Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence is accumulating that bile acids induce apoptosis in colonic cells. Therefore, it becomes important to study the underlying molecular mechanisms and the role of this phenomenon in tumor promotion. Minutes after exposure of HCT 116 and HT-29 cells to deoxycholate (DCA), DNA damage, measured using the COMET assay, was evident. Caspase-3 was rapidly activated in HCT 116 cells exposed to DCA, whereas in HT-29 cells, caspase-3 activation was delayed. Using transient transfections with reporter constructs, we showed that the transcription factors activator protein-1 (AP-1) and NF-kB were increased in HCT 116 cells, in a dose-dependent fashion, by DCA COX-2 promoter activity was also induced by DCA and using mutant COX-2 promoter plasmids, we showed that the ability of DCA to induce promoter activity was partly dependent upon a functional NF-kB and C/EBP site, and completely dependent on a functional c-AMP response element site. DNA damage thus appears to be the initiating event in DCA-induced apoptosis. In conclusion, the bile acid, DCA, has a major impact on apoptotic mechanisms in colonic cells and this may be contributing to its effect as a tumor promoter.
Carcinogenesis 2002 May
PMID:Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-kB and AP-1. 1201 58

Previous studies in our laboratories demonstrated that overexpression of manganese superoxide dismutase (MnSOD) suppressed both the incidence and multiplicity of papillomas in a DMBA/TPA multi-stage skin carcinogenesis model. The activity of activator protein-1 (AP-1), which is associated with tumor promotion, was reduced in MnSOD transgenic mice overexpressing MnSOD in the skin, suggesting that MnSOD may reduce tumor incidence by suppressing AP-1 activation. In the present study, we report that reduction of MnSOD by heterozygous knockout of the MnSOD gene (Sod2 -/+, MnSOD KO) increased the levels of oxidative damage proteins and the activity of AP-1 following TPA treatment. RNA levels of ornithine decarboxylase (ODC) were also increased, suggesting an increase in cell proliferation in the KO mice. Histological examination confirmed that the number of proliferating cells in DMBA/TPA-treated mouse skin were higher in the KO mice. Interestingly, histological examination also demonstrated greater numbers of apoptotic cells in the KO mice after DMBA/TPA treatment. Evidence of apoptosis, including DNA fragmentation, cytochrome c release from mitochondria, and caspase 3 activation were also observed by biochemical assays of the skin tissues. Apoptosis was associated with an increase in nuclear levels of p53 as determined by Western analysis. Quantitative immunogold ultrastructural analysis confirmed that p53 immunoreactive protein levels were increased to a greater level in the nuclei of epidermal cells from MnSOD KO mice compared to epidermal nuclei from wild type mice similarly treated. Moreover, p53 levels further increased in the mitochondria of DMBA/TPA treated mice, and this increase was much greater in the MnSOD KO than in the wild type mice, suggesting a link between MnSOD deficiency and mitochondrial-mediated apoptosis. Pathological examination reveals no difference in the incidence and frequency of papillomas comparing the KO mice and their wild type littermates. Taken together, these results suggest that: (1) MnSOD deficiency enhanced TPA-induced oxidative stress and AP-1 and p53 levels, consistent with the increase in both proliferation and apoptosis events in the MnSOD KO mice, and (2) increased apoptosis may negate increased proliferation in the MnSOD deficient mice during an early stage of tumor development.
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PMID:Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model. 1203 21

