Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KAI1/CD82 has been shown to be a metastasis suppressor for several human cancers, and a recent study revealed that wild-type tumor suppressor p53 can directly activate KAI1/CD82 gene expression. However, the response of KAI1/CD82 expression in cancer cells to exogenous stimulants has not been investigated. The present study examined whether tumor necrosis factor (TNF), which mediates many of the cellular responses associated with inflammatory reactions or cancer progression, can affect the KAI1/CD82 expression in lung cancer cells and, if so, whether nuclear factor (NF)-kappaB, a key molecule in TNF-mediated gene expression, is involved in the mechanism of KAI1/CD82 induction. Our results demonstrated that expression of KAI1/CD82 in PC-14 cells expressing mutant p53 could be augmented by TNF-alpha, and that transfer of the gene for a specific inhibitor of NF-kappaB, IkappaB alphaSR (mutant IkappaB alpha; NF-kappaB super-repressor), into PC-14 cells could inhibit this augmentation. The amount of NF-kappaB in the nucleus of PC-14/IkappaB alphaSR cells correlated well with KAI1/CD82 mRNA and protein expression. In addition, IkappaB alphaSR gene transfer inhibited the spontaneous expression of KAI1/CD82 protein in KAI1/CD82-high-expressing RERF-LC-OK cells, which contain a mutant-type p53. These observations indicate that NF-kappaB activation may play a role in the regulation of KAI1/CD82 expression in lung cancer cells independently of wild-type p53, and suggest that KAI1/CD82 expression may be regulated by interaction with the host microenvironment.
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PMID:Nuclear factor-kappaB-dependent expression of metastasis suppressor KAI1/CD82 gene in lung cancer cell lines expressing mutant p53. 1121 67

The Fas/tumor necrosis factor (TNF)/TRAIL receptors signal death through a cytoplasmic death domain (DD) containing six alpha-helices with positively charged helix 2 interacting with negatively charged helix 3 of another DD. DD mutation occurs in head/neck and lung cancer (TRAIL receptor KILLER/DR5) and in lpr mice (Fas). We examined the apoptotic potential of known KILLER/DR5 lung tumor-derived mutants (n = 6) and DD mutants (n = 18) generated based on conservation with DR4, Fas, Fas-associated death domain (FADD), and tumor necrosis factor receptor 1 (TNFR1). With the exception of Arg-330 required in Fas or FADD for aggregation or for TNFR1 cytotoxicity, surprisingly major loss-of-function KILLER/DR5 alleles (W325A, L334A (lpr-like), I339A, and W360A) contained hydrophobic residues. Loss-of-function of I339A (highly conserved) has not been reported in DDs. Charged residue mutagenesis revealed the following points. 1) E326A, conserved in DR4, is dispensable for death; the homologous residue is positively charged in Fas, TNFR1, and FADD and is critical for DD interactions. 2) K331A, D336A, E338A, K340A, K343A, and D351A have partial loss-of-function suggesting multiple charges stabilize receptor-adapter interactions. Analysis of the tumor-derived KILLER/DR5 mutants revealed the following. 1) L334F has partial loss-of-function versus L334A, whereas E338K has major loss-of-function versus E338A, examples where alanine and tumor-specific substitutions have divergent phenotypes. 2) Unexpectedly, S324F, E326K, K386N, and D407Y have no loss-of-function with tumor-specific or alanine substitutions. Loss-of-function KILLER/DR5 mutants were deficient in recruitment of FADD and caspase 8 to TRAIL death-inducing signaling complexes. The results reveal determinants within KILLER/DR5 for death signaling and drug design.
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PMID:Death domain mutagenesis of KILLER/DR5 reveals residues critical for apoptotic signaling. 1127 61

