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)

Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.
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PMID:Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer. 217 11

The antimetastatic activity of the prostacyclin analog Iloprost has been examined in mice bearing Lewis lung carcinoma. An inhibition of lung colony formation is observed when 100 or 200 micrograms/kg Iloprost are administered i.v. 1 h before i.v. injection of tumor cells, which is dependent on the size of tumor inoculum. The effects of 200 micrograms/kg Iloprost persist for 24 h, and are of the same magnitude as those obtained with 10 mg/kg prostacyclin, which last only for 30 min. When treatment with Iloprost is followed by surgical removal of primary tumor, spontaneous metastasis formation is reduced, and the survival time of the treated animals is significantly increased over controls treated with surgery only. The antimetastatic effects of Iloprost appear dissociated from drug's effects on the hemostatic system of the host as indicated by the clot retraction assay, performed after in vivo treatment, using ADP or tumor cells as platelet aggregating agents. Iloprost thus appears to reduce spontaneous metastasis formation and intraoperative tumor cell dissemination, with pharmacological properties more favourable to therapeutic use than those of prostacyclin.
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PMID:Antimetastatic action of the prostacyclin analog iloprost in the mouse. 247 73

We studied the effects on platelet function of different human tumour cells cultured "in vitro": Mo T lymphocyte cell line, NCI-N592 small cell lung carcinoma cell line, and 5637 bladder carcinoma cell line. Mo and NCI-N592 cells possessed a slight, dose-dependent platelet aggregating activity, which was completely abolished by apyrase and unaffected by hirudin. The cell-free supernatant also induced an aggregation response, which was very similar to that obtained with tumour cell suspensions. The presence of ADP in the cell-free supernatants of cell suspensions was confirmed by HPLC analysis. On the contrary, aggregation induced by 5637 cells was preceded by a significant lag phase; it was not affected by apyrase but it was abolished by hirudin, and the cell-free supernatant had no effect. These data suggest that Mo and NCI-N592 cells activate platelets by producing ADP, while 5637 cells stimulate platelet function by generating thrombin. The amount of ADP produced by the first two tumour cell lines was measured by bioassay: the extent of such production was similar for both cell lines and the maximum was reached after 60 minutes and maintained for up to 3 hours. These results suggest that neoplastic cells can activate platelets by different mechanisms: such investigations should be performed in homologous systems and in well-defined experimental conditions.
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PMID:Human tumor cells cultured "in vitro" activate platelet function by producing ADP or thrombin. 262 35

Ticlopidine has been shown to markedly inhibit the platelet aggregability induced by ADP in control animals not receiving 3LL cells. Ticlopidine was administered orally at the selected dose (200 mg/kg/day), to the rodents using different dose schedules and the inhibitory effects on spontaneous lung metastases of the Lewis lung carcinoma were studied. Ticlopidine did not have any significant influence on the metastases formation and on the primary growth of 3LL, although it inhibited platelet aggregation in tumor-bearing mice. These data indicate that the antiaggregatory effects of ticlopidine are not related to an antimetastasic effect in our model.
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PMID:Effects of ticlopidine on metastasis production in mice bearing Lewis lung carcinoma. 358 21

Micrococcal nuclease digestion of nuclei from mouse Lewis lung carcinoma cells releases a protein mixture into the supernatant that lacks histone H1 and contains a full complement of high-mobility-group I (HMGI) proteins (i.e. I, Y and I-C). This implies that all three HMGI proteins are localized at the nuclease-sensitive regions of active chromatin. It is also shown that if Ca2+ ions are present in the nuclear incubation buffer (with or without exogenous nuclease), all three HMGI proteins become ADP-ribosylated. We propose that this modification of HMGI family proteins is part of the general poly(ADP-ribosyl)ation that accompanies DNA damage in apoptosis and other processes.
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PMID:Calcium-dependent ADP-ribosylation of high-mobility-group I (HMGI) proteins. 876 Mar 75

