Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolidase (EC 3.4.13.9) is an ubiquitously distributed imidodipeptidase that catalyzes the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. The enzyme plays an important role in the recycling of proline for collagen synthesis and cell growth. We have shown previously that prolidase activity in normal human skin fibroblasts is regulated by the interaction of type I collagen with beta1 integrin receptor. In the present study, we investigate prolidase activity in MCF-7 cells and find it is only one-third of that in normal human skin fibroblasts. The relative difference in prolidase activity is corroborated by enzyme protein with Western immunoblot analysis. We propose that the decrease in prolidase activity is due to derangement of regulation by the collagen-beta1 integrin receptor axis. Supporting evidence comes from the following observations: (1) relative collagen content elaborated by MCF-7 cells as compared to fibroblasts is lower by 30% in sparse cells and by 80% at confluence; (2) collagenase treatment of both cell types results in decreased enzyme activity; (3) in contrast to fibroblasts, prolidase activity in MCF-7 cells is not stimulated by the addition of type I collagen or beta1 integrin antibodies (agonist for beta1 integrin receptor); and (4) in contrast to fibroblasts, MCF-7 cells express only trace amounts of beta1 integrin receptor as shown by Western immunoblot analysis. Thus, we conclude that depressed prolidase activity in MCF-7 cells may be a result of disturbances in signaling mediated by beta1 integrin-collagen interaction.
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PMID:Prolidase in human breast cancer MCF-7 cells. 961 59

Dietary genistein, a natural flavone compound found in soy, has been proposed to be responsible for the low rate of breast cancer in Asian women. The cellular mechanisms of genistein's chemopreventive effects in vio have been largely unexplored. In our previous studies, we found that genistein exerted pronounced antiproliferative effects on both estrogen receptor-positive and -negative human breast carcinoma cells through G2-M arrest, induction of p21WAF1/CIP1 expression, and apoptosis. Because chemopreventive effects need not be limited to antiproliferation, we decided to examine whether genistein exerted other suppressive effects on breast carcinoma progression. Genistein inhibited invasion in vitro of MCF-7 and MDA-MB-231 cells. This inhibition was characterized by down-regulation of MMP (matrix metalloproteinase)-9 and up-regulation of tissue inhibitor of metalloproteinase-1, the former of which was transcriptionally regulated at activation protein-1 sites in the MMP-9 promoter. Genistein's in vitro effects on MMP-9 and tissue inhibitor of metalloproteinase-1 were also demonstrated in in vivo studies in nude mouse xenografts of MDA-MB-231 and MCF-7 cells. In these xenograft studies, genistein inhibited tumor growth, stimulated apoptosis, and upregulated p21WAF1/CIP1 expression. In the MDA-MB-231 xenograft, genistein also inhibited angiogenesis by decreasing vessel density and decreasing the levels of vascular endothelial growth factor and transforming growth factor-beta1. These in vitro and in vivo studies demonstrate that genistein exerts multiple suppressive effects on breast carcinoma cells, suggesting that its mechanism of chemoprevention is pleiotropic.
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PMID:Genistein exerts multiple suppressive effects on human breast carcinoma cells. 980 90

One of the primary antioxidant enzymes, manganese-containing superoxide dismutase (MnSOD), has shown the ability to reverse malignant phenotypes in a variety of human tumor cells that are low or absent in MnSOD expression. We have observed that overexpression of human MnSOD in human breast cancer MCF-7 cells inhibits tumor growth both in vitro and in vivo. The signaling pathway underlying the MnSOD induced tumor suppression is unknown. We demonstrate here that transcriptional and DNA binding ability of AP-1 and NF-kappaB, but not SP-1, were inhibited (by 50%) in the MCF-7 cell line overexpressing MnSOD. When transiently expressing, MnSOD inhibited AP-1 but increased NF-kappaB transactivation, which can be abolished by sodium pyruvate, a hydrogen peroxide scavenger. To analyze the target genes responsible for MnSOD-induced tumor suppression, genes related to tumor growth and responsive to AP-1 or NF-kappaB were analyzed. AP-1 responsive collagenase I, stromelysin I, and NF-kappaB responsive IL-1 and IL-6 were down-regulated in the MnSOD stable transfectants compared to the control cell lines. Since TPA induces differentiation in human breast cancer cells and up-regulates MnSOD gene in HeLa cells, MnSOD expression and AP-1 and NF-kappaB activity were measured under TPA treatment. The results showed that TPA induced endogenous MnSOD expression and inhibited both AP-1 and NF-kappaB. Together, these results suggest that tumor suppression by overexpressing MnSOD is related to a modulation of AP-1 and NF-kappaB, which causes a down-regulation of genes responsible for tumor malignant phenotype.
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PMID:Inhibition of AP-1 and NF-kappaB by manganese-containing superoxide dismutase in human breast cancer cells. 983 61

