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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the estradiol sensitivity of primary human breast carcinomas in organ culture in a prospective pilot series of 109 tumors. The effect on plasminogen activator (PA) production was used as the end-point of estrogen action. We found that: (i) All tumors secreted detectable levels of urokinase-type PA (uPA); the level of basal uPA production was markedly heterogeneous but showed a weak association with the level of estrogen receptor positivity (p = 0.049). (ii) Only 23.5% of the tumors secreted tissue-type PA (tPA) in addition to uPA; a higher proportion of these tumors had histological characteristics indicative of good prognosis (18% vs. 3% of tumors secreting only uPA). (iii) Estradiol modulated uPA production and this effect was receptor-mediated. (iv) Responsiveness to estradiol was limited to a subset (25 of 60 or 41.7%) of estrogen and progesterone-receptor-positive tumors. (v) Of 20 evaluable patients with lymph-node and receptor-positive breast cancer who received adjuvant anti-estrogen therapy, 11 were identified as estradiol-sensitive by the in vitro PA assay; of these, 10 had no evidence of disease after a median follow-up period of 3+ years. In contrast, of 9 patients with tumors identified as estradiol-insensitive, 4 developed metastases within 3+ years of follow-up. (vi) Consistent with the previously reported inhibitory effect of corticosteroids on uPA production in organ cultures of human tumors, the basal culture level of uPA produced by tumors from patients receiving corticosteroids at the time of surgery was significantly lower than the level of uPA in the remaining tumors (p = 0.029). Also, tumors from patients receiving thyroid hormone, known to stimulate uPA in vitro, showed a slight trend toward increased production of uPA. These results show that hormone effects on tumor PA production are qualitatively similar in organ culture and in the host. This and the emerging individual correlation between sensitivity to estradiol in vitro, as determined by PA, and the clinical effectiveness of anti-estrogen therapy, underscore the potential usefulness of the organ culture approach.
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PMID:Estradiol modulation of plasminogen activator production in organ cultures of human breast carcinomas: correlation with clinical outcome of anti-estrogen therapy. 190 Dec 98

ES-1 cells, which showed a higher sensitivity to the cytocidal action of estradiol were isolated from a human breast cancer MCF-7 cell line. Growth of ES-1 cells was inhibited by a dose of 17-beta estradiol that stimulated the growth of the parental MCF-7 cells. Proteins secreted from MCF-7 and ES-1 cells when cultured with 17-beta estradiol were compared by sodium dodecyl sulfate-containing polyacrylamide gel electrophoresis (SDS-PAGE). Addition of estradiol to culture medium enhanced secretion of a protein of molecular mass of 52 kDa in media for both MCF-7 and ES-1 cell lines, but the secretion of a second 67 kDa protein was enhanced about 10-fold only in ES-1 cells. The analysis by SDS-PAGE of culture medium immunoprecipitated with anti-tissue-type plasminogen activator (t-PA) antibody demonstrated that the band of 67 kDa protein specifically secreted from estradiol-treated ES-1 cells contained t-PA. Zymography assays, quantitative immunoreactive assays, and Northern analysis showed about 5-fold specific increase by estradiol of t-PA with molecular mass of 65-70 kDa in ES-1 but not in its parental MCF-7 cells. Cellular level of the plasminogen activity was also specifically enhanced in ES-1 cells by estradiol, but only a slightly in MCF-7 cells. By contrast, another urokinase-type PA (u-PA) with molecular weight of 55 kDa showed very low level activity in both MCF-7 and ES-1 cell lines in the presence of estradiol. Formation of t-PA mRNA was specifically enhanced in ES-1 cells when ES-1 cells were treated for more than 12 h with 10(-8) M 17-beta estradiol. Estradiol did not elongate the lifetime of t-PA mRNA in ES-1 cells. A unique phenotype of ES-1 cells in response to estradiol is discussed in relation to activating expression of the t-PA gene.
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PMID:Enhanced production of tissue-type plasminogen activator by estradiol in a novel type variant of human breast cancer MCF-7 cell line. 211 58

