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)

UCN-01 (7-hydroxystaurosporine) inhibits the growth of various malignant cell lines in vitro and in vivo. In this study, a human small cell lung carcinoma subline resistant to UCN-01, SBC-3/UCN, was established and characterized. SBC-3/UCN cells showed 8-fold greater resistance to the UCN-01-induced growth-inhibitory effect than the parent cells, SBC-3. No UCN-01-induced G1 accumulation in SBC-3 cells was observed in SBC-3/UCN cells and decreased expression of phosphorylated RB protein was found in SBC-3 cells. Neither basal expression nor induction of p21(Cip1) by UCN-01 treatment was detected in the SBC-3/UCN cell line. An inhibitory effect of UCN-01 on CDK2 activity, which is mediated by p21(Cip1)/CDK2 complex formation upon UCN-01 treatment, was observed in SBC-3 but not in SBC-3/UCN cells. SBC-3/UCN showed higher CDK6 activity than SBC-3 cells. UCN-01 did not inhibit the CDK4 and CDK6 activities in both cells. We screened the cell cycle regulatory molecules associated with G(1)/S progression and found a remarked decrease in interferon regulatory factor 1 (IRF-1), which is known to cooperate with p53 in p21(Cip1) induction. Our results suggest that p21(Cip1) regulation via the IRF-1-associated pathway may represent a major determinant of UCN-01-induced growth inhibition in human lung cancer cells.
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PMID:Molecular determinants of UCN-01-induced growth inhibition in human lung cancer cells. 1062 89

The purpose of the present communication was to determine in patients with chronic obstructive pulmonary disease (COPD), untreated lung cancer and healthy controls if there was a possible association between the disease state and biomarkers of cytogenetic damage and ras p21 oncoprotein levels, and if various exogenous confounding factors such as smoking habit and endogenous ones (sex, cancer in the immediate family) could affect these biomarkers. The individuals in all groups were as well-matched as possible for age to determine if this could be eliminated as a confounder. Peripheral blood and plasma were collected from 20 COPD patients, 31 cancer patients and 20 healthy controls. Chromosomal aberrations (CA), sister chromatid exchanges (SCE) and high frequency SCE cells (HFC) were examined from the blood and ras p21 oncoproteins from the plasma. These parameters were used as biomarkers of genotoxic anomalies. All the biomarkers were examined for their relationship to the confounding factors. Results were analysed by a t-test, analysis of variance (ANOVA) and stepwise multivariate regression analysis. There was an increase in CA, although not statistically so, in COPD and cancer patients by comparison with healthy controls, but there was a statistically significant increase in SCE, HFC and ras p21 oncoproteins. There was also a statistically significant difference between respiratory volume parameters in COPD patients and controls. Respiratory parameters were not measured in cancer patients. Ras p21 oncoproteins were also statistically significantly increased in the COPD and cancer patients, suggesting that the disease state alone might be sufficient to increase the oncoproteins, or that some of the COPD patients were in the process of developing cancer or perhaps some would die from COPD before cancer developed. Smoking was shown to have a marked effect on all parameters investigated. Ex-smokers showed less effects. Since age was very well controlled, there was little effect due to age. There was an effect due to sex, but cancer in the immediate family had little effect on any of the parameters.
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PMID:Cytogenetic damage and ras p21 oncoprotein levels from patients with chronic obstructive pulmonary disease (COPD), untreated lung cancer and healthy controls. 1065 91

Previous lines of evidence have shown that inhibition of DNA methyltransferase (MeTase) can arrest tumor cell growth; however, the mechanisms involved were not clear. In this manuscript we show that out of 16 known tumor suppressors and cell cycle regulators, the cyclin-dependent kinase inhibitor p21 is the only tumor suppressor induced in the human lung cancer cell line, A549, following inhibition of DNA MeTase by a novel DNA MeTase antagonist or antisense oligonucleotides. The rapid induction of p21 expression points to a mechanism that does not involve demethylation of p21 promoter. Consistent with this hypothesis, we show that part of the CpG island upstream of the endogenous p21 gene is unmethylated and that the expression of unmethylated p21 promoter luciferase reporter constructs is induced following inhibition of DNA MeTase. These results are consistent with the hypothesis that the level of DNA MeTase in a cell can control the expression of a nodal tumor suppressor by a mechanism that does not involve DNA methylation.
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PMID:DNA methyltransferase inhibition induces the transcription of the tumor suppressor p21(WAF1/CIP1/sdi1). 1069 35

