Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis and etiology of Hodgkin's disease, a common human malignant lymphoma, is still unresolved. As a unique characteristic, we have identified constitutive activation of the transcription factor nuclear factor (NF)-kappaB p50-RelA in Hodgkin/Reed-Sternberg (H/RS) cells, which discriminates these neoplastic cells from most cell types studied to date. In contrast to other lymphoid and nonlymphoid cell lines tested, proliferation of H/RS cells depended on activated NF-kappaB. Furthermore, constitutive NF-kappaB p50-RelA prevented Hodgkin's lymphoma cells from undergoing apoptosis under stress conditions. Consistent with this dual function, Hodgkin's lymphoma cells depleted of constitutive nuclear NF-kappaB revealed strongly impaired tumor growth in severe combined immunodeficient mice. Our findings identify NF-kappaB as an important component for understanding the pathogenesis of Hodgkin's disease and for developing new therapeutic strategies against it.
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PMID:Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. 939 41

IL-12 is a central cytokine in the activation of inflammation and immunity and in the generation of Th1-type responses. Tumor-associated macrophages (TAM) from mouse and human tumors showed defective production of IL-12. Defective IL-12 production was associated with lack of p50/p65 NF-kappa B activation. TAM produced increased amounts of the immunosuppressive cytokine IL-10. Abs against IL-10 restored the defective capacity of TAM to produce IL-12. Our data suggest that during tumor growth an IL-10-dependent pathway of diversion of macrophage function can be activated into the tumor microenvironment and results in the promotion of the IL-10+ IL-12- phenotype of TAM. Blocking IL-10, as well as other immunosuppressive cytokines present in the tumor microenvironment, such as TGF-beta, may complement therapeutic strategies aimed at activating type I antitumor immune responses.
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PMID:Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. 1062 21

In this study we examined the effect of the synthetic peptide thymosin-alpha1 (T(alpha)1) on MHC class I expression in FRTL-5 cells. Treatment with T(alpha)1 increased expression of MHC class I surface molecules and mRNA, which reached its peak (153 +/- 8 % of the control value) after 12 h. Chloramphenicol acetyltransferase (CAT) analysis, following transfection with a plasmid containing the regulatory sequence of MHC class I (or its deletion derivatives) with the CAT reporter gene, and electrophoretic mobility shift assay experiments demonstrated that the action of T(alpha)1 was at the transcriptional level, and its mechanism of action is likely due to increased binding between the complex p50/fra-2 and the enhancer A sequence of the 5' flanking region of a swine class I gene (PD1). An increase in the expression of MHC class I surface molecules was also observed by flow cytometry in murine and human tumor cell lines and in primary cultures of human macrophages. This study shows for the first time an effect of Talpha1 on the regulation of gene expression at the molecular level, and may further contribute to explaining the results obtained using Talpha1 in the control of infectious diseases and tumor growth.
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PMID:Thymosin-alpha1 regulates MHC class I expression in FRTL-5 cells at transcriptional level. 1074 92

TAL-1/SCL activation is a common genetic event in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Expression of tal-1/scl or a DNA binding mutant of tal-1/scl induces arrest of thymocyte development, resulting in decreases in double-positive and single-positive CD4 thymocytes. Moreover, nuclear p65/p50 heterodimers are detected in premalignant tal-1/scl and mut tal-1/scl thymocytes, suggesting that E2A depletion may induce developmental arrest and stimulate NF-kappaB activation. Increased NF-kappaB activity is also observed in tal-1/scl tumors and bcl-2 is overexpressed. To examine the contribution of NF-kappaB to tal-1/scl tumor growth in vivo, we expressed a mutant form of IkappaBalpha in tal-1/scl tumor cells. Although expression of mutant IkappaBalpha inhibited the tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB response, it had no effect on tumor growth in mice. These data suggest that NF-kappaB activation is an early event in tal-1/scl-induced leukemogenesis, associated with arrest of thymocyte development, and does not appear to contribute to tal-1/scl-induced tumor growth.
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PMID:NF-kappaB activation in premalignant mouse tal-1/scl thymocytes and tumors. 1281 68

The acute and cumulative dose-related toxicity and drug resistance, mediated via nuclear factor kappaB (NFkappaB), of anthracycline anticancer drugs pose a major problem in cancer chemotherapy. Here, we report that oral silibinin (a flavanone) suppresses human non-small-cell lung carcinoma A549 xenograft growth (P = 0.003) and enhances the therapeutic response (P < 0.05) of doxorubicin in athymic BALB/c nu/nu mice together with a strong prevention of doxorubicin-caused adverse health effects. Immunohistochemical analyses of tumors showed that silibinin and doxorubicin decrease (P < 0.001) proliferation index and vasculature and increase (P < 0.001) apoptosis; these effects were further enhanced (P < 0.001) in combination treatment. Pharmacologic dose of silibinin (60 mumol/L) achieved in animal study was biologically effective (P < 0.01 to 0.001, growth inhibition and apoptosis) in vitro in A549 cell culture together with an increased efficacy (P < 0.05 to 0.001) in doxorubicin (25 nmol/L) combination. Furthermore, doxorubicin increased NFkappaB DNA binding activity as one of the possible mechanisms for chemoresistance in A549 cells, which was inhibited by silibinin in combination treatment. Consistent with this, silibinin inhibited doxorubicin-caused increased translocation of p65 and p50 from cytosol to nucleus. Silibinin also inhibited cyclooxygenase-2, an NFkappaB target, in doxorubicin combination. These findings suggest that silibinin inhibits in vivo lung tumor growth and reduces systemic toxicity of doxorubicin with an enhanced therapeutic efficacy most likely via an inhibition of doxorubicin-induced chemoresistance involving NFkappaB signaling.
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PMID:Oral silibinin inhibits lung tumor growth in athymic nude mice and forms a novel chemocombination with doxorubicin targeting nuclear factor kappaB-mediated inducible chemoresistance. 1562 48

