolic acid for 72 h. Our study found inhibition of both the PI3K-Akt pathway and the MAPK pathway in two endometrial cancer cell lines, SNG-II and the poorly differentiated HEC108 cell line.
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PMID:Regulation of the phosphatidylinositol 3-kinase-Akt and the mitogen-activated protein kinase pathways by ursolic acid in human endometrial cancer cells. 1721 63

To investigate whether PTEN can augment doxorubicin-induced apoptosis in PTEN-null Ishikawa cells. We previously demonstrated that Ishikawa cells do not possess functional PTEN protein because of protein truncations. Clones expressing the steady-state level of the PTEN protein from PTEN-null Ishikawa cells have been established and were used in this study. Doxorubicin is a commonly used anticancer drug in endometrial carcinoma. The cytotoxic effect of doxorubicin was evaluated using the methyl thiazoleterazolium (MTT) assay. We used the Hoechst 33258 staining to confirm the induction of apoptosis. Immunoprecipitation and Western blot analysis were performed to evaluate the effects of doxorubicin on phosphorylation of Bcl-2 antagonist of cell death (Bad) and protein kinase B (Akt/PKB). Doxorubicin induced death of all cell lines in a dose-dependent manner, but the death was more significant in PTEN-expressing clones than in parent Ishikawa cells. A low concentration of doxorubicin (0.1 muM) did not affect apoptosis in PTEN-null Ishikawa cells, but it induced apoptosis in PTEN-expressing clones. A high concentration (1 microM) induced apoptosis in all cell lines, but the percentages of apoptotic cells were higher in PTEN-expressing clones than in parent Ishikawa cells. In the clones, phospho-Akt/PKB and phospho-Bad (Ser-136) were downregulated. Doxorubicin reduced the levels of phospho-Akt/PKB and phospho-Bad (Ser-136) in all the cell lines, but the reduction was most significant in the PTEN-expressing clones. Our present results indicate that PTEN transfection significantly enhances doxorubicin chemosensitivity through effective induction of apoptosis by downregulation of the PI3K/Akt/PKB signaling pathway in Ishikawa cells.
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PMID:PTEN augments doxorubicin-induced apoptosis in PTEN-null Ishikawa cells. 1735 93

The incidence of lymph node metastasis by endometrial carcinoma (EMCA) increases with the depth of myometrial invasion, and this depth of invasion has been found to have a major impact on the outcome. In the present study, we assessed the effect of tumor-stromal interactions on the invasive behavior of EMCA cells and examined the involvement of SDF-1alpha/CXCL12-CXCR4 in the interaction of EMCA cells and uterine smooth muscle cells (UtSMCs). We investigated whether SDF-1alpha/CXCL12 produced and secreted from UtSMCs induces EMCA cell migration by using 5 human EMCA cell lines such as AMEC and RL95 cells. The SDF-1alpha/CXCL12 concentration in conditioned medium (CM) of UtSMCs(was 4,120 +/- 530 pg/ml. Treatments with CM of UtSMCs and plated UtSMCs significantly induced both AMEC and RL95 cell migration. The induced cell migrations were significantly inhibited by CXCR4 mAb (12G5) and CXCR4 antagonist (AMD3100) pre-treatments. Treatments with UtSMCs CM to AMEC and RL95 cells stimulated Akt phosphorylation in a time-dependent manner. Pre-treatment of AMEC and RL95 cells with wortmannin as a PI3K inhibitor significantly inhibited UtSMCs CM-induced cell migration. The SDF-1alpha/CXCL12-CXCR4 chemokine axis between UtSMCs and EMCA played an important role in the muscular infiltration of endometrial cancer through activation of PI3K-Akt signaling pathway. Suppression of this pathway could be an effective target for the treatment of early uterine body cancer in particular.
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PMID:Uterine smooth muscle cells increase invasive ability of endometrial carcinoma cells through tumor-stromal interaction. 1758 87


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