Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF beta) is a growth modulator which stimulates the growth of fibroblasts but acts as a strong growth inhibitor for cells of epithelial origin. TGF beta also influences the production of extracellular matrix proteins and of proteases and protease inhibitors by cultured cells. One important protease inhibitor whose production is affected rapidly by TGF beta is the type-1 plasminogen activator inhibitor (PAI-1). To investigate the relationships between PAI-1 and the extracellular matrix, we analyzed the regulation by TGF beta of PAI-1, fibronectin, and type I procollagen in malignant human lung carcinoma cells (A549) and in human lung fibroblasts (WI-38). The expression of the respective genes was examined by polypeptide analyses and by measurements of the steady-state levels of the corresponding mRNAs by Northern hybridization. The mRNA levels for PAI-1 were elevated rapidly by TGF beta in both cell lines. This induction occurred in the presence of cycloheximide and thus was not dependent on protein synthesis. In fact, the effects of TGF beta and cycloheximide on PAI-1 mRNA were additive. In contrast, the induction of fibronectin, beta-actin, and type I procollagen (synthesized only in WI-38 cells) was abrogated by cycloheximide. In general, the effects of TGF beta on the steady-state levels of mRNAs for fibronectin, actin, and type I procollagen mRNA were similar in the two cell types. However, the production of PAI-1 mRNA in response to TGF beta differed in the two cell types, being transient (peak within 5 h) in the carcinoma cells and more persistent in fibroblasts. Thus, the major difference in TGF beta regulation of PAI-1 mRNA between lung fibroblasts and carcinoma cells was the duration of the effect. These results, together with previous data, suggest that PAI-1 and plasminogen activators may be regulated oppositely by TGF beta. We therefore propose a model for TGF beta in the regulation of extracellular proteolytic activity.
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PMID:Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells. 312 75

We investigated the effect of Lewis Lung carcinoma cells on the production of C3 by murine macrophages and examined the capacity of secreted C3 to opsonize Lewis Lung carcinoma cells. C3 released in culture from macrophages obtained from tumor-bearing C57Bl/6 mice as well as from normal macrophages exposed to Lewis Lung carcinoma cells in vitro was measured by hemolytic assays and by Western blot. We found that contact with tumor cells in vivo as well as in vitro enhanced the amount of C3 secreted by murine macrophages by a factor of 2-3. The inflammatory agent carrageenan caused only a small increase in the amount of secreted C3. On Western blots of concentrated macrophage supernatants, there was partial cleavage of secreted C3 which was, however, not more pronounced in the case of C3 from tumor-stimulated macrophages than from normal macrophages. Supernatants from normal as well as tumor-stimulated macrophages were capable of opsonizing Lewis Lung carcinoma cells as shown by their capacity to bind human erythrocyte in an immune adherence reaction. Pretreatment of the tumor cells with a protease inhibitor, PMSF, inhibited the capacity of the tumor cells to bind C3, suggesting that a tumor cell-associated protease might be involved in the binding of C3 to the tumor cell surface.
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PMID:Lewis lung carcinoma cells enhance the synthesis of C3 and are opsonized by C3 secreted from murine macrophages. 316 40

A synthetic protease inhibitor FOY-305 (Foypan) not only inhibited the skin tumorigenesis in mice but also suppressed the growth of autochthonous solid tumor in mice. Furthermore, administration of FOY-305 inhibited the metastasis of Lewis lung carcinoma and colon adenocarcinoma to the lung in mice, experimentally and spontaneously. Clinically, FOY-305 prevented both recurrence and metastasis in the patients who had received many anticancer drugs. In 2 terminal secondary cases, tumor remission and elongation of survival time were observed. Above results suggest a possibility for applying a new type chemotherapy using protease inhibitors.
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PMID:[Protease inhibitors as anticancer chemotherapy--experimental and clinical studies]. 788 33

The Bowman-Birk inhibitor (BBI) is a soybean-derived anticarcinogenic protease inhibitor with anti-inflammatory activity. To assess the possibility of utilizing BBI for alleviating the side effects associated with lung cancer radiation and chemotherapy, we have determined the effects of BBI and a soybean concentrate enriched in BBI (known as BBIC) on radiation- and cis-platinum-induced cytotoxicity in A549 human lung cancer cells. The results demonstrated that neither BBI nor BBIC protected A549 cells from radiation- and cis-platinum-induced cytotoxicity. In fact, BBI and BBIC potentiated the cell-killing effects induced by cis-platinum alone, and BBIC treatment led to significantly enhanced cell killing by cis-platinum in combination with radiation treatment in the lung carcinoma cells. BBI conferred a significant protective effect onto mouse fibroblasts (10T1/2 cells) treated with cis-platinum in combination with 6 Gy of X-ray irradiation. These results suggest that BBI and BBIC, when given to lung cancer patients, are unlikely to interfere with cancer treatment utilizing radiation and cis-platinum.
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PMID:Effects of the Bowman-Birk protease inhibitor on survival of fibroblasts and cancer cells exposed to radiation and cis-platinum. 887 58

