Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several proteinases from different multigene families have been implicated in the uterine invasion required for establishment of pregnancy in some mammals. In this study, the expression of matrix metalloproteinase gelatinase B (MMP-9), urokinase-type plasminogen activator (uPA) and their inhibitors was investigated during early mouse embryo development. Transcripts for tissue inhibitors of metalloproteinases (TIMP-1,-2,-3) and uPA receptor were detected throughout pre- and peri-implantation development whilst MMP-9 and uPA mRNAs were first detected in peri-implantation blastocysts associated with the invasive phase of implantation. Through use of in situ hybridization, it was shown that MMP-9 transcripts were strongly expressed in the network of trophoblast giant cells at the periphery of implanting 7.5 day embryos and TIMP-3 transcripts were strongly expressed in the decidua immediately adjacent to the implanting embryo. uPA transcripts were preferentially expressed in the ectoplacental cone and its derivatives. Because these proteinases are regulated by growth factors and cytokines in other tissues, the effect of leukaemia inhibitory factor (LIF) and epidermal growth factor (EGF) on their activity was investigated. Both LIF and EGF, like the proteinases, have been implicated in peri-implantation development. Blastocysts collected on day 4 of pregnancy were cultured 2 days in TCM 199 + 10% fetal bovine serum to allow outgrowth followed by 24 hour culture in defined media containing either LIF or EGF. Conditioned media were assayed for uPA activity by a chromogenic assay and MMP activity by gelatin zymography. Both LIF and EGF stimulated uPA and MMP-9 activity in blastocyst outgrowths after 3 days of culture (day 7). Proteinase activity was assayed again at the 5th to 6th day of culture (day 9 to 10). EGF was found to have no effect whereas LIF decreased production of both proteinases. These results demonstrate that proteinase activity in early embryos can be regulated by growth factors and cytokines during the implantation process and, in particular, they demonstrate the possible involvement of LIF in establishment of the correct temporal programme of proteinase expression.
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PMID:Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor. 774 17

92-kDa type IV collagenase/gelatinase (matrix metalloproteinase-9; MMP-9; gelatinase B) expression and secretion has been shown to correlate with the invasive and metastatic potential of various malignant cells. MMP activity is tightly controlled by specific tissue inhibitors of metalloproteinases (TIMPs). We found the leukemic cell line HL-60 constitutively to release a 94-kDa gelatinase which we identified as MMP-9 shortened by nine amino acids at its N-terminal end. An additional gelatinolytic activity was present in small amounts and identified as a 63-kDa fragment of MMP-9 generated by autocatalytical processing. Both enzymes were identical regarding their N-terminus, indicating C-terminal truncation for the former. Incubation of cells with phorbol ester resulted in elevated amounts of both enzymes in conditioned media and in the secretion of TIMP-1. Both gelatinases were shown to be activated by trypsin and organomercurials and to possess similar activities towards various substrates. However, the 63-kDa enzyme differed from the 94-kDa enzyme in a significantly reduced inhibition by recombinant TIMP-1 and TIMP-2. Thus, the 63-kDa fragment of MMP-9 once activated may escape the regulatory influence of its specific inhibitors and may thereby promote matrix degradation during invasion of leukemic cells.
Leukemia 1996 Sep
PMID:HL-60 leukemia cells produce an autocatalytically truncated form of matrix metalloproteinase-9 with impaired sensitivity to inhibition by tissue inhibitors of metalloproteinases. 875 73

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

The matrix metalloproteinases (MMPs) are important in tumour cell invasion and metastasis in many common cancers. However, relatively few studies have investigated the role of MMPs and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), in leukaemia cell invasion. This study examined two leukaemia cell lines, K562 and HL-60 and showed that the K562 cell line was four times more invasive than the HL-60 cell line. The expression of MMP-2, matrilysin (MMP-7), MMP-9. TIMP-1, TIMP-2 and TIMP-3 was analysed. Both cell lines produced similar amounts of MMP-2, MMP-9 and TIMP-2. The K562 cells expressed more TIMP-1 than the HL-60 cells and neither cell line expressed TIMP-3. Interestingly, only the K562 cells expressed matrilysin suggesting a potential role for matrilysin in leukaemia cell invasion. in vitro invasion assays performed in the presence of a matrilysin blocking antibody showed a 40% reduction in invasive ability. This data suggests that matrilysin plays an important role in leukaemia cell invasion.
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PMID:The role of matrilysin (MMP-7) in leukaemia cell invasion. 1146 72

