Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2) expression and certain growth hormones, such as gastrin, have been related to gastric carcinogenesis, but little is known about the factors that enhance this COX-2 expression and whether specific blockade of this enzyme has any influence on tumor growth and progression. Our objective was to determine the influence of a specific COX-2 inhibitor, rofecoxib (Vioxx), on serum and tumor levels of gastrin and its precursor, progastrin, as well as on tumor gene expression of COX-2, peroxisome proliferator-activated receptor gamma (PPARgamma), and apoptosis-related proteins (Bax and Bcl-2, caspase-3, and survivin). Twenty-four gastric cancer (GC) patients entered this study and were examined twice, once before and then following a 14-day treatment with Vioxx at a dose of 25 mg twice daily. For comparison, 48 age- and sex-matched healthy controls and 24 similarly matched Helicobacter pylori (Hp)-positive subjects were enrolled and treated with Vioxx as GC patients. Serum levels of anti-Hp and anti-CagA antibodies as well as IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA), while serum and tumor contents of progastrin and amidated gastrin were determined by specific RIA. Tumor gene and protein expressions of COX-2, PPARgamma, Bax and Bcl-2, caspase-3, and survivin were determined by RT-PCR and western blot. The overall Hp and CagA seropositivity in 24 GC patients was significantly higher (82% and 47%) than in 48 controls (61% and 22%) but not in 24 Hp-infected subjects (100% and 38%). Serum IL-8 and TNF-alpha values were significantly higher in GC patients than in controls without GC or Hp-infected controls. Median serum progastrin and gastrin levels were found to be significantly higher in GC than in controls without GC and in Hp-positive subjects. Treatment of GC patients with Vioxx resulted in a significant decrease in plasma and tumor contents of both progastrin and gastrin, and this was accompanied by the increment in tumor expression of COX-2, PPARy, Bax, and caspase-3 with a concomitant reduction in Bcl-2 and survivin expression. We conclude that: (1) GC patients show significantly higher Hp and CagA seropositivity than age- and sex-matched controls, but not Hp-positive subjects, indicating that infection with cytotoxic Hp is linked to GC. (2) Serum progastrin and gastrin levels are significantly higher in GC patients than in matched controls, confirming that both gastrins may be implicated in gastric carcinogenesis. (3) GC patients exhibit significantly higher levels of IL-8 and TNF-alpha than non-GC controls and Hp-positive subjects, probably reflecting more widespread gastritis in GC. (4) COX-2, PPARgamma, Bcl-2, and survivin were overexpressed in gastric tumor, but the inhibition of COX-2 activity by Vioxx resulted in a significant reduction in serum and tumor levels of progastrin and gastrin and serum IL-8 and TNF-alpha levels, suggesting that gastrin and proinflammatory cytokines could mediate the up-regulation of COX-2 in gastric cancerogenesis. (5) Vioxx also enhanced expression of COX-2, PPARy, Bax, and caspase-3, while inhibiting the expression of Bcl-2 and survivin, suggesting that COX-2 blockade might be useful in chemoprevention against gastric cancer possibly due to enhancement of the PPARy- and proapoptotic proteins-dependent apoptosis and the reduction in progastrin/gastrin-induced promotion of tumor growth.
 ...
PMID:Influence of COX-2 inhibition by rofecoxib on serum and tumor progastrin and gastrin levels and expression of PPARgamma and apoptosis-related proteins in gastric cancer patients. 1462 49

Both heme oxygenase-1 (HO-1) and p21(WAF1/Cip1) (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NF-kappaB and the inhibition of NF-kappaB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK- and ERK-mediated pathway with elevated c-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-kappaB.
 ...
PMID:Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells. 1464 39

Survivin, a member of the inhibitor-of-apoptosis family, inhibits apoptosis by blocking caspase-3 and -7 activation. Gastric cancer, which is among the most intractable of malignant tumors, is known for resistance to various drugs, including cis-diamminedichloroplatinum (CDDP). Since this agent induces apoptosis via caspase-3 activation, survivin may mediate the drug resistance. We investigated survivin messenger RNA (mRNA) expression in gastric cancers and the relationship between expression and sensitivity to CDDP. Expression of the survivin gene was significantly up-regulated in gastric cancers compared to the tissues of normal mucosa, atrophic gastritis, and intestinal metaplasia (P < 0.0001) as assessed by a quantitative reverse transcription-polymerase chain reaction (RT-PCR), and was negatively associated with overall survival of patients who received CDDP-based chemotherapy. To investigate whether survivin is a resistance factor against CDDP-induced apoptosis, we transfected wild-type and dominant-negative mutants of the survivin gene into gastric cancer cells using a lipofection method. Overexpression of survivin protected MKN45 cells from CDDP-induced apoptosis. Expression of the dominant-negative mutant of the survivin gene sensitized NUGC-3 cells to drug-induced apoptosis. These results indicate that survivin may be pivotal in the development of gastric cancer and resistance to CDDP, and therefore controlling expression of the survivin gene may be therapeutically useful.
 ...
PMID:Survivin as a predictor of cis-diamminedichloroplatinum sensitivity in gastric cancer patients. 1472 Mar 26

