Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The caspases are known to play a crucial role in the triggering and execution of apoptosis in a variety of cell types. We assessed the expression of caspase-1 in 42 pancreatic cancer tissue samples, 38 chronic pancreatitis specimens, and nine normal pancreatic tissues by immunohistochemistry and Western blot analysis. We found a clear overexpression of caspase-1 in both disorders, but differences in the expression patterns in distinct morphologic compartments. Pancreatic cancer tissue showed a clear cytoplasmatic overexpression of caspase-1 in tumor cells in 71% of the tumors, whereas normal pancreatic tissue showed only occasional immunoreactivity. In chronic pancreatitis an overexpression of caspase-1 was found in atrophic acinar cells (89%), hyperplastic ducts (87%), and dedifferentiating acinar cells (84%). Although in atrophic cells a clear nuclear expression was found, hyperplastic ducts and dedifferentiating acinar cells showed clear cytoplasmic expression. Western blot analysis revealed a marked expression of the 45 kDa precursor of caspase-1 in pancreatic cancer and chronic pancreatitis (80% and 86%, respectively). Clear bands at 30 kDa, suggested to represent the p10-p20 heterodimer of active caspase-1, were found in 60% of the cancer tissue and 14% of the pancreatitis tissue specimens. Since we found a highly significant correlation between cytoplasm overexpression of caspase-1 in pancreatic cancer and overexpression of the known prognostic factors cyclin D1, epidermal growth factor, and epidermal growth factor receptor, it is plausible that caspase-1 has a yet unknown function in proliferative processes in addition to its well-known role in the apoptotic pathway.
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PMID:Overexpression of caspase-1 in pancreatic disorders: implications for a function besides apoptosis. 1198 74

Endothelial injury is a major manifestation of septic shock induced by LPS. Recently, LPS was shown to induce apoptosis in different types of endothelial cells. In this study, we observed that pretreatment with vascular endothelial growth factor (VEGF), a known cell survival factor, blocked LPS-induced apoptosis in endothelial cells. We then further defined this LPS-induced apoptotic pathway and its inhibition by VEGF. We found that LPS treatment increased caspase-3 and caspase-1 activities and induced the cleavage of focal adhesion kinase. LPS also augmented expression of the pro-apoptotic protein Bax and the tumor suppressor gene p53. The pro-apoptotic Bax was found to translocate to the mitochondria from the cytosol following stimulation with LPS. Pretreatment of endothelial cells with VEGF inhibited the induction of both Bax and p53 as well as the activation of caspase-3. These data suggest that VEGF inhibits LPS-induced endothelial apoptosis by blocking pathways that lead to caspase activation.
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PMID:Lipopolysaccharide-induced apoptosis of endothelial cells and its inhibition by vascular endothelial growth factor. 1202 90

We have recently reported the identification of four novel members of the interleukin-1 (IL-1) family which we designated as IL-1 homologue 1-4 (IL-1H1-4). These proteins exhibit significant sequence homology to other members of the IL-1 family. Of these homologues, only IL-1H4 (renamed IL-1F7b) was predicted to contain a propeptide domain and a caspase cleavage site. We now report that caspase-1 cleaves IL-1F7b at the predicted site to generate mature IL-1F7b. Caspase-4 was also able to process IL-1F7b, albeit inefficiently. Other caspases and Granzyme-B did not cleave IL-1F7b. Furthermore, adenovirus-mediated expression of IL-1F7b in HEK 293 cells led to in situ processing and secretion of mature IL-1F7b. In a screen to identify a potential receptor, both pro and mature IL-1F7b bound to the soluble IL-18 receptor alpha-Fc (IL-18Ralpha-Fc) but not to the soluble IL-1R-Fc or ST2R-Fc fusion proteins. Mature IL-1F7b bound to the IL-18Ralpha-Fc protein with higher affinity than the pro form, although the affinities for both proteins were significantly lower than that observed for IL-18. Consistent with this observation, only IL-18 and not IL-1F7b induced IFN-gamma production by KG1a cells. We also report that pro and mature IL-1F7b form homodimers with association constants of 4 microM and 5 nM, respectively, suggesting biological relevance to IL-1F7b processing. Finally, we have localized the expression of IL-1F7b protein in discrete cell populations including plasma cells and tumor cells. These data suggest that IL-1F7b may be involved in immune response, inflammatory diseases and/or cancer.
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PMID:Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. 1209 20