Epidemiological evidence firmly implicated an interactive effect between Fe2O3 and benzo(a)pyrene (B(a)P) in causing lung cancer. However, despite intensive investigation, the mechanism involved is not precisely established. Since the accumulation of reactive oxygen intermediates (ROI)-mediated damage and/or immune-induced injury might be a possible cause of lung cancer, we studied the oxidative and the inflammatory effects of Fe2O3 (3 mg), B(a)P (3 mg) or B(a)P (3 mg)-coated onto Fe2O3 (3 mg) particles on this relevant organ target in Sprague-Dawley rats. We investigated lipid peroxidation (malondialdehyde; MDA) and secretion of some inflammatory mediators (tumor necrosis factor-alpha, TNF-alpha; interleukin-1 beta, IL-1beta; nitric oxide, NO) in lungs. In addition, mRNA expressions of TNF-alpha, IL-1beta and inducible nitric oxide synthase (iNOS) were evaluated. Our results show that exposure to Fe2O3 and B(a)P, alone or in association, induced 2-fold increases in MDA production suggesting thereby oxidative stress conditions (P<0.01). Exposure to Fe2O3, B(a)P or B(a)P-coated onto Fe2O3 particles significantly increased both mRNA expression and/or synthesis of inflammatory mediators. The main findings of this work were that the association of Fe2O3 and B(a)P induces more pronounced induction of inflammatory mediators (IL-1beta secretion, P<0.01; IL-1beta mRNA expression, P<0.01; iNOS mRNA expression, P<0.05) than B(a)P by itself. Hence, our results may explain why concurrent exposure to Fe2O3 and B(a)P is more deleterious in lungs than exposure to B(a)P alone.
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PMID:Pulmonary induction of proinflammatory mediators following the rat exposure to benzo(a)pyrene-coated onto Fe2O3 particles. 1132 61

Allelic loss of chromosome 8p21-22 occurs frequently in cancer, including lung and head and neck squamous cell cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, including proapoptotic DR4 and KILLER/DR5, are located on 8p21-22. TRAIL receptors are candidate tumor suppressor genes, because their inactivation would be expected to result in deficient apoptotic signaling. To investigate the involvement of DR4 in human cancer, we have determined the genomic structure of DR4 and screened 31 lung cancer cell lines [14 small cell lung cancer and 17 non-small cell lung cancer (NSCLC)], many with deletions at 8p21-22, and 21 primary NSCLC samples for mutations in DR4. We found two missense alterations in the ectodomain of DR4. One, at nucleotide 626, changes a cytosine to a guanine (C626G) and results in a substitution of an arginine for threonine. The other, at nucleotide 422, changes a guanine to adenine (G422A) and results in a substitution of a histidine for arginine. Using genomic DNA sequencing and RFLP analysis, we show that these two alterations cosegregated in 96% of all of the samples (n = 243) evaluated (tumor and normal). The frequency of being homozygous for both altered alleles was 35% in the lung cancer cell lines but only 13% in age- and race-matched controls, which was a significant increase (chi(2) = 5.2, P = 0.023). The frequency of homozygosity for both alleles was also significantly increased in the primary NSCLC samples (chi(2) = 9.2, P = 0.002) as compared with the age- and race-matched controls. To determine whether the altered alleles are specific for lung cancer, we evaluated 19 head and neck squamous cell cancer and 25 gastric adenocarcinoma samples. Forty-seven % of the former and 44% of the latter were homozygous for both the C626G and G422A alterations, and this was significantly elevated relative to age- and race-matched controls (chi(2) = 8.6, P = 0.003 and chi(2) = 8.2, P = 0.004). These alterations result in amino acid changes in or near the ligand-binding domain of DR4 and, based on the crystal structure of DR5 and its homology with DR4, have the potential to affect TRAIL binding to DR4. Our results suggest that the altered DR4 alleles may be associated with, and should be investigated additionally as potential markers for, predisposition to common malignancies.
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PMID:Nucleotide substitution in the ectodomain of trail receptor DR4 is associated with lung cancer and head and neck cancer. 1141 May 8

TK5048 and its derivatives, AM-132, AM-138, and AM-97, are recently developed antimitotic (AM) compounds. These 1-phenylpropenone derivatives induce cell cycle arrest at the G2 / M phase of the cell cycle. TK5048 inhibited tubulin polymerization in human lung cancer PC-14 cells in a concentration-dependent manner. In a polymerization assay using bovine brain tubulin, AM-132 and AM-138 were quite strong, AM-97 was moderately strong, and TK5048 was a relatively weak inhibitor of tubulin polymerization. A murine leukemia cell line resistant to a sulfonamide antimitotic agent, E7010, which binds to colchicine-binding sites on tubulin, was cross-resistant to the in vitro growth-inhibitory effect of AM compounds. Inhibition of tubulin polymerization is therefore one of the mechanisms of action of these AM compounds against tumor cells. To profile the antitumor effect of AM compounds, the in vivo antitumor effect of AM-132 was evaluated against cytokine-secreting Lewis lung carcinoma (LLC). Tumor-bearing mice were treated with intravenous AM-132 using three different treatment schedules. LLC tumors expressing tumor necrosis factor-alpha (TNF-alpha), granulocyte macrophage colony-stimulating factor (GM-CSF), or interleukin (IL)-6 were very sensitive to AM-132. In particular, LLC tumors expressing IL-6 were markedly reduced by AM-132 treatment, and showed coloring of the tumor surface and unusual hemorrhagic necrosis. These results suggest a combined effect of AM-132 and cytokines on the blood supply to tumors.
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PMID:Enhancement of in vivo antitumor activity of a novel antimitotic 1-phenylpropenone derivative, AM-132, by tumor necrosis factor-alpha or interleukin-6. 1147 28