When NIH 3T3 fibroblasts were transduced with a retroviral vector containing a cDNA for porcine pancreatic elastase 1 and cultured in the presence of affinity-purified human plasminogen, the exogenously added plasminogen was digested to generate the kringle 1-3 segment known as angiostatin, a potent angiogenesis inhibitor. This was evidenced by immunoblot analysis of the plasminogen digests using a monoclonal antibody specifically reacting with the kringle 1-3 segment, and by efficient inhibition of proliferation of human umbilical vein endothelial cells by the plasminogen digests isolated from the culture medium of 3T3 fibroblasts. However, when Lewis lung carcinoma cells were transduced with the same vector and injected subcutaneously into mice in their back or via the tail vein, their growth at the injection sites or in the lungs was markedly suppressed compared with the growth of similarly treated nontransduced Lewis lung carcinoma cells. Nevertheless, the transduced cells were able to grow as avidly as the control cells in vitro. Assuming that the elastase 1 secreted from the transduced cells is likely to be exempt from rapid inhibition by its physiological inhibitor, alpha1-protease inhibitor, as shown in the inflammatory tissues, the elastase 1 secreted from the tumor cells may effectively digest the plasminogen that is abundantly present in the extravascular spaces and generate the kringle 1-3 segment in the vicinity of implanted tumor cell clusters. Although the selection of more profitable virus vectors and cells to be transduced awaits further studies, such a protease gene transfer strategy may provide us with a new approach to anti-angiogenesis gene therapy for malignant tumors and their metastasis in vivo.
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PMID:A novel strategy for the tumor angiogenesis-targeted gene therapy: generation of angiostatin from endogenous plasminogen by protease gene transfer. 1081 77

In previous studies, we have shown that human breast and lung carcinoma cells and mouse nontransformed type II lung cells fail to undergo cell-cycle arrest in G(1) phase in response to treatment with hydrocarbon carcinogens but rather accumulate in the S phase with damaged DNA. This situation may lead to replication of DNA on a damaged template and enhance frequency of mutations. The mechanism of this G(1) arrest failure was examined. Western immunoblot analyses of MCF7 human mammary cancer cells exposed to actinomycin D (used as a positive control for G(1) cell-cycle arrest) or hydrocarbon carcinogens revealed that while all of these chemicals caused an increase in p53, only trace levels of p21(waf1/cip1) protein were observed in the hydrocarbon carcinogen-treated samples. Similarly, in murine lung E10 type II cells, p53 but not p21(waf1/cip1) protein increased in response to benzo[a]pyrene dihydrodiol epoxide. Treatment of either MCF7 mammary or E10 lung cells with the protease inhibitor calpain I resulted in increased levels of p21(waf1/cip1) protein and enhancement of arrest of the cells in early phases of the cell cycle (G(1) and early S phase). The results suggest that failure of cell-cycle arrest in carcinogen-treated mammary and lung cells is related to increased protease-mediated degradation of p21(waf1/cip1) and/or related regulatory proteins.
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PMID:Protease inhibitor-induced stabilization of p21(waf1/cip1) and cell-cycle arrest in chemical carcinogen-exposed mammary and lung cells. 1180 52

The orthopoxvirus serpin SPI-1 is an intracellular serine protease inhibitor that is active against cathepsin G in vitro. Rabbitpox virus (RPV) mutants with deletions of the SPI-1 gene grow on monkey kidney cells (CV-1) but do not plaque on normally permissive human lung carcinoma cells (A549). This reduced-host-range (hr) phenotype suggests that SPI-1 may interact with cellular and/or other viral proteins. We devised a genetic screen for suppressors of SPI-1 hr mutations by first introducing a mutation into SPI-1 (T309R) at residue P14 of the serpin reactive center loop. The SPI-1 T309R serpin is inactive as a protease inhibitor in vitro. Introduction of the mutation into RPV leads to the same restricted hr phenotype as deletion of the SPI-1 gene. Second-site suppressors were selected by restoration of growth of the RPV SPI-1 T309R hr mutant on A549 cells. Both intragenic and extragenic suppressors of the T309R mutation were identified. One novel intragenic suppressor mutation, T309C, restored protease inhibition by SPI-1 in vitro. Extragenic suppressor mutations were mapped by a new procedure utilizing overlapping PCR products encompassing the entire genome in conjunction with marker rescue. One suppressor mutation, which also rendered the virus temperature sensitive for growth, mapped to the DNA polymerase gene (E9L). Several other suppressors mapped to gene D5R, an NTPase required for DNA replication. These results unexpectedly suggest that the host range function of SPI-1 may be associated with viral DNA replication by an as yet unknown mechanism.
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PMID:Suppressors of a host range mutation in the rabbitpox virus serpin SPI-1 map to proteins essential for viral DNA replication. 1599 11