We investigated a potentially central role of protein kinase C (PKC) in controlling multiple pathways in breast cancer cell invasiveness. To do this we evaluated the ability of pharmacologic agents that alter PKC activity to regulate the behavior of the poorly invasive human breast cancer cell line MCF-7. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) produced a dramatic induction of the invasiveness of these cells (18-fold), an effect that concurrent treatment with the PKC inhibitor Bryostatin-1 was able to block. To characterize alterations in the cellular properties that might be responsible for these effects we measured the impact of these two agents on a number of processes thought to be important for invasiveness. The motility of the cells was first examined; it was markedly increased by treatment with TPA (20-fold) and again, Bryostatin-1 inhibited this stimulation. We next examined the expression of MMP-1, 3, 9, 10, and 11 (matrix metalloproteinases), all of which have been shown to be PKC responsive in other systems. We found that the expression and secretion of MMP-9 were increased by at least 100-fold, though all of the enzyme secreted was in the latent form. Finally, the expression of both urokinase plasminogen activator (UPA) and its receptor (UPAR) were induced after TPA treatment by 8- and 7-fold, respectively. In conclusion, we have shown that stimulation of PKC activity markedly increases the invasiveness of MCF-7 cells, and that this change in behavior is correlated with a coordinated set of biochemical and cellular changes which are likely to contribute to this process. These data highlight the possible utility of PKC inhibitors such as Bryostatin-1 as anti-invasive and/or antimetastatic agents. Bryostatin-1 is currently in early clinical trials as an anticancer agent.
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PMID:Regulation of motility and protease expression in PKC-mediated induction of MCF-7 breast cancer cell invasiveness. 1004 52

Prolidase [EC 3.4.13.9] plays an important role in the recycling of proline for collagen synthesis and cell growth. The increase in the enzyme activity is correlated with the increased intensity of collagen turnover, thus reflecting the intensity of collagen metabolism. Since estrogens alter collagen metabolism, it can be assumed that the changes may be reflected by prolidase activity. The effects of estrogen and antiestrogen (tamoxifen on the prolidase and collagenase activities and collagen biosynthesis) were measured in the estrogen-receptor (ER)-positive breast cancer cell line. Estradiol stimulated collagen biosynthesis and extracellular prolidase and collagenase activities in cultured MCF-7 cells without an effect on collagen accumulation in the extracellular matrix produced by these cells. On the other hand, tamoxifen inhibited the estrogen-dependent stimulatory effect on collagen biosynthesis but did not inhibit the stimulatory effect of estrogen on prolidase and collagenase activities. The inhibitory effect of tamoxifen on estrogen-dependent stimulation of collagen synthesis in MCF-7 cells and lack of its effect on estrogen-dependent stimulation of prolidase and collagenase activities suggest that both processes (collagen synthesis and degradation) are independently regulated in MCF-7 cells, possibly through antagonist, agonist and other estrogen receptor-independent actions of tamoxifen. Increased extracellular prolidase activity in estrogen-stimulated MCF-7 cells indicates potential diagnostic value of tissue prolidase in determining the ER status of breast cancer.
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PMID:Estrogen-dependent regulation of prolidase activity in breast cancer MCF-7 cells. 1045 8

