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)

Benzo(a)pyrene (BaP), a prototype of polycyclic aromatic hydrocarbons (PAHs), is a potent procarcinogen generated during the combustion of fossil fuels and cigarette smoke. In addition to the carcinogenic and mutagenic effects, BaP and other PAHs, including 7,12-dimethylbenz[a]anthracene and 2,3,7,8-tetrachlorodibenzo[p]dioxin, have been shown to induce programmed cell death or apoptosis. However, the molecular mechanisms by which PAHs such as BaP induce apoptosis are not clear. To investigate the molecular events leading to apoptosis induced by BaP, we studied the involvement of the interleukin 1beta-converting enzyme (ICE)/Ced-3 family of proteases (caspases) and c-Jun NH2-terminal kinase 1 (JNK1), which have been shown to mediate numerous extracellular stimuli-induced apoptosis. On treatment of mouse Hepa 1c1c7 hepatoma cells with BaP, the induction of apoptosis, as determined by genome digestion, was observed at concentrations of 1-30 microM after 24 h of treatments. Importantly, at the apoptosis-inducing concentrations, BaP also induced the activation of an ICE/Ced-3 cysteine protease caspase-3 but not caspase-1 (ICE). The activation of caspase-3 by BaP preceded apoptosis. Furthermore, a specific inhibitor of caspase-3-like proteases, acetyl-Asp-Glu-Val-Asp-aldehyde, significantly blocked caspase-3 activity and attenuated apoptosis induced by BaP. Treatment with BaP also caused a time- and dose-dependent activation of JNK1 activity. Interestingly, a much lower concentration (5 nM), as well as much earlier kinetics, were observed in JNK1 activation as compared with caspase-3 activation or induction of apoptosis by BaP. In summary, our results demonstrate that BaP induced apoptosis in the mouse hepatoma Hepa1c1c7 cell line via a caspase-dependent pathway, which may be independent of JNK activation.
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PMID:Induction of apoptosis and activation of interleukin 1beta-converting enzyme/Ced-3 protease (caspase-3) and c-Jun NH2-terminal kinase 1 by benzo(a)pyrene. 960 52

Recently, we described a new in vivo pathway in the metabolism of benzo[a]pyrene (BP) that involves an opening of the aromatic ring system. One of the products of this pathway, isolated from rat urine, was the anhydride of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid (ABADA). We have now investigated the effect of ABADA on several cellular targets, known to be important in tumor formation. ABADA was as efficient as BP-7,8-diol-9,10-epoxide in inducing direct strand breaks but not alkali labile sites in DNA in HT-29 cells and exhibited weak mutagenic activity in Salmonella typhimurium strain TA 102. The cytotoxicity of ABADA to HCT 116 cells appeared to be due to apoptosis, as caspase-3 activity and poly-ADP-ribose polymerase (PARP) cleavage was observed. COX-2 promoter activity was induced by ABADA in HCT 116 cells. In conclusion, this novel metabolic pathway may also be contributing to the carcinogenicity of BP.
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PMID:Toxicological characterization of a novel in vivo benzo[a]pyrene metabolite, 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid anhydride. 1238 25

We employed cDNA microarray analysis to identify, in mammary adenocarcinomas induced by 7,12-dimethylbenz[a] anthracene (DMBA) in the rat, target genes as potential biomarkers for cancer chemoprevention by 1,4-phenylenebis(methylene)selenocyanate (p-XSC). Confirmation of selected genes was conducted by reverse transcription polymerase chain reactions (RT-PCR). The glutathione conjugate, p-XSeSG, a putative metabolite of p-XSC was also employed to test our hypothesis that p-XSeSG is a more effective cancer chemopreventive agent in the mammary cancer model than p-XSC. Mammary adenocarcinomas were induced by a single oral administration of 5 mg DMBA in 0.2 ml olive oil per rat at 50-55 days of age. Consistent with our previous reports, dietary p-XSC at a non-toxic dose (10 p.p.m. as selenium) significantly inhibited adenocarcinoma development, independent of feeding duration. Moreover, p-XSeSG appears to be just as effective as p-XSC when fed after DMBA administration, but was significantly less effective than p-XSC in inhibiting the induction of mammary adenocarcinomas when it was fed before DMBA and continued until termination. To delineate the molecular basis for cancer chemoprevention by organoselenium compounds, we focused our analysis on differential expression of genes known to be involved in DMBA metabolism, as well as those related to cell cycle, cell proliferation and apoptosis. p-XSC and p-XSeSG were significantly and equally effective in inhibiting levels of expression of genes associated with cytochrome P450 isoforms, but the former was more active than the latter in up-regulating the expression of those related to certain phase II enzymes. p-XSC and p-XSeSG were significantly more effective in the up-regulation of pro-apoptotic genes, such as p21CIP1/WAF1, p27KIP1, APO-1 and Caspase-3, while down-regulating cell growth regulatory genes, such as c-myc, cyclin D1, cyclin D2 and proliferating cell nuclear antigen (PCNA). To our knowledge, this is the first report that provides insights into the effects of p-XSC and p-XSeSG at the molecular level that may account for mammary cancer chemoprevention in vivo in the rat.
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PMID:Elucidation of molecular targets of mammary cancer chemoprevention in the rat by organoselenium compounds using cDNA microarray. 1284 80

