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)

Insulin is a major regulator of circulating insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), suppressing the hepatic production of IGFBP-1. Postmenopausal age, obesity, hypertension, and impaired glucose tolerance, which are known risk factors for endometrial cancer, are all associated with hyperinsulinemia and insulin resistance. In this study, we investigated the relationship among serum insulin, glucose, insulin-like growth factors (IGF-I and IGF-II), and IGFBP-, -2, and -3 in 32 nondiabetic postmenopausal women with endometrial cancer and in 18 healthy controls. The mean fasting levels of glucose and insulin were higher, whereas the mean basal IGF-I, IGF-II, and IGFBP-3 levels were lower in the endometrial cancer patients than in the healthy control subjects. The mean fasting IGFBP-1 and IGFBP-2 levels did not differ between the groups, and no correlation was found between fasting insulin and IGFBP-1 concentrations or between insulin and IGFBP-2 concentrations in either of the study groups. During an oral glucose tolerance test, the mean glucose levels at 1 and 3 h as well as the mean insulin level at 3 h were significantly higher in the endometrial cancer patients than in the controls, and the area under the glucose curve was larger in the first group. An oral glucose load resulted in a similar fall in serum IGFBP-1 levels in endometrial cancer patients and controls (51% and 55% at 3 h). When the cancer patients were divided into two subgroups according to the body mass index (kilograms per m2), the obese group had higher glucose and insulin indices than the nonobese group. No difference was found by the same measures in healthy controls. The fasting serum IGFBP-1 levels tended to be lower in the obese than in the normal weight subjects, but the difference did not reach statistical significance. In summary, these results provide preliminary evidence that the inverse relation between fasting insulin and IGFBP-1, well established in children and young adults, disappears in elderly women, although short term suppression by insulin still occurs. Further, our data indicate that in addition to carbohydrate metabolism, postmenopausal women with endometrial cancer have alterations in their circulating IGF system compared to controls.
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PMID:Relationship between carbohydrate metabolism and serum insulin-like growth factor system in postmenopausal women: comparison of endometrial cancer patients with healthy controls. 768 14

Insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins (IGFBPs) were examined in Ishikawa endometrial cancer cells. Our findings suggest that about 95% of [125I]IGF-I is bound to membrane-associated IGFBPs rather than to IGF-I receptors. Specifically, [125I]IGF-I binding to cell membranes could be completely displaced by cold IGF-I or IGF-II, but not by insulin, suggesting that binding was primarily due to IGFBPs. This was confirmed by using [125I]des-(1-3)IGF-I as the ligand. Des-(1-3) IGF-I binds with high affinity to IGF-I receptors, but with markedly lower affinity to IGFBPs. [125I]Des-(1-3)IGF-I bound to Ishikawa cells was displaced by IGF-I, IGF-II, and insulin. These results suggest that measuring IGF-I receptor levels using labeled IGF-I may be misleading. Accordingly, we evaluated the differential binding of [125I]IGF-I and [125I]des-(1-3)IGF-I to study the involvement of the IGF system in the stimulation of Ishikawa cell growth by estradiol. IGF-I stimulates Ishikawa cell proliferation, but at low concentrations, and this stimulation is largely dependent on the presence of estradiol. Estradiol caused a 2.5-fold increase in IGF-I receptor levels. Moreover, estradiol reduced soluble IGFBP levels, presumably increasing the availability of IGFs for their receptors. This elevation in IGF-I receptor levels and the decrease in IGFBP levels were accompanied by a 3.5-fold increase in IGF-I receptor messenger RNA and a 2.5-fold decrease in IGFBP messenger RNAs. These experiments suggest that estradiol sensitizes endometrial cancer cells to the effects of IGFs by simultaneously elevating receptor levels and decreasing (potentially inhibitory) IGFBP levels.
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PMID:Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol. 775 Apr 75

Several lines of evidence suggest that estrogen is an important determinant of cardiovascular risk in women. Epidemiologic data document low rates of coronary heart disease (CHD) in premenopausal women, a narrowing of the gender gap in CHD mortality after menopause, and elevated risk of CHD among young women with bilateral oophorectomy not treated with estrogen. Nearly all of the more than 30 observational studies of exogenous estrogen replacement therapy have indicated a reduced risk of CHD among women receiving estrogen therapy. In a meta-analysis comparing estrogen users and nonusers, the estimated reduction of CHD among users was 44%. In angiographic studies, women taking estrogen were less likely to have coronary artery stenosis. Estrogen is known to affect a wide range of physiologic processes that may have an impact on CHD risk. Use of oral estrogen has favorable effects on serum lipid profiles; it increases high-density lipoprotein cholesterol levels by 10% to 15% and decreases low-density lipoprotein cholesterol levels by a similar magnitude. Other proposed mechanisms include inhibition of endothelial hyperplasia, reduced arterial impedance, enhanced production of prostacyclin, increased insulin sensitivity, and inhibition of oxidation of low-density lipoprotein. Nevertheless, the role of hormone replacement therapy in preventing clinical atherosclerotic events in women remains inconclusive because of the absence of randomized trial data. The benefit-to-risk ratio must be reliably assessed, because estrogen has complex actions, including postulated benefits (CHD, osteoporosis, and menopausal symptoms) and postulated risks (endometrial cancer, breast cancer, and gallstones.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postmenopausal hormone therapy and atherosclerotic disease. 797 16