We studied the molecular events underlying butyrate-induced apoptosis in two different colon cancer cell lines: Caco-2, a well defined cancer cell and RSB, a cell line obtained from a colonic tumor of an ulcerative colitis patient. Caco-2 and RSB cells were exposed to 2, 5 and 10 mmol/L butyrate for 48 h. Caspase-1 was cleaved in Caco-2-cells at all butyrate concentrations, whereas in RSB-cells caspase-1 expression was undetectable. In RSB cells, butyrate dose-dependently induced caspase-3 cleavage, whereas in Caco-2-cells, butyrate up-regulated expression of the caspase-3 active subunit. Caspase-3-specific activity, cytoplasmic nucleosome concentration and growth were directly correlated with butyrate doses in both cell lines; however, the response was more pronounced in Caco-2 than in RSB cells. Expression of the cleaved poly(ADP-ribose) polymerase (PARP) product was elevated in both cell lines at the highest butyrate concentration. Bak expression gradually increased as a function of butyrate concentrations in both cell lines. At 10 mmol/L butyrate, expression increased by fivefold and sevenfold in Caco-2 and RSB cells, respectively. The highest expression of Bcl-2 was observed in control Caco-2 cells, and expression decreased with increasing butyrate concentration. This effect was not observed in RSB cells. Inactivation of caspase-1 with Z-YVAD-FMK abrogated butyrate-induced apoptosis in Caco-2 but not in RSB cells. Inactivation of caspase-3 with Z-DVED-FMK completely inhibited butyrate-induced apoptosis in RSB cells whereas this effect was less pronounced in Caco-2 cells. Our data demonstrate that butyrate-induced apoptosis is activated via different apoptotic pathways in diversely stratified colon cancers.
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PMID:Different molecular events account for butyrate-induced apoptosis in two human colon cancer cell lines. 1209 52

Although biotherapy of gastroenteropancreatic neuroendocrine tumors (NET) provides excellent control for the hypersecretion syndrome, tumor regression is rarely observed, implying the need for novel antiproliferative strategies. Here, we demonstrate that human pancreatic QGP-1 NET cells express functionally intact interferon-gamma (IFN-gamma) receptors and downstream effectors, including the putative tumor suppressor interferon regulatory factor-1 (IRF-1). IFN-gamma treatment profoundly inhibited anchorage-dependent and anchorage-independent growth of QGP-1 cells. Concomitant with the onset of growth inhibition, apoptotic cells were detected in cell cycle analyses of IFN-gamma treated cultures. Apoptosis was confirmed by evaluation of DNA fragmentation and PARP cleavage. Immunoblots of IFN-gamma treated QGP-1 cells revealed a substantial upregulation of caspase-1, followed by the appearance of active proteolytic fragments of caspase-3, suggesting that autocatalytic activation of caspase-1 might initiate the caspase cascade. Apoptosis induction by IFN-gamma was also observed in two of four primary cultures established from tumors of patients with for- and midgut NETs, respectively. Taken together our results characterize IFN-gamma as a potent proapoptotic stimulus in a subset of gastrointestinal NETs and suggest an IRF-1 mediated induction of caspase-1 as a relevant underlying mechanism. Based on these results, the potential of IFN-gamma in experimental biotherapeutic treatment of NETs can be further explored.
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PMID:Interferon-gamma inhibits growth of human neuroendocrine carcinoma cells via induction of apoptosis. 1237 Jul 65

Malignant mesothelioma is a very rare tumor in childhood. Presently, treatment of this disease continues to be frustrating and prognosis remains poor. We here report a pediatric case of malignant pleural mesothelioma who gave a complete response to ICE-VAC chemotherapy regimen and achieved a long-term survival. An eight-year-old girl underwent exploratory thoracotomy and decortication because of a unilateral loculated and multicystic pleural effusion. Histopathological diagnosis was sarcomatoid pleural malignant mesothelioma. After decortication, chemotherapy with ICE (ifosfamide, carboplatin, etoposide) - VAC (vincristine, adriamycin, cyclophosphamide) combination was started. Six courses of chemotherapy resulted in complete clinical and radiological tumor response. She did not receive any further therapy and remains disease-free three years after the first remission. ICE-VAC chemotherapy combination resulted in a complete tumor response and a long-term disease-free survival for the presented case. The efficacy of this chemotherapy regimen in malignant mesothelioma needs to be documented in future trials.
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PMID:Malignant pleural mesothelioma in a child: long-term survival with ICE-WAC chemotherapy regimen. 1240 38