Red meat and fiber rich foods are the dietary factors most consistently related to colon carcinogenesis. Although several components in these dietary sources may contribute, the biochemical mechanism by which red meat and fiber affect colorectal carcinogenesis has not yet been established. Sphingomyelin metabolism is a novel signal transduction pathway that may have an impact on colonic tumorigenesis. The present study investigated the activity changes of sphingomyelinase (SMase), ceramidase and caspase-3 in colonic mucosa of rats fed on a high fat control diet, the control diet with beef and the control diet with fiber (cellulose). After a three week feeding period the colonic mucosa were scraped and homogenized and enzyme activities were determined. The fiber diet significantly increased the activities of neutral and acid SMases but had no effect on those of alkaline SMase and neutral ceramidase. The beef diet, on the other hand, significantly reduced neutral ceramidase activity, but had no effect on the activities of any SMase. In addition, the beef diet significantly reduced and the fiber diet increased caspase-3 activity in the colonic mucosa when compared with the control diet. The changes of caspase-3 activities were abolished by preincubating the samples with caspase-3 inhibitor. No significant changes of intestinal alkaline phosphatase could be found among the three dietary groups. In conclusion, fiber and red meat in the high fat diet affected in an opposite way the enzymes responsible for sphingomyelin metabolism and apoptosis in the colon. The effects may have implications in colorectal tumorigenesis.
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PMID:Effects of red meat and fiber in high fat diet on activities of sphingomyelinase, ceramidase and caspase-3 in rat colonic mucosa. 1216 63

Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.
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PMID:The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. 1220 Jan 39

To identify genes involved in cervical carcinogenesis, the mRNA differential display method was used. A 220-bp cDNA fragment called CA11 was present in normal cervical tissue but not in primary cervical cancer tissue or cervical cancer cell lines. CA11 exhibited 98% homology with the recorded human secreted frizzled-related protein (hsFRP) sequence. A dominant hsFRP mRNA transcript of approximately 4.6 kb was present in three normal cervical tissues examined. Expression of the transcript was nearly absent from three cervical cancer tissues and from five human cervical cancer-derived cell lines. Results from in situ hybridization showed that the hsFRP transcript was confined to the normal cervical epithelial layer. When hsFRP-transfected HeLa and CUMC-6 cervical cancer cells were cultured in serum-free medium, most of the cells died within 8 days. This effect is associated with the apoptotic process. The caspase-3 inhibitor 1, Ac-DEVD-CHO, blocked hsFRP-induced apoptotic cell death. Additionally, cleavage of poly (ADP-ribose) polymerase in hsFRP-transfected cells was confirmed by colorimetric assay. These results indicate that the hsFRP gene probably functions as a tumor suppressor in normal cervical epithelium and down-regulation of hsFRP contributes to development of cervical cancer.
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PMID:Human secreted frizzled-related protein is down-regulated and induces apoptosis in human cervical cancer. 1241 93

Grape seed extract (GSE), rich in the bioflavonoids commonly known as procyanidins, is one of the most commonly consumed dietary supplements in the United States because of its several health benefits. Epidemiological studies show that many prostate cancer (PCA) patients use herbal extracts as dietary supplements in addition to their prescription drugs. Accordingly, in recent years, we have focused our attention on assessing the efficacy of GSE against PCA. Our studies showed that GSE inhibits growth and induces apoptotic death of human PCA cells in culture and in nude mice. Here, we performed detailed studies to define the molecular mechanism of GSE-induced apoptosis in advanced human PCA DU145 cells. GSE treatment of cells at various doses (50-200 micro g/ml) for 12-72 h resulted in a moderate to strong apoptotic death in a dose- and time-dependent manner. In the studies assessing the apoptotic-signaling pathway induced by GSE, we observed an increase in cleaved fragments of caspases 3, 7 and 9 as well as PARP in GSE-treated cells after 48 and 72 h of treatment. Pre-treatment of cells with general caspases inhibitor, z-Val-Ala-Asp(OMe)-FMK or caspase 3-like proteases inhibitor [z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-FMK], almost completely (approximately 90%) inhibited the GSE-induced apoptotic cell death. In a later case, GSE-induced caspase-3 activity was completely inhibited. Selective caspase 9 inhibitor [z-Leu-Glu(OMe)-His-Asp(OMe)-FMK] showed only partial inhibition of GSE-induced apoptosis whereas GSE-induced protease activity of caspase 9 was completely inhibited. Upstream of caspase cascade, GSE showed disappearance of mitochondrial membrane potential and an increase in cytochrome c release in cytosol. Together, these results suggest that GSE possibly causes mitochondrial damage leading to cytochrome c release in cytosol and activation of caspases resulting in PARP cleavage and execution of apoptotic death of human PCA DU145 cells. Furthermore, GSE-caused caspase 3-mediated apoptosis also involves other pathway(s) including caspase 9 activation.
Carcinogenesis 2002 Nov
PMID:Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. 1241 35