Basic fibroblast growth factor (bFGF) has been demonstrated to exert an angiogenic activity in vivo. Here, the ability of bFGF to stimulate plasminogen activator (PA) production in bovine capillary endothelial cells was used as an assay for the presence of bFGF-like molecules in the extracts of the human endometrial adenocarcinoma AN3CA, HEC-1-A, and HEC-1-B cell lines. The identity of the PA-stimulating activity with bFGF was confirmed by its high affinity for heparin and by its cross-reactivity with antibodies to human placental bFGF. Western blot analysis and immunoprecipitation experiments showed that, in the extracts of the three cell lines, these antibodies recognize a protein with an apparent molecular weight of approximately 17,000 daltons. 17 beta-Estradiol stimulates the synthesis of this bFGF-like molecule in all the endometrial cell lines tested. This stimulation can be abolished by treating the cells with progesterone. These data demonstrate the capacity of sex hormones to regulate bFGF synthesis in tumor endometrial cells, and they suggest that bFGF may play a role in the vascularization of the endometrial adenocarcinoma as well as of the normal endometrium.
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PMID:Sex hormones modulate the synthesis of basic fibroblast growth factor in human endometrial adenocarcinoma cells: implications for the neovascularization of normal and neoplastic endometrium. 246 82

1. Regulatory mechanism of cell growth of endometriosis in comparison with endometrium. Estradiol alone has no growth-promoting effect on both endometriotic and endometrial cells. Epidermal growth factor (EGF) stimulates cell growth of both cell types. Endometrial cells but not endometriotic cells produce and release EGF into culture media so that stimulatory effect of exogenous addition of EGF is blunted in endometrial cells. Estradiol exerts its mitogenic action by enhancing the mitogenic effect of EGF in endometrium. By contrast, the effect of estradiol is minimal in endometriotic cells, showing less dependency on estradiol for their proliferation. Progesterone inhibits cell growth of the both cell types in the same manner. 2. A biological role of EGF in endometriosis. Endometriotic cells possess EGF receptors. The affinity of the receptor is the same as that of endometrial cells. However, the number of receptor per cell is about half of that for endometrium. Estradiol increases the number of EGF receptors in endometrial cells which may explain the mitogenic effect of estradiol in the face of EGF. However, stimulatory effect of estradiol for EGF receptors is less pronounced in endometriotic cells. Mitogenic action of EGF is suggested to be mediated by phosphorylation of tyrosine residues of 170 kd protein in the tissues. EGF increases the production of tissue plasminogen activator (t-PA) and activates the aromatase activity of the both cell types. However, the stimulatory action of EGF on progestin receptor is observed only in endometrial cells. 3. Biochemical characterization of endometriotic cells in comparison with endometrial cells. Endometriotic tissues accumulate less amount of glycogen and XIII factor of blood coagulation as compared to endometrial tissues. The ability of endometriotic cells to release prostaglandin is also weaker, suggesting suppressed differentiated function of endometriotic cell. Endometriotic cells produce the same amount of CA125 as endometrial cells. Danazol and EGF inhibit the release of CA125 into culture media when standardized per cell. Therefore, normalization of CA125 levels during the treatment dose not always mean the reduction of the lesions but reflect the suppressed function of the endometriotic tissues. 4. Altered microenvironment of endometriotic tissues. An analysis of peritoneal fluid. The amount of peritoneal fluid (PF) with endometriosis increased throughout the menstrual cycle. A number of macrophage is reported to increase in PF with endometriosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Fundamental and clinical studies on biochemical properties of endometriosis in comparison with endometrium]. 250 2

As stated earlier, the mammalian ovary maintains the continuous development of follicles, but only a few are selected to ovulate and form corpora lutea. These processes are regulated primarily by the gonadotropins and involve specific, sequential changes in the function of theca cells and granulosa cells. Data from recent studies (summarized in Figure 3) show that specific genes are turned on or off at different stages of follicular growth in response to estradiol and different amounts of gonadotropins and cAMP. For example, mRNA for RII51 in granulosa cells and theca cells increases in association with small increased in cAMP but is markedly reduced by the LH surge and high cAMP. The content of mRNA for other kinase subunits, RI and C alpha, show little or no change during similar hormonal changes. In theca cells, mRNA for 17 alpha-hydroxylase increased and decreased in a manner similar to that for RII51. In contrast, levels of mRNA for P450scc increased only gradually in follicles but were markedly increased by the LH surge and high concentrations of cAMP and then appeared to be constitutively expressed in rat corpora lutea in a cAMP-independent manner. PGS and t-PA appear to follow yet another pattern: rapid induction by the LH surge followed by a rapid decline in association with ovulation. One major task for reproductive endocrinologists and molecular biologists now is to determine how low and high concentrations of cAMP act to turn on and turn off the expression of these specific genes at specific times during follicular maturation. A working model of the molecular events occurring in theca and granulosa cells of PO follicles is shown in Figure 4. LH acts on theca cells via cAMP ro regulate both P450scc and P450(17) alpha mRNA levels, leading to increased biosynthesis of androstenedione. The mechanisms by which cAMP acts in theca cells remain to be determined but appear to involve an increase in the content of RII51, P450scc, and P450(17) alpha. In granulosa cells, androstenedione is converted to estradiol by the aromatase P450 enzyme system. Estradiol, in turn, binds to estradiol receptors present in these cells and may thereby regulate gene expression. However, despite the presence of estradiol and estradiol receptors, little or no effect of estradiol is observed unless FSH acts via the FSH receptor to increase intracellular concentrations of cAMP. In a manner not yet understood, cAMP appears to enhance the actions of estradiol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular aspects of hormone action in ovarian follicular development, ovulation, and luteinization. 328