Angiostatic substance TNP-470 displayed moderate cytotoxicity towards human leukemia HL-60, HL-60/ADR, HL-60/VCR and myeloma ARH77 cell lines with IC50 in the range 5-10 microM of concentrations and slightly higher IC50 for myeloma cell line U266. IC50 for ovarian CH-1, A2780 and A2780/ADR cell lines was in the range 10-15 microM with the exception of platinum-resistant SKOV3 cell line (more than 40 microM ). The IC50 values for MDA-MB-231 and MCF-7 breast carcinoma cell lines were 15 and 25 microM, respectively. In human hemopoietic neoplastic cell lines examined, TNP-470 induced the appearance of subpopulation with sub-G0 DNA content, suggesting the apoptosis-inducing potential of TNP-470 in these cells. No TNP-470-induced drug uptake modulation in drug-resistant leukemia cell line HL-60/VCR was observed. TNP-470 induced accumulation of cells in G0/G1 phase of cell cycle. There was no TNP-470-induced inhibition of MMP collagenase activity or MMP (MMP2 and MMP9) production in the human fibrosarcoma cells HT 1080 in vitro.
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PMID:Angiogenesis inhibitor TNP-470: cytotoxic effects on human neoplastic cell lines. 1066 43

Two invasive breast cancer cell lines (MDA-MB-231 and BT-549) were found to be more adherent and have greater migratory capacity on bone marrow fibroblasts than three non-invasive cell lines (MCF-7, T47D and BT-483). Antibodies to the adhesion molecules CD44, E-cadherin, ICAM- 1, and integrin chains alpha2, alpha3, alpha4, alpha5, alpha6, alpha v, beta1, beta3 and beta7 failed to inhibit breast cancer cell migration through bone marrow fibroblasts. Inhibitors of matrix metalloproteases, 1, 10-phenanthroline, Ro-9790, TIMP-1 and TIMP-2 were able to attenuate the migration of MDA-MB-231 cells through bone marrow fibroblast monolayers suggesting a role for these enzymes in the migration of breast cancer cells through bone marrow adherent layers. Co-culture of MDA-MB-231 cells and bone marrow fibroblasts resulted in augmentation of the levels of the matrix metalloproteases MMP-1 and MMP-2 in culture supernatants. Soluble factors produced by bone marrow fibroblasts were responsible for the increase in MMP-1 levels. However, maximal MMP-2 production was dependent on direct contract between the breast cancer cells and the bone marrow fibroblasts. Modulation of MMP production by cell-cell contact or soluble factors suggests a mechanism by which breast cancer cells can enhance their ability to invade the bone marrow microenvironment.
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PMID:Induction of matrix metalloproteinases MMP-1 and MMP-2 by co-culture of breast cancer cells and bone marrow fibroblasts. 1109 87

Several matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were studied in highly invasive (MDA-MB-231) and slightly invasive (MCF-7, T47D, BT-20) breast cancer cell lines. Investigations were carried out at the protein level and/or at the mRNA level, either in cells cultured as monolayers on plastic, or in cells seeded on a thin layer of Matrigel basement membrane matrix. Analysis of MMP expression by RT-PCR showed expression of MMP-1. MMP-3, and MMP-13 in highly invasive MDA-MB-231 cells, but not in slightly invasive cell lines. The extracellular secretion of MMP-1 and MMP-3 by MDA-MB 231 cells could be also shown by ELISA. TIMP-1 and TIMP-2 mRNAs were found in all cell lines, however, the extracellular secretion of both TIMPs was much higher in MDA-MB-231 cells than in the other cell lines. When the cells were cultured on Matrigel matrix, MMP-9 expression was induced in MDA-MB-231 cells only, as assessed by RT-PCR and zymography experiments. The invasive potential of MDA-MB-231 cells evaluated in vitro through Matrigel was significantly inhibited by the MMP inhibitor BB-2516, by 25% and 50% at the concentrations of 2 x 10(-6) M and 10(-5) M, respectively. In conclusion, our data show that highly invasive MDA-MB-231 cells but not slightly invasive T47D, MCF-7 and BT-20 cells express MMP-1, MMP-3, MMP-9 and MMP-13. MMP-9 which is specifically up-regulated by cell contact to Matrigel, may play a key role in the invasiveness of MDA-MB-231 cells through basement membranes.
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PMID:Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro. 1123 93