The aim of this study was to investigate the mechanism of cell death by photodynamic therapy (PDT) in the gastric cancer cell line MKN45 with focus on the mechanism of apoptosis. Gastric cancer cells (MKN45) were incubated with Photofrin for up to 24 h before exposure to He-Cd laser (441 nm, 1 J/cm2). Cell viability was assessed by the methyl-tetra-zolium assay after exposure to light. A 95% cell death (LD95) was measured with 10 microg/ml of Photofrin. DNA ladder formation and chromatin condensation were seen within 60 min. Caspase-3-like and caspase-9-like activities increased from 15 min after exposure to light. Reduction of rhodamine 123 uptake started at 30 min. Caspase-inhibitor VAD-fmk (10 mM) inhibited apoptosis, but did not influence cell viability. In conclusion, Photofrin-mediated PDT in the gastric cancer cell line MKN45 induces apoptosis within 60 min, and mitochondrial damage is likely as the first event of apoptosis.
 ...
PMID:Apoptosis of gastric cancer cell line MKN45 by photodynamic treatment with photofrin. 1533 43

We performed this study to understand the molecular basis underlying the antitumor effects of Saussurea lappa, Pharbitis nil, Plantago asiatica and Taraxacum mongolicum, which have been used for herbal medicinal treatments against cancers in East Asia. We analyzed the effects of these medicinal herbs on proliferation and on expression of cell growth/apoptosis related molecules, with using an AGS gastric cancer cell line. The treatments of Saussurea lappa and Pharbitis nil dramatically reduced cell viabilities in a dose and time-dependent manner, but Plantago asiatica and Taraxacum mongolicum didn't. FACS analysis and Annexin V staining assay also showed that both Saussurea lappa and Pharbitis nil induce apoptotic cell death of AGS. Expression analyses via RT-PCR and Western blots revealed that Saussurea lappa, but not Pharbitis nil, increased expression of the p53 and its downstream effector p21Waf1, and that the both increased expression of apoptosis related Bax and cleavage of active caspase-3 protein. We also confirmed the translocation of Bax to mitochondria. Collectively, our data demonstrate that Saussurea lappa and Pharbitis nil induce growth inhibition and apoptosis of human gastric cancer cells, and these effects are correlated with down- and up-regulation of growth-regulating apoptotic and tumor suppressor genes, respectively.
 ...
PMID:Induction of apoptosis by Saussurea lappa and Pharbitis nil on AGS gastric cancer cells. 1546 4

LDOC1 was isolated as a gene encoding a leucine-zipper protein whose expression was decreased in pancreatic and gastric cancer cell lines in 1999. Here, we found that overexpression of LDOC1 caused externalization of the cell membrane phosphatidylserine, which was characteristic for early-phase apoptotic events, and reduced cell viability in some human cell lines. The apoptotic process was triggered by a loss of the mitochondrial membrane potential, leading to both caspase-3-dependent and -independent pathways. Furthermore, a transcription factor, MZF-1, was revealed to interact with LDOC1 and enhance the activity of LDOC1 for inducing apoptosis.
 ...
PMID:LDOC1, a novel MZF-1-interacting protein, induces apoptosis. 1567 Aug 15

Expression of an interferon inducible gene 6-16, G1P3, increases not only in type I interferon-treated cells but also in human senescent fibroblasts. However, the function of 6-16 protein is unknown. Here we report that 6-16 is 34 kDa glycosylated protein and localized at mitochondria. Interestingly, 6-16 is expressed at high levels in gastric cancer cell lines and tissues. One of exceptional gastric cancer cell line, TMK-1, which do not express detectable 6-16, is sensitive to apoptosis induced by cycloheximide (CHX), 5-fluorouracil (5-FU) and serum-deprivation. Ectopic expression of 6-16 gene restored the induction of apoptosis and inhibited caspase-3 activity in TMK-1 cells. Thus 6-16 protein has anti-apoptotic function through inhibiting caspas-3. This anti-apoptotic function is expressed through inhibition of the depolarization of mitochondrial membrane potential and release of cytochrome c. By two-hybrid screening, we found that 6-16 protein interacts with calcium and integrin binding protein, CIB/KIP/Calmyrin (CIB), which interacts with presenilin 2, a protein involved in Alzheimer's disease. These protein interactions possibly play a pivotal role in the regulation of apoptosis, for which further detailed analyses are need. These results overall indicate that 6-16 protein may have function as a cell survival protein by inhibiting mitochondrial-mediated apoptosis.
 ...
PMID:G1P3, an interferon inducible gene 6-16, is expressed in gastric cancers and inhibits mitochondrial-mediated apoptosis in gastric cancer cell line TMK-1 cell. 1568 48