In this study, we investigated the generation of dendritic cells (DCs) from blood monocytes and mature macrophages from untreated primary lung cancer patients. Blood monocytes were separated by adherence from blood mononuclear cells (MNC) from ten lung cancer patients and ten control subjects, and cultured for 7 days in medium with granulocyte/macrophage colony-stimulating factor (GM-CSF) plus interleukin (IL-) 4. In all cases examined, DCs with typical characteristics were obtained even in lung cancer patients after 7 days culture with these cytokines, and there was no significant difference in phenotype and stimulatory activity in allogeneic lymphocyte proliferation between DCs derived from monocytes from lung cancer patients and those from control subjects. Next, we examined whether alveolar and pleural macrophages in malignant pleural effusion separated by magnetic beads could differentiate to immunostimulatory DCs. Conventional culture conditions with GM-CSF and IL-4 did not induce efficient numbers of DCs from mature macrophages, whereas the addition of tumor necrosis factor-alpha (TNF-alpha) to GM-CSF and IL-4 effectively contributed to generate DCs. These findings suggest that both mature macrophages and blood monocytes from lung cancer patients could differentiate to DCs, and might be a useful source of DCs for immunotherapy.
Lung Cancer 2001 Nov
PMID:Efficient generation of dendritic cells from alveolar and pleural macrophages as well as blood monocytes in patients with lung cancer. 1167 78

Reactive oxygen species (ROS) are important in the initiation and promotion of cells to neoplastic growth. In this context, cigarette smoke exposure, the primary risk factor in lung cancer development, leads to high levels of ROS within the human airway. Although well-equipped with an integrated antioxidant defense system consisting of low-molecular weight antioxidants such as glutathione and intracellular enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, the lungs are vulnerable to increased endogenous and exogenous oxidative insults. Antioxidants increase in response to oxidative stress and minimize ROS-induced injury in experimental systems, indicating that antioxidant levels may determine whether ROS can initiate lung carcinogenesis. On this basis, we hypothesized that antioxidants would be decreased in lung carcinoma cells as compared with tumor-free adjacent lung tissues. Antioxidant expression was evaluated in 16 lung tumor and 21 tumor-free lung tissues collected between the years 1993 and 2001 from 24 individuals with surgically resectable non-small cell lung cancer, i.e., adenocarcinoma and squamous cell carcinoma. Total SOD activity was increased (P = 0.035), catalase activity decreased (P = 0.002), and glutathione and glutathione peroxidase were similar in tumors compared with tumor-free lung tissues. Alterations in antioxidant activities were attributable to increased manganese SOD and decreased catalase protein and mRNA expression in tumors. Immunohistochemical localization of catalase in the lung revealed decreased or no expression in the tumor cells, although healthy adjacent airway epithelial cells were strongly positive for catalase. Parallel changes in antioxidant activities, protein, and mRNA expression were noted in A549 lung carcinoma cell lines exposed to cytokines (tumor necrosis factor-alpha, interleukin 1beta, and IFN-gamma). Thus, inflammation in the lung may contribute to high levels of manganese SOD and decreased catalase, which together may lead to increased hydrogen peroxide intracellularly and create an intracellular environment favorable to DNA damage and the promotion of cancer.
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PMID:Differential expression of manganese superoxide dismutase and catalase in lung cancer. 1173 45