Diabetes occurs in more than 13 million persons in the United States, and approximately 60% of the new cases are diagnosed in women. This review examines health issues related to women with diabetes mellitus. The following issues are discussed in the review. The prevalence of diabetes is higher in Native-American, black, and Hispanic women than in white women. Women with upper-body obesity are at risk for developing non-insulin-dependent diabetes mellitus (NIDDM) and women with diabetes are at risk for developing heart disease. Diabetes, obesity, and heart disease are all modifiable by nutrition. White women with diabetes derive approximately 40% of energy from fat, which is 10% greater than the national goal. Women with a history of gestational diabetes are at risk for developing NIDDM. Women with insulin-dependent diabetes mellitus (IDDM) are at high risk of developing complications in pregnancy, and pregnancy outcomes improve with preconceptual counseling. Women with IDDM are at risk for developing eating disorders, although not to a greater extent than the nondiabetic population. Women with diabetes are at risk for developing endometrial cancer. Both IDDM and NIDDM prevention clinical trials are in progress, although none target women specifically. Dietetics practitioners are encouraged to use local and national diabetes resources.
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PMID:Diabetes mellitus--a priority health care issue for women. 807 95

A plasminogen activator (PA) system is involved in ovulation, implantation, tumor invasion and metastasis. In order to clarify the regulation of this PA system in endometrial cells, we examined which agent affecting cellular function altered tissue-type plasminogen activator (t-PA) secretion by endometrial carcinoma cell line (KLE cells) in vitro. Triiodothyronine, retinoic acid, insulin, 8-bromo-cAMP, PDGF, IGF-I, basic FGF or TNF-alpha did not alter t-PA secretion while the activator of protein kinase C, phorbol myristate acetate (PMA) stimulated t-PA secretion in a dose-dependent fashion (10(-10)-10(-8) M). The time required to give a statistically significant increase in t-PA over control was 3 hours, and the maximal increase was seen after 24 hours of exposure. Another active phorbol ester, PDD also stimulated t-PA secretion while inactive forms of phorbol ester, 4 alpha-PDD and phorbol did not alter it. Cholera toxin or 8-bromo-cAMP did not affect t-PA secretion, but enhanced PMA-stimulated t-PA secretion. Cycloheximide and actinomycin D completely abolished PMA-stimulated t-PA secretion. These results suggest that (1) t-PA secretion in the endometrial carcinoma cell is modulated by a protein kinase C system, (2) This effect is through new RNA production and protein synthesis. (3) There is a complicated relationship between protein the kinase C and protein kinase A system as to the regulation of t-PA secretion. This would be a suitable model to clarify the PA system in endometrial cells.
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PMID:[Effect of phorbol ester on tissue-type plasminogen activator (t-PA) secretion in endometrial carcinoma cell line in vitro]. 812 84

The involvement of IGFs in growth regulation of the Ishikawa endometrial tumor cell line and the possible interference of LH-RH analogues with a potential autocrine or paracrine loop involving IGFs was evaluated. The mitogenic effects of IGF-I, IGF-II, and insulin were compared. IGF-I was found to be 3-fold more potent than IGF-II and 30-fold more potent than insulin, suggesting that the effects of these growth factors are mediated by the IGF-I receptor. Ishikawa endometrial cancer cells secrete IGF-II, but not IGF-I, and insulin (1 microM) stimulates IGF-II release. The LH-RH antagonist [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-GnRH (SB-75, CETRORELIX) inhibited basal and IGF-induced growth. Moreover, this antagonist almost completely inhibited IGF-II release from Ishikawa cells, while having no significant effect on the number or affinity of IGF-I binding sites. Inhibition of IGF-II release occurred at a lower SB-75 concentration than that needed for a reduction in cell number. The ED50 of SB-75 for IGF-II release was 0.3 microM as compared to 1.5 microns concentration which is required for reduction in cell number, suggesting that inhibition of growth factor release precedes cell growth inhibition. We conclude that the LH-RH antagonist SB-75 can inhibit the growth of endometrial cancer cells by interfering with the autocrine action of IGF-II and also by directly inhibiting the growth-stimulatory effects of IGFs, probably through effects on a post-receptor mechanism.
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PMID:Regulation of endometrial cancer cell growth by insulin-like growth factors and the luteinizing hormone-releasing hormone antagonist SB-75. 826 21