MMP inhibitors are used clinically for the stabilization of tumor growth, thus prolonging survival in cancer patients. However, their role in the treatment of hematopoietic malignancies remains unclear. In the present study, we investigated the effects of a new MMP inhibitor, SI-27, in hematopoietic malignancies. SI-27 alone induces apoptosis in several human myeloid leukemia cell lines such as U937, NB4, and HL60 cells by activating caspase 8, 9, and 3. Apoptosis was measured with annexin V positive staining, a drop in mitochondrial transmembrane potential (deltapsim), presence of hypodiploid DNA, and cleavage of PARP and IkappaBalpha. Furthermore, at lowered concentrations, which did not directly induce apoptosis, SI-27 acted to sensitize U937 cells and other cells to tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis. The accumulation of membrane Fas, the Fas ligand, and TNFR1 were not apparent due to exposure to SI-27, and antagonistic anti-Fas or anti-Fas ligand antibodies did not block SI-27-induced apoptosis. Thus, SI-27-induced apoptosis is not mediated by the Fas pathway. These results suggest that MMP inhibitors, alone or in combination with other cytotoxic agents, can provide a unique method for treating acute myeloid leukemia, refractory to classical anti-cancer drugs, and may thus suppress recurrence.
Leukemia 2001 Aug
PMID:A new matrix metalloproteinase inhibitor SI-27 induces apoptosis in several human myeloid leukemia cell lines and enhances sensitivity to TNF alpha-induced apoptosis. 1148 May 63

Gelatinase A and B (MMP-2 and MMP-9) are secreted by cytotrophoblast (CTB); these enzymes digest the major constituents of the endometrial extracellular matrices (ECM). Direct evidence links the expression of MMPs to the metastatic phenotype of tumour cells and tissue inhibitor of metalloproteinases (TIMP) to the inhibition of metastatisation. Gelatinase B (MMP-9, and no other MMP) has been shown in vitro to mediate CTB invasion. ECM components are known to influence adhesion, spreading, migration and differentiation of cells through specific cell surface receptors called integrins. While CTB migrate from the villous into the decidua they modulate their integrin repertoire, secrete MMP-9 and acquire the capacity to digest their environment. Although CTB behave like metastatic cells, in vivo they are only transiently invasive (first trimester) and their invasion is essentially limited to the endometrium and to the proximal myometrium. This temporal and spatial regulation seems to be mediated in a paracrine way by uterine factors and in an autocrine way by trophoblastic factors. We investigated the effects of endometrial regulators such as leukaemia inhibitory factor (LIF), tumour necrosis factor (TNF), transforming growth factor beta (TGFb), interleukin-1 and 6 (IL-1, IL-6) and insulin-like growth factor binding protein-1 (IGFBP-1) as well as trophoblastic factors such as hCG and leptin. All these factors markedly influenced the secretion and/or activation of MMP-2 and MMP-9. Most cytokines influence cell behaviour by modulating phosphorylation of transcription factors. Among these we identified two oncogene products (Jun and Fos) which were activated by TNF or phorbol esters and which promoted the synthesis of MMP-9. We conclude that decidual and trophoblastic products are autocrine or paracrine regulators of trophoblastic invasion of the endometrium and that some of these products act by activating the transcription of early response genes such as transcription factors.
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PMID:Endocrine, paracrine and autocrine regulation of trophoblastic metalloproteinases. 1175 1

All-trans retinoic acid (ATRA) has been shown to induce differentiation of human acute promyelocytic leukaemia (APL) cells and eventual elimination of the malignant clone. Matrix metalloproteinase-9 (MMP-9) is produced by neutrophils and its expression appears to be linked with myeloid cell differentiation. We investigated effects of ATRA on MMP expression in two human myeloid leukaemia cell lines, PL-21 and NB4. Both cells could differentiate into neutrophils after exposure to ATRA. Both the activity and antigen levels of MMP-9 were much higher in NB4 cells than in PL-21 cells. Stimulation with ATRA significantly increased MMP-9 levels approximately three- to fivefold in both PL-21 and NB4-conditioned media. MMP-9 mRNA levels increased in ATRA-treated cells and was almost in parallel with the increase in MMP-9 activity, suggesting that ATRA induced MMP-9 by activating its gene expression. ATRA can induce interleukin 8 (IL-8) in APL cells. IL-8, chemokine for neutrophils and a potent inducer of MMP-9, was also induced by ATRA in PL-21 cells. However, recombinant IL-8 did not induce MMP-9 expression. In addition, a neutralizing antibody against IL-8 did not inhibit ATRA-induced MMP-9 expression in either cell type. These observations suggest that ATRA can induce both MMP-9 and IL-8, but IL-8 is not involved in ATRA-induced MMP-9 expression. As MMP-9 can truncate and activate IL-8, simultaneous induction of MMP-9 and IL-8 by ATRA could activate leucocytes excessively, causing the hyper-inflammatory events in retinoic acid syndrome.
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PMID:Simultaneous induction of matrix metalloproteinase-9 and interleukin 8 by all-trans retinoic acid in human PL-21 and NB4 myeloid leukaemia cells. 1213 25