X-linked inhibitor of apoptosis (XIAP) is the most potent member of the inhibitor of apoptosis protein (IAP) gene family in terms of its ability to inhibit caspases and suppress apoptosis. Recent evidence has suggested that XIAP is a key determinant in chemoresistance of cancer cells. To explore a novel approach for ameliorating chemotherapy of gastric cancer, the antisense expression vector for the XIAP gene was constructed and transferred into gastric cancer cell lines, MKN-45 (wild-type p53) and MKN-28 (mutant-type p53). This transfer resulted in significant downregulation of XIAP expression, decreased in vitro cell viabilities, and induced apoptosis. In transferred cells, inactive caspase-3 precursors were cleaved into the active subunits (p20 and p17) during apoptosis induced by downregulation of XIAP. The inhibitory effects of cisplatin and mitomycin C on the growth of XIAP downregulated cancer cells were significantly enhanced. In addition, this process occurred only in wild-type p53 (MKN-45), but not in mutant-type p53 (MKN-28) gastric cancer cells. The data presented suggest that downregulation of XIAP via antisense RNA can lead to apoptosis of gastric cancer cells in vitro, correlating with cellular p53 status and activation of caspase-3. This finding could lead to a potential strategy for improving the efficiency of therapies for gastric cancer.
 ...
PMID:Downregulation of XIAP expression induces apoptosis and enhances chemotherapeutic sensitivity in human gastric cancer cells. 1570 55

Citrus fruits have been known to reduce the proliferation of many cancer cells. The antiproliferative effects of Citrus reticulata Blanco (CR) extract, the immature tangerine peel, on human gastric cancer cell line SNU-668 were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 4,6-diamidineo-2-phenylindole staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, reverse transcription-polymerase chain reaction expressions of BCL-2, BAX and CASP-3 genes, caspase-3 activity, and immunocytochemistry of caspase-3. From the results of the morphological and biochemical assays, CR (50 microg/ml) increased the apoptosis of human gastric cancer cells with typical apoptotic characteristics, including morphological changes of chromatin condensation and apoptotic body formation. CR (50 microg/ml) reduced the expression of BCL-2, whereas the expression of BAX and CASP-3 was increased compared with the control group. Furthermore, caspase-3 activity and caspase-3 protein expression in the CR-treated group was significantly increased compared with that in control group. These results suggest that CR may induce the apoptosis through the caspase-3 pathway in human gastric cancer cells.
 ...
PMID:Citrus Reticulata blanco induces apoptosis in human gastric cancer cells SNU-668. 1574 33

The death receptors Fas and DR5 are known to be expressed not only in immune cells but also in various tumor cells. The aim of the present study was to determine whether X irradiation enhanced induction of apoptosis in Tp53 wild type and Tp53-mutated tumor cell lines treated with agonists against these death receptors. We showed that 5 Gy of X irradiation significantly up-regulated the expression of death receptors Fas and DR5 on the plasma membrane in gastric cancer cell lines MKN45 and MKN28, lung cancer cell line A549, and prostate cancer cell line DU145, and that subsequent treatments with agonistic molecules for these death receptors, Fas antibody CH11 and TRAIL, increased the formation of active fragment p20 of caspase 3 followed by the induction of apoptosis. This death-receptor-mediated apoptosis was independent of Tp53 status since MKN28 and DU145 were Tp53-mutated. The post-irradiation treatment of the cells with N-acetyl-L-cysteine (NAC) abolished the up-regulation of the expression of Fas and DR5 on the plasma membrane. NAC also attenuated the increase in the formation of p20 and the induction of apoptosis by agonistic molecules. These results suggested that the increase in the induction of apoptosis by combined treatment with X irradiation and CH11 or TRAIL occurred through a change of the intracellular redox state independent of Tp53 status in human carcinoma cell lines.
 ...
PMID:Enhanced induction of apoptosis by combined treatment of human carcinoma cells with X rays and death receptor agonists. 1580 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>