An association between the Arg allele of the p21WAF1/CIP1 codon 31 polymorphism and lung cancer has been reported. However, the genotype distribution of the p21 codon 31 polymorphism, as well as the association of this polymorphism with lung cancer risk and prognosis, remain undefined in the Taiwanese population. Therefore, we investigated the genotype distribution of the p21 codon 31 polymorphism in 155 lung cancer patients and 189 non-cancer controls. The genotype frequencies in the Taiwanese non-cancer controls were 0.51 (Ser) and 0.49 (Arg). Chi2 analysis indicated significant differences in Taiwanese genotype distribution of p21 from those reported for Swedes (P=0.001), Caucasians (P=0.001), Indians (P=0.001), and African-Americans (P=0.001). However, our data did not demonstrate an association of the Arg allele of the p21 polymorphism with lung cancer risk in Taiwan. Lung cancer patients with Ser/Arg and Arg/Arg genotypes were at a nonsignificant 1.15-fold increased risk of lung cancer when compared to individuals with the Ser/Ser genotype (95%CI, 0.70-1.86). In addition, although p21 is a downstream target of p53, we found no significant correlation of the p21 polymorphism with the p53 polymorphism and p53 gene mutation in lung cancer patients. We further investigated the association of the p21 polymorphism with prognosis in 154 lung cancer patients. Patients with the Ser/Ser genotype tended to have a poorer prognosis than those with the Ser/Arg and Arg/Arg genotypes (P=0.097, by the log rank test). Our data suggest that the p21 codon 31 polymorphism may not play a significant role in cancer susceptibility and the prognosis of lung cancer patients in Taiwan.
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PMID:Lack of evidence of association of p21WAF1/CIP1 polymorphism with lung cancer susceptibility and prognosis in Taiwan. 1074 39

Cytotoxic effect of either cisplatin or p53 gene transfection of lung cancer cells may be different depending on the p53 status of cells. We investigated cytotoxic effects on the combined treatment of cisplatin and adenovirus mediated p53 gene transfer (Avp53) in both H460 and H1299 cells in vitro. The results showed the highest numbers of apoptotic cells in both H460 and H1299 cells following the combined treatment regardless of p53 status in comparison with either cisplatin or Avp53 alone. The expression levels of p53, p21, Bax and ICE were examined to understand a possible cellular signal path of the combined treatment. In western analyses, the patterns of phosphorylated p53 protein were different between Avp53 and combined treatment. The expressions of p21 and Bax were increased in combined treatment, whereas the cleaved form of ICE (20 kD) was not detected. These results suggest that cisplatin induced p53 protein phosphorylation and may activate the downstream of p53 gene expression such as p21 and Bax. The enhanced apoptosis of lung cancer cells by the combined treatment may be useful in the development of clinical therapeutic modality of lung tumors.
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PMID:Enhanced induction of Bax gene expression in H460 and H1299 cells with the combined treatment of cisplatin and adenovirus mediated wt-p53 gene transfer. 1076 58

Although MDM2, p21/WAF1, and p53 are considered as regulating each other based on in vitro studies, the relation in human lung cancer is not fully understood. The expressions of these proteins were examined immunohistochemically in 112 resected non-small cell lung cancer specimens and the correlation between them were analyzed. MDM2 was expressed in 45% of all lung cancers. In advanced stage, MDM2-positive cases were observed more frequently than in early stage, showing significant difference. No significant difference was observed in the prognosis of the patients regardless of the expression of any protein. Although no correlation was observed between MDM2 expression and p53 expression, or between p21/WAF1 expression and p53 expression, MDM2 expression was strongly related with p21/WAF1 expression. Therefore, MDM2 expression may relate to the progress of the stage of lung cancer, and MDM2 expression and p21/WAF1 expression may be associated not through the p53-related pathway.
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PMID:MDM2 expression is associated with progress of disease and WAF1 expression in resected lung cancer. 1081 14

Retinoids are promising agents for the prevention and treatment of several human malignancies including lung cancer. In this study, the effect of retinoic acid (RA) on cell growth and the mechanism of growth modulation were examined in human lung squamous carcinoma CH27 cells. Here we report that RA mediated the dose- and time-dependent growth arrest in G1 phase, accompanied by the up-regulation of p27(Kip1) and the down-regulation of the cyclin-dependent kinase 3 (Cdk3) and p21(CIP1/Waf1) proteins. Furthermore, RA-induced growth arrest of CH27 cells was also associated with increased retinoic acid receptor beta (RARbeta) and reduced c-Myc expression. However, RA had no effect on the levels of cyclins A, D1, D3, E, or H, or on Cdk2, Cdk4, Cdk5, CDk6, Cdk7, p16(Ink4A), p15(Ink4B), p53, or pRb proteins in CH27 cells. Evaluation of the kinase activity of cyclin-Cdk complexes showed that RA increases p27(Kip1) expression in CH27 cells leading to markedly reduced cyclin A/Cdk2 kinase activity and slightly reduced cyclin E/Cdk2 kinase activity, with no effect on cyclin D/Cdk4 and cyclin D/Cdk6 activities. Moreover, coincident with the decrease in kinase activity was a drastic increase in cyclin A-bound p27(Kip1). These results suggest that increases in the levels of p27(Kip1) and its binding to cyclin A, as well as reduction of Cdk3 protein expression, are strong candidates for the cell cycle regulator that prevents the entry into the S phase in RA-treated CH27 cells, with prolongation of G1 phase and inhibition of DNA synthesis.
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PMID:Retinoic acid-mediated G1 arrest is associated with induction of p27(Kip1) and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells. 1089 83