Metastasis is one of the most important factors responsible for the pathogenesis of small cell lung carcinoma (SCLC). SCLC cells express cadherins, which are homophilic cell-cell adhesion molecules that play an important role in the regulation of metastasis. We present the first evidence that altering the activity of the small GTP-binding protein Rho induces cadherin-mediated adhesion. ADP-ribosylation of Rho upon incubation or electroporation with recombinant C3 exoenzyme induces rapid aggregation and compaction of SCLC cells. Aggregation and compaction induced by C3 exoenzyme are diminished by removal of extracellular Ca2+ and by the HECD blocking antibody to E-cadherin but not by antibodies to other adhesion molecules. Altering the activity of Rho by ADP-ribosylation does not alter surface expression of E-cadherin, but it alters G actin content, as indicated by the binding of DNase I. Treatment with cytochalasin D also alters G actin content and increases aggregation and compaction of SCLC cells. These findings implicate Rho in the regulation of cadherin-mediated adhesion and identify Rho as a potential therapeutic target for the control of SCLC metastasis.
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PMID:Regulation of cadherin-mediated adhesion by the small GTP-binding protein Rho in small cell lung carcinoma cells. 913 23

The two major forms of lung carcinoma, small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), are clinically distinct, and are also differentiated by morphology and behavior in culture. SCLC cells have a greater metastatic potential than NSCLC cells in vivo, and exhibit a unique spherical morphology in culture due to their inability to adhere and spread on the substratum. Because the small GTPase RhoA affects metastatic properties and regulates cell morphology, we examined whether differences in RhoA expression and activity contribute to the distinct SCLC and NSCLC phenotypes. We found that the expression and GTPgammaS-dependent activation of RhoA are generally greater in SCLC cell lines (SCC-9, NCI-H69, NCI-H146, and NCI-H345) than in NSCLC cell lines (NCI-H23, NCI-H157, NCI-H520, and NCI-H522). The effects of inhibiting Rho-mediated signaling in these cells were investigated by transfecting the cells with cDNA coding for C3 exoenzyme, which ADP-ribosylates and inactivates Rho. Expression of C3 exoenzyme in SCLC cells induces cell-cell compaction, and causes NCI-H345 cells to adhere and spread on collagen IV. In contrast, expression of C3 exoenzyme in NSCLC cells does not induce detectable compaction, but induces cell spreading of NCI-H23 and NCI-H157 cells. Cell proliferation is diminished by Rho inactivation in the majority of the NSCLC cell lines, but not the SCLC cell lines. Expression of p21Cip1/WAF1 is also diminished by Rho inactivation in two of the SCLC cell lines, but is not significantly altered in the NSCLC lines. These results indicate that Rho-mediated signaling may regulate different events in SCLC and NSCLC cells, including adhesion of SCLC cells and proliferation of NSCLC cells.
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PMID:The small GTPase RhoA has greater expression in small cell lung carcinoma than in non-small cell lung carcinoma and contributes to their unique morphologies. 1257 23

In this study, we investigated the role of reduced glutathione (GSH) and nuclear factor-kappaB (NFkappaB) in hypoxia-induced apoptosis. Hypoxia caused p53-dependent apoptosis in murine embryonic fibroblasts transfected with Ras and E1A. N-Acetyl-l-cysteine (NAC) but not other antioxidants, such as the vitamin E analog trolox and epigallocatechin-3-gallate, enhanced hypoxia-induced caspase-3 activation and apoptosis. NAC also enhanced hypoxia-induced apoptosis in two human cancer cell lines, MIA PaCa-2 pancreatic cancer cells and A549 lung carcinoma cells. In murine embryonic fibroblasts, all three antioxidants blocked hypoxia-induced reactive oxygen species formation. NAC did not enhance hypoxia-induced cytochrome c release but did enhance poly-(ADP ribose) polymerase cleavage, indicating that NAC acted at a post-mitochondrial level. NAC-mediated enhancement of apoptosis was mimicked by incubating cells with GSH monoester, which increased intracellular GSH similarly to NAC. Hypoxia promoted degradation of an inhibitor of kappaB(IkappaBalpha), NFkappaB-p65 translocation into the nucleus, NFkappaB binding to DNA, and subsequent transactivation of NFkappaB, which increased X chromosome-linked inhibitor of apoptosis protein levels. NAC failed to block degradation by IkappaBalpha and sequestration of the p65 subunit of NFkappaB to the nucleus. However, NAC did abrogate hypoxia-induced NFkappaB binding to DNA, NFkappaB-dependent gene expression, and induction of X chromosome-linked inhibitor of apoptosis protein. In conclusion, NAC enhanced hypoxic apoptosis by a mechanism apparently involving GSH-dependent suppression of NFkappaB transactivation.
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PMID:N-Acetyl-L-cysteine enhances apoptosis through inhibition of nuclear factor-kappaB in hypoxic murine embryonic fibroblasts. 1537 56