Interleukin (IL)-18 exhibits antitumor as well as antiosteoclastogenic activities. These findings suggest that IL-18 is a potential tool for the treatment of cancers with associated osteolytic bone metastasis. We have previously shown that systemic daily administration of recombinant (r) IL-18 inhibits the development of osteolytic bone metastasis by human breast cancer cells. Here we demonstrate that systemic daily administration of rIL-18 (1 microg/mouse/d) for 21 days significantly inhibited the number and the total area of osteolytic bone metastasis by RWGT2 human lung cancer cells in nude mice. No severe adverse effects were observed. Natural killer (NK) cells did not increase in splenocytes from rIL-18-treated mice, and the in vitro NK activity of splenocytes against RWGT2 cells was only weakly enhanced in the presence of IL-18. The administration of rIL-18 made no difference in the growth of subcutaneous tumors, histologic indices (mitotic index, apoptotic index, and Ki-67-labeling index) of subcutaneous tumors or metastatic bone foci, or in the number of osteoclasts along the bone surface adjacent to tumors. Moreover, serum levels of cytokines including interferon-gamma, IL-1alpha, IL-6, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor, which regulate bone-resorbing activity of osteoclasts, were evaluated. Among them, IL-6 was remarkably downregulated in rIL-18-treated mice. These findings suggest that IL-18 inhibits osteolytic bone metastasis possibly through suppression of osteoclastic bone-resorption mediated in part by IL-6.
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PMID:Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice. 1204 51

We established a human lung cancer cell line, MI-4 from the pleural effusion of a 69-year-old male with advanced large cell undifferentiated carcinoma of the lung complicated by leukocytosis. The culture supernatant of MI-4 contained high levels of granulocyte colony stimulating factor (G-CSF). The intracellular localization of the G-CSF was identified by immunocytochemistry. Reverse transcription-polymerase chain reaction (RT-PCR) revealed G-CSF mRNA expression in this cell line. The cell line was successfully transplanted into nude mice. The transplanted nude mice also showed leukocytosis with a high serum G-CSF level. Southern blot analysis did not show amplification or rearrangement of the G-CSF gene in MI-4 cells. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses revealed that this cell line has an additional chromosome 17 attached to a segment of chromosome 10 besides two intact chromosomes 17, and that each of these three chromosomes 17 has a G-CSF gene on chromosome 17q. Inflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, significantly enhanced G-CSF expression at both the protein and mRNA levels in MI-4. However, these cytokines did not stimulate the growth of MI-4 cells, regardless of abundant G-CSF production. TNF-alpha rather suppressed it, in a dose-dependent manner. Exogenous recombinant human G-CSF and anti-G-CSF antibody did not promote or inhibit the growth of MI-4 cells at any concentration examined. In addition, RT-PCR analysis did not show G-CSF receptor mRNA expression. These results suggest that this cell line does not have an autocrine growth loop for G-CSF. This cell line should be very useful for understanding the biological activity of G-CSF in G-CSF-overproducing lung cancer.
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PMID:Establishment and characterization of a new lung cancer cell line (MI-4) producing high levels of granulocyte colony stimulating factor. 1207 15

We evaluated the antitumor activity of the Bax gene and green fluorescent protein/tumor necrosis factor-related apoptosis-inducing ligand (GFP/TRAIL) fusion gene driven by the human telomerase reverse transcriptase promoter both separately and combined in the human ovarian cancer lines SKOV3ip and DOV13 and human lung cancer line H1299. In vitro study showed that both TRAIL- and Bax-expressing vectors elicited significant cell killing in H1299 and SKOV3ip cells, but only the GFP/TRAIL gene elicited significant cell killing in DOV13 cells. Combined TRAIL and Bax therapy also produced more profound cell killing in SKOV3ip and H1299 cells, but not DOV13 cells without escalation of the vector doses. To further evaluate the combined effects of Bax and TRAIL, abdominally spread tumors were established in nude mice via intraperitoneal inoculation of SKOV3ip cells followed by that of adenoviral vectors. Tumor growth, ascites formation, survival duration and toxicity were evaluated after treatment. We found that treatment using the Bax- or TRAIL-expressing vector alone significantly suppressed tumor growth and ascites formation, and prolonged animal survival when compared with that of using PBS or a control vector. Combined TRAIL and Bax therapy further prolonged survival significantly when compared with therapy using the TRAIL or Bax gene alone. Transgene expression and apoptosis induction were not detected in normal human ovarian epithelial cells in vitro or normal mouse tissues in vivo after intraperitoneal vector administration. Also, liver toxicity was not detected after either treatment. Thus, combined TRAIL and Bax gene therapy may be useful for treatment of abdominally spread tumors.
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PMID:Combined TRAIL and Bax gene therapy prolonged survival in mice with ovarian cancer xenograft. 1236 3


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