MCF-7 human breast cancer cells secrete two immunologic types of plasminogen activator, one related to urokinase, the other unrelated. We have now examined whether estrogen stimulation of secreted plasminogen activator activity reflects an increase in one or both types. Examined semiquantitatively by sodium dodecyl sulfate-polyacrylamide gel electrophoretic zymography, the conditioned media of control cells were seen to contain a major activator band (Mr approximately 54,000) immunologically related to urokinase and a barely discernible doublet (Mr approximately 64,000 and Mr approximately 68,000). Addition of estradiol or, at much higher concentrations, testosterone led to marked enhancement of doublet activity, while the 54-kDa band was invariant. The 64-68-kDa doublet was immunoreactive with antiserum directed against Bowes melanoma tissue plasminogen activator but not with antiurokinase antibodies. Enhancement of doublet activity was correlated with hormone-induced increases in total secreted plasminogen activator activity. Neither progesterone nor dexamethasone increased total activity or the 64-68-kDa zones of lysis. Estradiol and testosterone alterations were blocked by appropriate concentrations of an estrogen antagonist (LY156758), actinomycin D, or cycloheximide. Regulation of MCF-7 cell-secreted tissue plasminogen activators thus appears to be mediated by an estrogen receptor process and to require sustained RNA and protein synthesis.
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PMID:Estradiol preferentially enhances extracellular tissue plasminogen activators of MCF-7 breast cancer cells. 654 3

The effect of the antiestrogens tamoxifen and nafoxidine on the growth of the human breast cancer cell line MCF-7 is modified by both serum and insulin. Tamoxifen inhibition of the growth of MCF-7 cells in culture is reduced as the concentration of serum in the medium is increased from 0.1% to 5 to 10%. Estradiol does not stimulate cell growth over the same range of serum levels. Insulin changes the sensitivity of MCF-7 cells to both estrogen and antiestrogens. Cells growing in media containing insulin are less sensitive to inhibition by either tamoxifen or nafoxidine than are cells growing in its absence. In addition, higher concentrations of estradiol are required to stimulate the production of plasminogen activator when cells are grown in media containing insulin. This effect of insulin can be accounted for by the finding that insulin lowers the level of estrogen receptor in MCF-7 cells without altering the binding constant for the hormone. Cells grown with insulin have an average of 21,000 +/- 4,700 (S.D.) estrogen binding sites/cell compared to 62,000 +/- 9,700 sites/cell in cells grown in the absence of insulin. This difference in receptor level is sufficient to account for the difference in the concentration of estradiol needed for equivalent induction of plasminogen activator in cultures with or without insulin. These results indicate that the level of estrogen receptor in breast cancer cells can be changed and that the sensitivity of such cells, both to estrogen and to antiestrogens, is altered by changes in the level of estrogen receptor. They also have implications concerning the mechanism by which antiestrogens act to inhibit the growth of mammary tumor cells.
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PMID:Effects of serum and insulin on the sensitivity of the human breast cancer cell line MCF-7 to estrogen and antiestrogens. 700 31