Induction of apoptosis is an approach to suppress carcinogenesis. The effects of a 12-week treatment of female Sprague-Dawley rats with indole-3-carbinol (I3C), beta-naphthoflavone or vehicle (40% ethanol in corn oil), by oral gavages starting 3 weeks after initiation of mammary tumorigenesis with 7,12-dimethylbenz[alpha]anthracene, on apoptotic activities in the mammary adenocarcinomas were examined. Apoptotic cells in tumor sections were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and quantitated by light microscopy and an Image-Plus Program. Activities of caspase-3, caspase-8 and caspase-9 were determined by colorimetric assays using the specific substrate and total tumor protein. There were no significant treatment-related effects on the numbers of apoptotic cells and caspase activities in the mammary adenocarcinomas. Likewise, protein expression levels of Bcl-2 and Bax genes in these tumors, determined by Western blot analysis, showed no treatment-related stimulation of apoptotic process. In the absence of tumorigenesis, the activities of caspase-3, caspase-8 and caspase-9 were increased up to approximately 3.6-fold in the mammary gland of rats treated with I3C at 5 or 25 mg/kg of body weight for 4 or 10 days. The I3C-effected induction of caspase-3 activity in the mammary gland was further confirmed by the cleavage of poly (ADP-ribose) polymerase. Treatment of rats with 3,3'-diindolylmethane, a major product of I3C in vivo, at the dose levels equimolar to those of I3C above, did not increase the caspase activities in the mammary gland. Thus, this I3C dimer does not seem to account for the increases of apoptotic activities in the mammary gland observed with I3C. The results suggest that increase of apoptosis in the mammary gland induced by I3C before initiation of tumorigenesis may contribute to suppression of tumor development.
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PMID:Effects of treatment of rats with indole-3-carbinol on apoptosis in the mammary gland and mammary adenocarcinomas. 1289 30

This study examined the effects of variety and quantity of dietary fat consumed by rats during pregnancy and lactation on female offspring's response to chemically induced mammary cancer. Groups of six female rats were fed diets containing 7% corn oil (7-CO), 15% CO (15-CO), 7% olive oil (7-OO), or 15% OO (15-OO) for 5 wk prior to, and during, pregnancy and lactation. Female offspring (n = 15 per group) were fed a 7-CO diet, and mammary cancer was induced with 7,12-dimethylbenz[a]anthracene (DMBA). Three months following cancer induction tumor incidence and size were recorded, and markers of apoptosis, serum estrogen concentrations, and hepatic phase II enzymes were measured. Tumor incidence was 47% in offspring born to mothers fed the 7-OO diet, rose to 67% in 7-CO and 15-OO offspring, and reached 86% in 15-CO. A trend toward smaller tumors was observed in the 7-OO group, and offspring of mothers fed high-fat diets had significantly more tumors. Estradiol levels at the end of lactation were significantly lower in mothers fed 7-OO but were similar in all groups of offspring. In tumor tissue, Bcl-2 expression was highest in the 15-CO offspring, and Bak expression was significantly higher in rats exposed to OO. A distinct trend toward increased caspase-3 expression (20 kDa) was observed in the 7-OO offspring, and both low-fat diets significantly elevated caspase activity. In healthy mammary tissue, rats exposed to low-fat diets had significantly higher caspase-3 (32-kDa) levels, and caspase-3 activity was significantly higher in the healthy tissue from both OO groups. Hepatic quinone reductase activity was significantly lower in offspring of mothers fed the low-fat diets. These results indicate that perinatal exposure to OO may have a protective effect against future development of mammary cancer in female offspring, whereas high-fat diets fed to pregnant and lactating rats, in particular CO, may be deleterious.
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PMID:Olive oil consumption during pregnancy and lactation in rats influences mammary cancer development in female offspring. 1292 5