We have shown that a combination of fish oil (high in n-3 fatty acids) with the butyrate-producing fiber pectin, upregulates apoptosis in colon cells exposed to the carcinogen azoxymethane, protecting against colon tumor development. We now hypothesize that n-3 fatty acids prime the colonocytes such that butyrate can initiate apoptosis. To test this, 30 Sprague-Dawley rats were provided with diets differing in the fatty acid composition (corn oil, fish oil or a purified fatty acid ethyl ester diet). Intact colon crypts were exposed ex vivo to butyrate, and analyzed for reactive oxygen species (ROS), mitochondrial membrane potential (MMP), translocation of cytochrome C to the cytosol, and caspase-3 activity (early events in apoptosis). The fatty acid composition of the three major mitochondrial phospholipids was also determined, and an unsaturation index calculated. The unsaturation index in cardiolipin was correlated with ROS levels (R = 0.99; P = 0.02). When colon crypts from fish oil and FAEE-fed rats were exposed to butyrate, MMP decreased (P = 0.041); and translocation of cytochrome C to the cytosol (P = 0.037) and caspase-3 activation increased (P = 0.032). The data suggest that fish oil may prime the colonocytes for butyrate-induced apoptosis by enhancing the unsaturation of mitochondrial phospholipids, especially cardiolipin, resulting in an increase in ROS and initiating apoptotic cascade.
Carcinogenesis 2002 Nov
PMID:Fish oil increases mitochondrial phospholipid unsaturation, upregulating reactive oxygen species and apoptosis in rat colonocytes. 1241 41

Recent clinical trials comparing concurrent chemotherapy and radiation with radiation alone in cervical cancer have shown that chemoradiation reduces the risk of death by 30-50%. Despite the clinical success, treatment responses at the cellular level are still inadequately explored. A key event in cervical carcinogenesis is the disruption of p53 tumor suppressor pathway by human papillomavirus (HPV) E6 oncogene. We found that regardless of the HPV type in SiHa (HPV 16+) CaSki (HPV 16+), HeLa (HPV 18+), and UT-DEC-1 (HPV 33+) cell lines, cisplatin, carboplatin, and a novel platinum compound, oxaliplatin, activated a p53 reporter and reduced the HPV E6 mRNA. Carboplatin and oxaliplatin treatment led also to stabilization of p53, whereas none of the platinums changed p73 levels. After irradiation (IR) alone, a decrease in HPV E6 mRNA levels and an activation of the p53-reporter were detected in SiHa, CaSki, and HeLa cells, but not in UT-DEC-1 cells. Concomitant platinum treatment and IR led to poly(ADP-ribose) polymerase cleavage as a sign of caspase-3 activation and apoptosis. Clonogenic survival was enhanced by expressing a dominant negative p53 or ectopic HPV16 E6 in SiHa and HeLa cells treated with IR, carboplatin, or oxaliplatin or with a combination of IR + carboplatin or oxaliplatin. In contrast, dominant negative p53 or ectopic HPV 16 E6 sensitized the cells to cisplatin. Pt chemotherapeutics and radiation had a synergistic cytotoxic effect as determined by Bliss independence criterion. Taken together, p53 has a significant role in the cellular response to chemoradiation treatment in cervical cancer cell lines, but p53 activity may have a dramatically different effect on cell survival depending on the platinum carrier ligand.
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PMID:Chemoradiation of cervical cancer cells: targeting human papillomavirus E6 and p53 leads to either augmented or attenuated apoptosis depending on the platinum carrier ligand. 1249 81