The present studies examined the biochemical characteristics which were carried on from parent cells during fusion of human skin fibroblasts (HSF) with spleen cells of BALB/c mice preimmunized with hormone-responsive and nonresponsive human malignant melanoma cells (HMMC-ShA and HMMC-SR). The melanoma cells used as immunogens were either unmodified or preincubated with vibrio cholera neuraminidase (VCN), with estradiol (E), or with progesterone (P). Responsiveness was monitored by (3H) thymidine and (35S) methionine incorporation. Responsiveness to estradiol, concanavalin A (Con A) and to phytoheamagglutinin (PHA) were carried out, whereas malignancy was suppressed extensively in the cloned hybrids. On the immunizing tumor cells, VCN treatment enhanced (3H) thymidine but reduced (35S)-methionine incorporation and malignancy of the estradiol responsive melanoma cells (HMMC-ShA). VCN treatment enhanced (3H)-thymidine incorporation, but had no effect on (35S)-methionine incorporation and malignancy of the estradiol nonresponsive HMMC-SR cells. Estradiol treatment enhanced plasminogen activator (PA) activity and malignancy, whereas progesterone treatment reduced (inhibited) plasminogen activator activity and suppressed malignancy of the immunizing tumor cells. The PA from estradiol-responsive and from nonresponsive melanoma cells differed in their electrophoretic mobility on polyacrylamide gel electrophoresis.
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PMID:Correlation between plasminogen activator activity of immunizing tumor cells and complement-mediated cytotoxic antibodies secreted by cloned hybrid cells. 719 36

To elucidate potential mechanisms involved in the increased incidence of endometrial carcinomas in tamoxifen-treated patients, we examined the in-vitro effects of tamoxifen on endometrial cancer cells. The effects of tamoxifen, alone and in combination with oestradiol, on cell proliferation, plasminogen activator (PA) activity, glycogen synthase and phosphorylase activities, p53 protein concentration, and collagenase expression were assessed in two human adenocarcinoma cell lines. These lines were the oestrogen receptor-positive (Ishikawa) cells, representing a well-differentiated endometrial adenocarcinoma, and oestrogen receptor-negative (HEC-1A) cells, derived from a poorly differentiated endometrial adenocarcinoma. Tamoxifen or oestradiol alone and their combination significantly enhanced cellular proliferation of Ishikawa but not of HEC-1A cells. Both lines produced appreciable PA activity, most of which was of the urokinase type. Tamoxifen and oestradiol stimulated this activity in Ishikawa cells but not in HEC-1A cells. The effect of oestradiol was dose-dependent in a linear fashion, while tamoxifen produced a stimulation peaking at 10(-8) M and declining at higher concentrations. Tamoxifen in combination with oestradiol exhibited a synergistic effect on proliferation and on PA activity. The response of PA extended beyond the increase in proliferation, leading to higher specific activity of PA in the tamoxifen-treated cultures. In Ishikawa cells, oestradiol also increased glycogen synthase and glycogen phosphorylase activities, while tamoxifen markedly suppressed these enzymes. Oestradiol, tamoxifen, and their combination had no apparent effect on the expression of protein p53 in Ishikawa cells, or on gelatinase activity in either Ishikawa or HEC-1A cells. The present findings imply that tamoxifen produces oestrogen-agonistic effects on cell proliferation and PA activity, and oestrogen antagonistic effects on glycogen synthase and glycogen phosphorylase activities, but fails to regulate p53 and gelatinase expression. The tamoxifen-responsive systems were only observed in oestrogen-responsive adenocarcinoma cells. Thus, only certain potential oncogenic effects of tamoxifen can be simulated in vitro, and when present, these effects are enhanced in the presence of oestradiol.
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PMID:Tamoxifen exerts oestrogen-agonistic effects on proliferation and plasminogen activation, but not on gelatinase activity, glycogen metabolism and p53 protein expression, in cultures of oestrogen-responsive human endometrial adenocarcinoma cells. 946 46

The purpose of this study was to determine whether aging influences the sex-related differences in fibrinolytic activity in rats. We measured plasminogen activator (PA) activity and plasminogen activator inhibiting (PAI) activity in 5-, 12-, 45-, and 60-week-old male and female rats. We also examined the effects of gonadectomy and sex hormone-treatments in adult male and female rats. The increase in age did not influence the PA activity in the male or female rats. However, the PA activity was higher in the female rats than in the males in all four age groups. Orchidectomy caused a significant increase in PA activity in the male rats. Estradiol treatment induced a significant increase of PA activity in ovariectomized female rats. Testosterone treatment resulted in a decrease of PA activity in orchiectomized male rats. The increase in age had an effect on PAI activity; the activity level in the 45- and 60-week-olds was stronger than that in the 12-week-old rats. The PAI activity was not significantly different between the normal rats of each sex. Gonadectomy did not influence the PAI activity in male or female rats, and testosterone and estradiol treatments also did not affect PAI activity in gonadectomized male and female rats. We found that the increase in age induced a decrease in the fibrinolytic system in the rats, and that there were sex-related differences in the fibrinolytic system in even 60-week-old rats.
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PMID:Sex-related differences in plasminogen activator and plasminogen activator inhibiting activities in young and aged rats. 1060 81


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