Transforming growth factor-beta 1 (TGF-beta 1) enhanced cell proliferation in a concentration-dependent manner in a human endometrial cancer cell line, IK-90. Scatchard analysis of TGF-beta 1 receptor in IK-90 cells, using 125I-TGF-beta 1 as a ligand, revealed the presence of a class of high-affinity TGF-beta 1 receptors (2,000 sites per cell, KD = 74pM). Moreover, IK-90 cells produced and secreted TGF-beta 1: TGF-beta 1 messenger RNA was detected at 2.5 and 4.0 kb by Northern-blot analysis using 32P-labeled TGF-beta 1 cDNA as a probe, and TGF-beta 1 activity in conditioned medium by the inhibition of 3H-thymidine uptake into CCl 64 mink lung epithelial cells. We investigated the regulation of TGF-beta 1 receptor by 4 kinds of growth factor: epidermal growth factor (EGF) but not TGF-beta 1, insulin or insulin-like growth factor-1 increased the level of TGF-beta 1 binding sites in a concentration- and time-dependent manner. These findings suggest that TGF-beta 1 may be a potential autocrine growth factor in a human endometrial cancer cell line IK-90 and that this autocrine mechanism may be affected by EGF.
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PMID:Autocrine growth mechanism by transforming growth factor (TGF)-beta 1 and TGF-beta 1-receptor regulation by epidermal growth factor in a human endometrial cancer cell line IK-90. 839 35

In 22 patients with endometrial carcinoma, Stage I-III (mean age 57.8 years) with obesity, initial and reactive hyperinsulinemia (during glucose load) was revealed. Significant correlations between values of "peak" and field-square of the insulin secretion curve and cytoplasmatic receptors to Estradiol and Progesterone in the tumor were found. In a group of the patients with high values of reactive hyperinsulinemia significantly larger amounts of steroid hormone receptors in the tumor were determined as compared to the group of the patients who had low insulinemia values. On considering these data a possible conclusion was reached as to the modifying influence of hyperinsulinemia on sensitivity of endometrial carcinoma to hormone receptor synthesis in the tumor by insulin.
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PMID:Hyperinsulinemia as a factor modifying sensitivity of endometrial carcinoma to hormonal influences. 850 Apr 94

The antiproliferative properties of lycopene, the major tomato carotenoid, were compared with those of alpha- and beta-carotene. Lycopene, delivered in cell culture medium from stock solutions in tetrahydrofuran, strongly inhibited proliferation of endometrial (Ishikawa), mammary (MCF-7), and lung (NCI-H226) human cancer cells with half-maximal inhibitory concentration of 1-2 microM; alpha- and beta-carotene were far less effective inhibitors. For example, in Ishikawa cells, a 4-fold higher concentration of alpha-carotene or a 10-fold higher concentration of beta-carotene was needed for the same order of growth suppression. The inhibitory effect of lycopene was detected after 24 hours of incubation, and it was maintained for at least three days. In contrast to cancer cells, human fibroblasts were less sensitive to lycopene, and the cells gradually escaped growth inhibition over time. In addition to its inhibitory effect on basal endometrial cancer cell proliferation, lycopene also suppressed insulin-like growth factor-I-stimulated growth. Insulin-like growth factors are major autocrine/paracrine regulators of mammary and endometrial cancer cell growth. Therefore, lycopene interference in this major autocrine/paracrine system may open new avenues for research on the role of lycopene in the regulation of endometrial cancer and other tumors.
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PMID:Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. 861 45

Transcription-modulating drugs achieve their therapeutic effects through the modulation of gene transcription. To understand how selectivity is achieved, four groups of such drugs - including immunosuppressants, estrogen analogs, the antidiabetic thiazolidinediones, and the anti-inflammatory salicylates - will be discussed. The immunosuppressants cyclosporin A and FK506, when complexed with immunophilins, inactivate the protein phosphatase calcineurin, resulting in the inhibition of interleukin-2 gene activation. Another immunosuppressant, rapamycin, binds to the same immunophilin as FK506 but inactivates a protein kinase p70(s6k). Estrogen analogs tamoxifen and rolaxifene antagonize one estrogen receptor transactivation function (AF-2) and agonize another (AF-1). They modulate expression of a wide variety of genes, including transforming growth factor-alpha, insulin-like growth factor-1, and transforming growth factor-beta3, which are important for breast and endometrial cancer proliferation and bone maintenance respectively. The antidiabetic drugs thiazolidinediones bind and activate peroxisome proliferator-activated receptor gamma and suppress insulin resistance mediated by tumor necrosis factor-alpha. Salicylates inhibit transcription factor NFkappaB, which is important for immune and inflammatory responses. Continuing understanding of molecular mechanisms of such drugs not only helps to identify better drugs for these targets but should also provide an insight into developing future transcription-modulating drugs with better selectivity and reduced toxicity.
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PMID:Transcription-modulating drugs: mechanism and selectivity. 893 43


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