It has been reported that inositol hexakisphosphate (InsP(6), phytic acid), a natural product, has an anticancer role. However, there is inadequate information regarding the mechanism by which InsP(6) exerts anticancer actions, and the effect requires relatively high concentration of the agent, both of which hinders the usage of InsP(6) as an anticancer drug. In the present study, we investigated the mechanism by which InsP(6) acts as an anticancer agent, and tried to reduce the concentration of effective InsP(6). Treatment of HeLa cells with InsP(6) at 1 mM induced apoptosis, as assessed by counting the cell number, and by Hoechst and TUNEL staining. This is probably mediated by intracellular InsP(6) itself and/or the dephosphorylated forms of metabolized InsP(6), because incubation of HeLa cells with [(3)H]InsP(6) produces dephosphorylated forms such as InsP(4) and InsP(5). Induction of apoptosis by InsP(6) was examined in two ways: inhibition of cell survival signaling and direct induction of apoptosis. Treatment of HeLa cells with tumor necrosis factor (TNF) or insulin stimulated the Akt-nuclear factor kappaB (NFkappaB) pathway, a cell survival signal, which involves the phosphorylation of Akt and IkappaB, nuclear translocation of NFkappaB and NFkappaB-luciferase transcription activity. InsP(6) blocked all these cellular events, but phosphatidylinositol 3-kinase activity was not affected. As well as inhibiting the Akt-NFkappaB pathway, InsP(6) itself caused mitochondrial permeabilization, followed by cytochrome c release, which later caused activation of the apoptotic machinery, caspase 9, caspase 3 and poly (ADP-ribose) polymerase. When InsP(6) was applied together with histone, the effective concentration to induce apoptosis was approximately 10-fold lower. These results revealed that extracellularly applied InsP(6) directly activates the apoptotic machinery as well as inhibits the cell survival signaling, probably by the intracellular delivery followed by a dephosphorylation.
Carcinogenesis 2002 Dec
PMID:Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFkappaB-mediated cell survival pathway. 1250 26

Evidence from live cell bioassays shows that the flat mucosa from patients with colon cancer exhibits resistance to bile salt-induced apoptosis. Three independent cell lines derived from the colonic epithelial cell line HCT-116 were selected for resistance to bile salt-induced apoptosis. These cell lines were developed as tissue culture models of apoptosis resistance. Selection was carried out for resistance to apoptosis induced by sodium deoxycholate (NaDOC), the bile salt found in highest concentrations in human fecal water. Cultures of HCT-116 cells were serially passaged in the presence of increasing concentrations of NaDOC. The resulting apoptosis resistant cells were able to grow at concentrations of NaDOC (0.5 mM) that cause apoptosis in a few hours in unselected HCT-116 cells. These cells were then analyzed for changes in gene expression. Observations from cDNA microarray, 2-D gel electrophoresis/MALDI-mass spectroscopy, and confocal microscopy of immunofluorescently stained preparations indicated underexpression or overexpression of numerous genes at either the protein or mRNA level. Genes that may play a role in apoptosis and early stage carcinogenesis have been identified as upregulated in these cell lines, including Grp78, Bcl-2, NF-kappaB(p50), NF-kappaB(p65), thioredoxin peroxidase (peroxiredoxin) 2, peroxiredoxin 4, maspin, guanylate cyclase activating protein-1, PKCzeta, EGFR, Ras family members, PKA, PI(4,5)K, TRAF2 and BIRC1 (IAP protein). Under-expressed mRNAs included BNIP3, caspase-6, caspase-3 and serine protease 11. NF-kappaB was constitutively activated in all three resistant cell lines, and was responsible, in part, for the observed apoptosis resistance, determined using antisense oligonucleotide strategies. Molecular and cellular analyses of these resistant cell lines has suggested potential mechanisms by which apoptosis resistance may develop in the colonic epithelium in response to high concentrations of hydrophobic bile acids that are associated with a Western-style diet. These analyses provide the rationale for the development of hypothesis-driven intermediate biomarkers to assess colon cancer risk on an individual basis.
Carcinogenesis 2002 Dec
PMID:Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. 1250 30


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