We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 microg/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity.
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PMID:Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. 1570

The murine chemokine CXCL1/KC is known as a chemoattractant for neutrophil infiltration and as a promoter of tumor growth. To determine its relevance in tumorigenesis, we first asked whether okadaic acid (OKA), a natural tumor promoter and a potent protein phosphatase 1 and 2A inhibitor, stimulates KC expression and if it does, through what pathway, in a promotable mouse epidermal-like JB6 cell line commonly used for studying molecules related to tumor promotion. We found that OKA stimulated the de novo synthesis of KC mRNA and protein in a dose- and time-dependent manner. To determine the mechanism by which OKA stimulated the expression of KC at the transcriptional level, transient transfection assays using serially deleted sections of KC promoter fused to luciferase reporter gene were performed. These studies showed that transactivation of KC promoter by OKA specifically involved the region between -104 and -59 containing the two nuclear factor-kappaB (NF-kappaB) response elements (kappaB1 and kappaB2). Further analyses using the mutated NF-kappaB response elements kappaB1 and kappaB2 indicated that both regions were required for optimum transactivation of KC by OKA with the former NF-kappaB response element playing a more significant role in regulating KC expression. Gel-shift and supershift analyses demonstrated the involvement of three NF-kappaB subunits, p65, p50 and c-Rel, with p65 as the major subunit in the NF-kappaB dimer complex. Additionally, immunohistochemistry and western blot analyses confirmed the presence of p65 in the nucleus with its transactivation domain phosphorylated at serine 536. In summary, this is the first report to show that the tumor promoter OKA can stimulate the de novo synthesis and secretion of KC, and that this stimulation is mediated through the NF-kappaB pathway in JB6 cells.
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PMID:Production of chemokine CXCL1/KC by okadaic acid through the nuclear factor-kappaB pathway. 1600 Apr 1

Using fluorescence resonance energy transfer technique, effects of polyamines (spermine and putrescine) on the binding of p50 subunit of the nuclear transcription factor NF-kappaB to specific DNA sequences were studied in model experiments. It is demonstrated that polyamines in the concentration range from 1 to 500 mcM facilitate the binding of NF-kappB to specific DNA sequences. The data currently obtained agree with our previous predictions made by the computer modelling techniques. Our results presented in this work allow us to suggest that polyamines (excessive synthesis of which proceeds in tumor growth) may participate in the regulation of transcription of several oncogenes by the factor NF-kappaB.
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PMID:[Effects of spermine and putrescine on the binding of the transcription factor NF-kappaB to specific DNA sequences]. 1635 Jul 47

Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes. The CYLD gene encodes a deubiquitinase that removes lysine 63-linked ubiquitin chains from TRAF2 and inhibits p65/p50 NF-kappaB activation. Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels. The cyclin D1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of Bcl-3-associated NF-kappaB p50 and p52. In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld binds and deubiquitinates Bcl-3, thereby preventing nuclear accumulation of Bcl-3 and p50/Bcl-3- or p52/Bcl-3-dependent proliferation. These data indicate that, depending on the external signals, Cyld can negatively regulate different NF-kappaB pathways; inactivation of TRAF2 controls survival and inflammation, while inhibition of Bcl-3 controls proliferation and tumor growth.
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PMID:Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. 1671 56

The continuous production of the CXC ligand 1 (CXCL1) chemokine by melanoma cells is a major effector of tumor growth. We have previously shown that the constitutive expression of this chemokine is dependent upon transcription factors nuclear factor-kappa B (NF-kappaB), stimulating protein-1 (SP1), high-mobility group-I/Y (HMGI/Y), CAAT displacement protein (CDP) and poly(ADP-ribose) polymerase-1 (PARP-1). In this study, we demonstrate for the first time the mechanism of transcriptional regulation of CXCL1 through PARP-1 in melanoma cells. In its inactive state, PARP-1 binds to the CXCL1 promoter in a sequence-specific manner and prevents binding of NF-kappaB (p65/p50) to its element. However, activation of the PARP-1 enzymatic activity enhances CXCL1 expression, owing to the loss of PARP-1 binding to the CXCL1 promoter, accompanied by enhanced binding of p65 to the promoter. The delineation of the role of NF-kappaB-interacting factors in the putative CXCL1 enhanceosome will provide key information in developing strategies to block constitutive expression of this and other chemokines in cancer and to develop targeted therapy.
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PMID:Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1. 1679 43


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