Posttranscriptional regulation of urokinase-type plasminogen activator receptor (uPAR) mRNA involves the interaction of a uPAR mRNA coding region sequence with phosphoglycerate kinase (PGK), a 50-kDa uPAR mRNA binding protein. PGK catalyzes a reversible transfer of a phosphoryl group from 1,3-biphosphoglycerate to ADP in the glycolytic pathway. Our previous studies showed that overexpression of PGK in uPAR-overproducing H157 lung carcinoma cells results in decreased cytoplasmic uPAR mRNA and cell surface uPAR protein expression through destabilization of the mRNA. In order to determine the role of PGK enzymatic activity on uPAR mRNA stability we mutated PGK by changing amino acid P204H and amino acid D219A. The mutant proteins were expressed in Epicurian coli BL21 cells, and the purified proteins were analyzed for PGK activity. We found that mutation of amino acid P204H and D219A reduced PGK activity by 99 and 83%, respectively. By gel mobility shift and Northwestern assay, we found that the mutant proteins were able to bind to uPAR mRNA as effectively as wild-type PGK. Overexpression of mutant, inactive PGK in H157 cells reduced cell surface uPAR protein as well as uPAR mRNA expression. Run-on transcription analysis indicated that overexpression of mutant PGKs fails to alter the rate of synthesis of uPAR mRNA, whereas transcription chase experiments demonstrated that both mutants and wild-type PGK reduce the stability of the uPAR mRNA transcripts to a similar extent. Overexpression of mutant PGK also inhibited the rate of DNA synthesis and the invasion-migration ratio. These results demonstrate that uPAR mRNA binding activity as well as PGK-mediated regulation of uPAR mRNA are independent of PGK enzymatic activity.
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PMID:Regulation of urokinase receptor expression by phosphoglycerate kinase is independent of its catalytic activity. 1595 30

Endoglin is a transforming growth factor-beta(1) (TGF-beta(1)) accessory receptor which is highly expressed in tumor vessels. To study the role of endoglin in tumor growth and angiogenesis we induced a highly vascularized tumor in mice heterozygous for endoglin (Eng+/-) and in their control littermates (Eng+/+) by injecting 10(6) Lewis lung carcinoma (3LL) cells subcutaneously. Nine days after injection, the tumor was removed and weighed. Capillary density (CD31 immunohistochemistry), hemoglobin content and vascular cell adhesion molecule-1 (VCAM-1) expression were used to assess tumor vascularization. Tumor perfusion rate was measured by laser-Doppler technique. Expression of the hypoxia-inducible factor (HIF), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were determined by Western blot analysis. The aerobic metabolism and oxygen dependency were inferred from the measurement of ATP in tumoral tissue. Tumor weight, capillary density, hemoglobin and VCAM-1 were reduced by about 30% in Eng+/- compared to Eng+/+ littermates. The protein levels of eNOS and phosphorylated eNOS were significantly reduced in Eng+/- compared to Eng+/+ mice. HIF expression was slightly reduced whereas VEGF level was slightly increased in Eng+/- compared to Eng+/+. Tumor tissue levels of ATP and ADP were similar in both types of mice. These data demonstrate that endoglin plays a major role in tumor neoangiogenesis.
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PMID:Reduced tumor growth and angiogenesis in endoglin-haploinsufficient mice. 1710 12


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