The estrogen receptor (ER) is known to mediate gene transcription from AP-1 enhancer elements as well as the well-documented estrogen responsive elements (EREs). Investigations of AP-1 mediated transactivation through ER have been performed with rather complex promoters such as insulin like growth factor 1 (IGF-1) and collagenase promoters. In the present study, we investigated AP-1 mediated transactivation through ERalpha and ERbeta with a less complicated reporter consisting of only consensus AP-1 motifs. NIH 3T3 cells were transiently transfected with human ERalpha and ERbeta expression plasmids and AP-1-luc and ERE-luc reporters. 17beta-Estradiol failed to activate ERbeta-AP-1 responses while activating ERalpha-AP-1, ERalpha-ERE, ERbeta-ERE mediated transcription. On the other hand, antiestrogens such as tamoxifen enhanced AP-1 mediated transactivation through both ERalpha and ERbeta. An ERalpha positive human breast cancel cell line, MCF-7, also showed the same manner of AP-1 mediated transactivation through ERalpha. When NIH 3T3 with ERalpha and MCF-7 were co-transfected with ERbeta, E2 dependent AP-1 responses decreased in both cell lines depending on the amount of the ERbeta expression plasmid. These results suggest that ERalpha and ERbeta may function in opposition with ERbeta actually suppressing the function of ERalpha in AP-1 mediated transactivation.
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PMID:Suppression by estrogen receptor beta of AP-1 mediated transactivation through estrogen receptor alpha. 1156 42

In the present study we investigated the presence, amount and activity of matrix metalloproteinases (MMPs)-1, -2, -3, -7, -8, -9, -10, -11 and -13 and TIMP-1 in three well-defined breast cancer cell lines with different biological behaviour; i.e. poorly-invasive MCF-7 cells, invasively growing MDA-MB-231 cells and invasive and highly-metastatic MDA-MB-435 cells. The parallel immunocytochemical determination of the degree of cellular differentiation, as monitored by the immunocytochemical expression of cytokeratins (CK), confirmed differences in the tumor cell differentiation. Thereby, MCF-7 cells expressed more glandular CKs than MDA-MB-231 cells, while MDA-MB-435 cells were only labelled by pancytokeratin markers, but neither by glandular nor by squamous epithelial CKs. Conditioned media were analyzed for the presence of MMPs and TIMP-1 using Western blot with specific polyclonal antibodies and for gelatinolytic and caseinolytic activity by zymography. In addition, the cellular pool of several MMPs was investigated by immunocytochemistry. An enhanced cytoplasmatic staining for MMP-3 and -9, MMP-1, -10 and -11 was seen in the highly metastatic cells at almost equal levels, while MMP-2 revealed only a minor intracellular staining in all three cell lines. Western blots of conditioned media showed enhanced amounts of MMP-1, -3, -7, -10 and -11 in media of the two metastatic cell lines. Casein zymography correlated with the results of the MMP-1 Western blots. By means of gelatin zymography, MMP-2 and -9 were detectable in cell culture supematants of all the three cell lines, while gelatinolytic activity was elevated in the media of the more malignant MDA-MB-435 cells. Separate addition of EDTA or Pefa bloc SL partially inhibited the gelatinoltic activity indicating the presence of metallo- and serine proteinases, respectively; combined application of both inhibitors resulted in a complete suppression of activity. We provide evidence that the deviation expression in secretion of various MMPs in breast cancer cell lines of different tumorigenicity correlates with the biological behaviour of these cells, ie. the more malignant cells synthesize more MMPs than the less malignant ones. In addition, the secretion of MMP-1, -3, -7, -10 and -11 was enhanced in the malignant MDA-MB-231 and -435 cells when compared to the corresponding intracellular pool. This analysis confirms previous results obtained in a keratinocyte tumor cell model and provides evidence for a more general biological association between MMP-expression and tumor cell growth.
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PMID:Matrix metalloproteinases (MMPs) in breast cancer cell lines of different tumorigenicity. 1191 Dec 53


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