Caspases exist as zymogens, and are activated by various extracellular stimuli, leading to apoptosis. One such stimulus is Fas/CD95, a member of the tumor necrosis factor receptor family, providing one means of cytotoxic T lymphocyte (CTL)-mediated cell lysis. Clinical evidence has shown that administration of cytokine leads to regression in selected patients with renal cell carcinomas (RCCs). Interferon-gamma (IFN-gamma) indicates its contribution to anti-tumor activity of immune cells. IFN-gamma elicits its effect through the transcription factor signal transducer and activator of transcription-1 (STAT-1), and through interferon regulatory factor-1 (IRF-1), one of the target genes of STAT-1. Our previous study demonstrated an increase in the susceptibility of ACHN cells, established from RCC, to Fas-mediated apoptosis by IFN-gamma, and the inhibition of this effect by the caspase-3 and -7 inhibitor, DEVD-CHO. We demonstrated the following phenomena in IFN-gamma-treated ACHN cells: 1) enhanced transcription of caspase-1, 3 and 7 mRNAs without any change in cleavage of their substrates; 2) increased cleavage DEVD (specific for caspase-3 and 7), but not YVAD (for caspase-1) or DMQD (for caspase-3), after anti-Fas/CD95 MAb treatment; 3) activation of the STAT-1 and IRF-1 pathway; and 4) partial abrogation of the IFN-gamma-induced increase in Fas-mediated apoptosis by antisense IRF-1 oligodeoxynucleotide. These results suggest that IRF-1 plays a pivotal role in the IFN-gamma-mediated-enhancement of Fas/CD95-mediated apoptosis, through regulation of DEVD-CHO-sensitive caspases, most likely caspase-7.
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PMID:Role of IRF-1 and caspase-7 in IFN-gamma enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells. 1258 35

We found that evodiamine, a major alkaloidal component of Evodiae Fructus (Goshuyu in Japan), inhibited proliferation of several tumor cell lines, but had less effect on human peripheral blood mononuclear cells (PBMC). We used human cervical cancer cells, HeLa, as a model to elucidate the molecular mechanisms of evodiamine-induced tumor cell death. The results showed that evodiamine induced oligonucleosomal fragmentation of DNA in HeLa cells and increased the activity of caspase-3, but not that of caspase-1, in vitro. Both evodiamine-induced DNA fragmentation and caspase-3 activity were effectively inhibited by a caspase-3 inhibitor, z-DEVD-fmk (z-Asp-Glu-Val-Asp-fmk). In addition, evodiamine increased the expression of the apoptosis inducer Bax, but decreased the expression of the apoptosis suppressor Bcl-2 in mitochondria. Taken together, our data indicated that evodiamine alters the balance of Bcl-2 and Bax gene expression and induces apoptosis through the caspase pathway in HeLa cells.
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PMID:Evodiamine, a constituent of Evodiae Fructus, induces anti-proliferating effects in tumor cells. 1270 81

Interferon-gamma is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN-gamma may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN-gamma differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN-gamma-induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-gamma- and Fas-mediated signaling. We found that although both cell populations exhibited a similar gene expression profile at the genome scale in response to IFN-gamma, the expression intensities of the IFN-gamma-regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN-gamma-mediated signaling, IFN consensus sequence-binding protein (ICSBP), and one involved in Fas-mediated signaling, caspase-1, were clearly shown to be differentially induced between the two cell lines. In the primary tumor cells, the expression of ICSBP and caspase-1 was strongly induced in response to IFN-gamma, whereas they were weakly to nondetectable in the metastatic tumor cells. Functional studies demonstrated that both caspase-1 and ICSBP were involved in Fas-mediated apoptosis following IFN-gamma sensitization, but proceeded via two distinct pathways. This study also reports for the first time the expression of ICSBP in a nonhemopoietic tumor exhibiting proapoptotic properties. Overall, in a human colon carcinoma cell model, we identified important functional contributions of two IFN-gamma-regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death.
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PMID:Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-gamma. 1279 66

Salvicine, a novel topoisomerase II inhibitor and a diterpenoid quinone compound, exerts potent in vitro and in vivo antitumor effects. In our study, we show that salvicine effectively kills multidrug-resistant (MDR) sublines, such as K562/A02, KB/VCR and MCF-7/ADR, and parental K562, KB and MCF-7 cell lines to an equivalent degree. These cytotoxic activities of salvicine were much more potent than those of several classical anticancer drugs (average resistance factor: 1.42 for salvicine vs. 344.35, 233.19 and 71.22 for vincristine, doxorubicin and etoposide, respectively). Flow cytometry and DNA agarose gel electrophoresis demonstrated that salvicine induced similar levels of apoptosis in MDR K562/A02 and parental cells. The compound activated caspase-1 and -3 (but not caspase-8) and increased the ratio of bax to bcl-2 mRNA via reduction of bcl-2 mRNA expression in the same cells. Furthermore, salvicine induced the downregulation of mdr-1 gene and P-gp expression but had no effect on MRP and LRP gene expression in MDR K562/A02 cells. These results suggest that the reduction of mdr-1 and bcl-2 expression by salvicine possibly contributes to its cytotoxicity and apoptotic induction in this system. The effectiveness, broad-spectrum activity and possibly novel mechanism of killing MDR tumor cells in vitro of salvicine signify promising in vivo and clinical activity. The novel chemical structure of this compound further implies a role for salvicine in future MDR tumor therapy.
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PMID:Cytotoxicity, apoptosis induction and downregulation of MDR-1 expression by the anti-topoisomerase II agent, salvicine, in multidrug-resistant tumor cells. 1279 65


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