Transforming growth factor-beta1 (TGF-beta1) plays a crucial role in adhesion and migration of human cancer cells. Besides, integrins are the major adhesive molecules in mammalian cells. Here we found that TGF-beta1 increased the migration and cell surface expression of beta1 integrin in human lung cancer cells (A549 cells). TGF-beta1 stimulation increased phosphorylation of p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) and Ser(473) of Akt was determined. Besides, we performed that PI3K inhibitor (Ly294002) or Akt inhibitor suppressed the TGF-beta1-induced migration activities of A549 cells. Treatment of A549 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also repressed TGF-beta1-induced cells migration and beta1 integrins expression. In addition, treatment of A549 cells with TGF-beta1 induced IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the TGF-beta1-mediated increases in IKKalpha/beta, IkappaBalpha phosphorylation and p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Co-transfection with p85alpha and Akt mutants also reduced the TGF-beta1-induced kappaB-luciferase activity. Taken together, our results suggest that TGF-beta1 acts through PI3K/Akt, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of beta1 integrins and contributing the migration of human lung cancer cells.
Lung Cancer 2009 Apr
PMID:Transforming growth factor-beta1 increases cell migration and beta1 integrin up-regulation in human lung cancer cells. 1877 13

Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Osteopontin (OPN), which is abundantly expressed in bone matrix, is involved in cell adhesion, migration, invasion and cell proliferation via interaction with its receptor, alphavbeta3 integrin. However, the effect of OPN on migration activity in human lung cancer cells is mostly unknown. Here we found that OPN increased the migration via activation of alphavbeta3 integrin in human lung cancer cells (A549 cells). Phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002), Akt inhibitor or ERK inhibitor (PD98059) inhibited the OPN-induced increase in the migration of lung cancer cells. OPN stimulation increased the phosphorylation of focal adhesion kinase (FAK), p85 subunit of PI3K, serine 473 of Akt and ERK. In addition, treatment of A549 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited OPN-induced migration of lung cancer cells. Stimulation of A549 cells with OPN also induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The OPN-mediated increases in IKK alpha/beta, IkappaBalpha and p65 Ser(536) phosphorylation were inhibited by Ly294002, Akt inhibitor and PD98059. Co-transfection with FAK, p85, Akt and ERK mutants also reduced the OPN-induced kappaB-luciferase activity. Taken together, these results suggest that OPN acts through alphavbeta3 integrin, which in turn activates the FAK, PI3K, Akt, ERK and NF-kappaB pathways, contributing to the migration of lung cancer cells.
Lung Cancer 2009 Jun
PMID:Osteopontin increases lung cancer cells migration via activation of the alphavbeta3 integrin/FAK/Akt and NF-kappaB-dependent pathway. 1899 13

Human epididymis protein 4 (HE4) acts as a protease inhibitor. It has been detected in the serum of patients with lung cancer patients and its utility for lung cancer screening was found in different studies. Nevertheless, little is known regarding the expression of HE4 in lung carcinoma subtypes. The aim of the present study was to investigate whether HE4 expression is a reliable marker for detecting any lung carcinoma subtypes, including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and adenocarcinoma (AC). In total, 141 lung carcinoma patients were enrolled in the study. Biopsy samples were obtained from bronchoscopic biopsy. The tumors were classified as SCLC (group 1, 54 cases) or NSCLC (group 2, 87 cases) based on histology and immunohistochemistry. The latter was sub-grouped as adenocarcinoma (group 2a, AC) and squamous cell carcinoma (group 2b, SCC). The immunohistochemical expression of HE4 was compared between the groups. The study revealed that the majority of the SCLC and SCC cases were devoid of HE4 (90.1 and 89.65%, respectively). Approximately 10% of cases had HE4 immune expression and the staining was focal and moderate throughout the tumor tissue. On the other hand, 78.8% of AC expressed HE4 and the staining was diffuse and strong. The overall HE4 expression in the lung cancer patients was 33.7%. In conclusion, the results of the present study have shown that HE4 is expressed in adenocarcinoma of the lung but it is not frequent in SCC and SCLC. The value of HE4 as a screening biomarker for lung cancer is limited but its presence exclusively in adenocarcinoma may provide new insight for targeted therapy.
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PMID:Human epididymis protein 4 may not be a reliable screening biomarker for detecting lung carcinoma patients. 2908 24


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