The International Agency for Research on Cancer (IARC) currently lists tetrachloroethylene [perchloroethylene (PCE)] as being carcinogenic in animals. PCE is listed as possibly carcinogenic to humans upon occupational exposure. Human exposure to PCE can produce oesophageal cancer, cervical cancer, non-Hodgkin's lymphoma, urinary bladder cancer and leukemia. This work shows that PCE modulates the expression of some genes implicated in cancer induction, cell differentiation, cell-cycle progression, and the survival and clonogenic potential of human cord blood cells. After exposure to the compound, the modulated genes were involved in inflammatory responses as with the mitogen-activated protein kinase 14 (MPK 14), or in tumor and metastasis progression as with the matrix metalloproteinase 17 (MMP 17), in cell proliferation as with c-jun and c-fos, and moreover in the apoptotic process as with interferon alpha-inducible protein (IFI), BAX and BCL-2. Analysis of cord blood cells via flow cytometry showed that PCE treatment induced a statistically significant increase in necrosis after 24 h, while the clonogenicity of Human Colony-Forming Unit-Granulocyte/Macrophage (CFU-GM) and Burst-Forming Unit-Erythrocyte (BFU-E) progenitors did not change. In conclusion, our data showed that PCE affected various pathways involved in cancer induction, but its action on cell proliferation and differentiation is not yet clearly understood.
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PMID:Sensitivity of human cord blood cells to tetrachloroethylene: cellular and molecular endpoints. 1601 May 55

This study was purposed to explore the tumorigenicity of a novel human monocytic leukemic cell line SHI-1 in nude mice and its mechinism. The tumorigenicity in mice was evaluated in sixteen nude mice subcutaneously injected with the SHI-1 cell line. The tumor specimen was studied by the conventional pathologic examination. The mononuclear cells (MNC) of the tumor was assayed by RHG banding, the transcription of MLL-AF6 fusion gene and the VEGF gene was detected by RT-PCR. Gelatin zymography method was used to study the expression of MMP-9 and MMP-2 in the supernatant of the SHI-1 cell line. Matrigel invasion assay was employed for the study of migration of the SHI-1 cell in vitro. The results showed that the tumor masses were found in all sixteen mude mice after subcutaneous injection of SHI-1 cells, the tumor mass was mainly composed of leukemia cells, the transcription of MLL-AF6 fusion gene and VEGF gene was proved by RT-PCR analysis, the expressions of MMP-2 and MMP-9 in the serum-free culture supernatant of the SHI-1 cell line were significantly higher than those in U937, K562, and NB4 cell lines. The SHI-1 cell line exhibited significantly higher in vitro invasiveness than other leukemia cell lines, the blocking antibody of MMP-2 could inhibit the migration of the SHI-1 cell line significantly. It is concluded that the SHI-1 cell line presents higher tumorigenicity in nude mice than other leukemia cell line and the mechanism is associated with p53 gene alteration, high transcription level of VEGF gene, high expression level of MMP, and significantly higher invasiveness.
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PMID:[High tumorigenicity of human acute monocytic leukemic cell Line SHI-1 in nude mice and its mechanism]. 1770 82

Chronic liver diseases are accompanied by changes in the biochemical pathways related to the regulation of apoptosis and extra-cellular matrix deposition. The present study was designed to investigate, using low density arrays, changes in the hepatic gene expression together with hepatic biochemical and histological alterations in rats that had liver impairment induced by chronic exposure to CCl(4). Further, we examined the possible recovery of genetic and pathological changes following the cessation of the hepatotoxic injury. Experimental fibrosis was induced in male Wistar rats by CCl(4) administration. Animals were subdivided into two groups. One group was given CCl(4 )and animals were killed at 8 and 12 weeks of treatment. The other group was treated with CCl(4) for 6 weeks, the CCl(4 )was then stopped and, subsequently, subgroups of animals were killed after 1 and 2 weeks of recovery. CCl(4) administration over 12 weeks was associated with significant changes in B-cell leukemia/lymphoma 2, procollagen type I alpha 2, matrix metalloproteinases 3 and 8, tissue inhibitors of metalloproteinases 1, 2, and 3 and the inhibitor of apoptosis 4 gene expressions. Recovery after CCl(4) cessation was associated with changes in procollagen type I alpha 2, matrix metalloproteinase 7, tissue inhibitors of metalloproteinases 1 and 2, inhibitor of apoptosis 4, and survivin gene expressions. This study shows an association between changes in the expression of several genes regulating hepatic cell apoptosis, the fibrosis process, and the recovery of the hepatic function after removal of the toxic injury.
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PMID:Changes in the expression of genes related to apoptosis and fibrosis pathways in CCl4-treated rats. 1793 67


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