Epidemiological studies and animal experiments showed that asbestos and cigarette smoking can act synergistically in the development of lung cancer. The mechanism of this synergism is largely unknown. It is well documented that DNA damage and activation of oncogenes play important roles in the development of cancer. The aim of our study was to find out if DNA damage could be increased and c-ras oncogene could be activated when human embryo lung cells were treated with chrysotile (CH) and cigarette smoking solution (CSS) separately or simultaneously. Human embryo lung (HEL) cells were treated with different doses of CH and CSS separately or simultaneously, then DNA strand breaks were detected with single-cell gel electrophoresis assay and the expression of p21 was detected by flow cytometry. Factorial analysis was used to evaluate the combined effect of chrysotile and cigarette smoking solution. The results showed that DNA strand breaks could be increased significantly when HEL cells were exposed to CH and CSS separately for 1 hour and increased in a dose-dependent relationship when cells were exposed to CH and CSS simultaneously for 1 hour. The expression of p21 increased significantly when cells were exposed to CH for 24 hours, but there was no significant increase when cells were exposed to CSS for 24 hours. However, there was an additive effect on the expression of p21 when cells were exposed to CH and CSS simultaneously for 24 hours. When cells were exposed to CH and CSS simultaneously three times (24 hours each time), then passaged for 1 month, the expression of p21 increased synergistically. In conclusion, DNA damage and activation of c-ras may be involved in the process of combined carcinogenesis of CH and CSS.
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PMID:DNA damage and activation of c-ras in human embryo lung cells exposed to chrysotile and cigarette smoking solution. 1090 3

Transforming Growth Factor-beta 1 (TGF-beta 1) regulates the proliferation of normal epithelial cells, and resistance to TGF-beta 1 growth inhibition is a common feature of human cancers including lung cancer. In order to understand the mechanism of resistance to growth inhibition by TGF-beta 1 and to reverse the regulation of proliferation in lung cancer, we determined the genomic structure of the genes involved in the signal transduction pathway of TGF-beta 1 and performed an initial mutation survey of the complete coding region of the genes in lung cancer and cell lines with the resistance to growth inhibition by TGF-beta 1. First, a mutation analysis of the TGF-beta type II receptor (TGF-beta RII) was performed. Point mutations of the gene were detected in several colon cancers and an adenocarcinoma of the lung in the poly-A sequence. No mutations of Smad 2, 3, 4, 5 and TGF-beta type I receptor (TGF-beta IR) genes were detected in a series of the tumors we tested, although several mutations of Smad 2 and 4 were previously reported. Frequent alterations of the p15 gene and reduced expression of p21 we already reported from our previous studies. We also determined the genomic structure of the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), which is involved in activating TGF-beta 1, and performed an initial mutation survey of the complete coding sequences of the gene. A point mutation at exon 40 was found in one lung adenocarcinoma cell line. In summary, alterations in the many genes involved in the signal transduction of TGF-beta 1 were found and may mediate the loss of TGF-beta 1 responsiveness in lung cancer. The molecular targets for the regulation of the proliferation of lung cancer are thought to be p15, p21 and the transcriptional regulators.
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PMID:[Mechanism of resistance to growth inhibition by transforming growth factor-beta 1 (TGF-beta 1) in primary lung cancer and new molecular targets in therapy]. 1094 24

Cyclin D1 is a key cell cycle regulatory protein, the expression and subcellular localization of which is often altered in human tumor cells. A common A/G single nucleotide polymorphism (A870G) in exon 4 of the cyclin D1 gene, CCND1, is associated with the presence of 2 distinct mRNA transcripts for this G1/S regulatory protein, and CCND1 genotype has been related to prognosis in lung cancer and head and neck carcinoma. We have investigated both the expression of cyclin D1 protein and the CCND1 A870G polymorphism in 100 colorectal cancer patients. Immunohistochemistry demonstrated cyclin D1 protein expression in 55% of tumors, and while the absence of cyclin D1 protein was not associated with outcome (p=0.81), high levels of protein expression (>50% of tumor cells expressing cyclin D1) correlated with significantly shortened overall survival (p=0.01). Using polymerase chain reaction restriction fragment length polymorphism analysis, we determined the frequency of each genotype and found that CCND1 genotype was not related to overall survival (p>0.05). In addition, genotype was unrelated to the level of expression and localization of cyclin D1 protein, as well as other key G1/S checkpoint proteins (p21, p27, p53, retinoblastoma) and tumor proliferation markers (proliferating cell nuclear antigen). However, higher levels of p27, and to a lesser extent p21, were associated with reduced cytoplasmic cyclin D1 protein (p=0.029 and p=0.054, respectively). In conclusion, we have demonstrated that high levels of cyclin D1 protein expression are related to outcome in colorectal cancer; however, the CCND1 A870G polymorphism is unrelated to either cyclin D1 protein expression or patient survival.
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PMID:Cyclin D1 protein expression and gene polymorphism in colorectal cancer. Aberdeen Colorectal Initiative. 1096 85


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