The role of peroxisome proliferator-activated receptor-beta (PPARbeta) in the molecular regulation of skin carcinogenesis was examined. Increased caspase-3 activity associated with apoptosis was found in the skin of wild-type mice after tumor promotion with 12-O-tetradecanoylphorbol-13-acetate, and this effect was diminished in PPARbeta-null mice. The onset of tumor formation, tumor size, and tumor multiplicity induced from a two-stage carcinogen bioassay (7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate) were significantly enhanced in PPARbeta-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPARbeta-dependent phenotype, microarray analysis was performed and a number of differentially regulated gene products were identified including ubiquitin C. Subsequent promoter analysis, reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays provide evidence that PPARbeta regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPARbeta. These results strongly suggest that activation of PPARbeta-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis.
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PMID:Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis. 1503 75

Inhibition or deletion of cyclooxygenase (COX)-2 has been demonstrated to protect against squamous cell cancer in many studies. Although much effort has focused on COX-2 inhibition, recent work indicates that COX-1 deletion may be nearly as protective. In this study, we used SKH-1 hairless mice in which COX-1 was selectively deleted to examine the role of COX-1 in photocarcinogenesis. After UV exposure, 40-60% less prostaglandin E2 was detected in COX-1-/- animals compared with wild-type (WT) controls. A 4-fold induction of keratinocyte apoptosis was observed in knockouts relative to WT animals, as documented by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and caspase-3 staining. Proliferation was not significantly different in COX-1+/+, COX-1+/-, and COX-1-/- animals. When susceptibility to UV-induced tumor formation was studied, tumor number, average tumor size, and time of tumor onset in COX-1-/- animals were identical to WT controls. Thus, enhanced apoptosis did not alter UV-induced skin carcinogenesis, suggesting other effects are key to nonsteroidal anti-inflammatory drug chemoprevention. These results contrast sharply with data obtained using the classic 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate cancer model in which a prominent protective effect of COX-1-/- is present. The lack of protection observed here confirms cancer mechanisms are distinct in UV- and tumor promotor-induced cancer models and indicates that chemoprevention strategies must specifically address cancer causes to be effective.
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PMID:Cyclooxygenase-1 deletion enhances apoptosis but does not protect against ultraviolet light-induced tumors. 1531 95

Glutamine (GLN) is a non-essential amino acid that is present in nearly every biochemical pathway and is the major intraorgan nitrogen carrier. GLN via glutamate, is one of the precursors for the synthesis of glutathione (GSH), the major endogenous antioxidant in mammalian cells, which protects them from oxidative injury and cell death. Cancer cells have higher GSH levels than the surrounding normal cells, which attributes to a higher rate of cell proliferation and resistance to chemotherapy. Therefore, selective tumor depletion of GSH presents a promising strategy in cancer treatment. Experimental studies have associated decreased GSH levels with inhibition of proliferation and stimulation of apoptosis. Previous results of our laboratory have provided evidence that dietary GLN diminished tumor development in implantable as well as 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer and elevated GSH in the host tissues. In this study we examined the effects of GLN on GSH levels in DMBA-induced mammary tumors and correlated the results with protein and mRNA expression of apoptosis-related proteins Bcl-2, Bax and caspase-3 in tumor cells. The results have shown that GLN supplementation caused a significant decrease in the tumor GSH levels and the ratio GSH/oxidized GSH (GSSG), accompanied by up-regulation of Bax and caspase-3, and down-regulation of Bcl-2. These findings suggest that dietary GLN supplementation suppresses mammary carcinogenesis by activation of apoptosis in tumor cells and this probably is a result of GSH down-regulation.
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PMID:Effect of dietary glutamine on tumor glutathione levels and apoptosis-related proteins in DMBA-induced breast cancer of rats. 1560 27

In this study, dietary modulation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced adrenal toxicity in rats was investigated. Beginning at postnatal day (PND) 21, female Sprague-Dawley rats were fed either soy-containing NIH-31 diet or soy- and alfalfa-free 5K96 diet. On the first day of diestrus when the animals were PND 50 +/- 5, rats received either an oral dose of 80 mg/kg DMBA or sesame oil, the vehicle, and were sacrificed at 24, 36, or 48 h after treatment. Apoptosis was manifested at 24 and 36 h after DMBA treatment in the zona reticularis (ZR) and the zona fasciculata (ZF) of the adrenal cortex; this was followed by severe hemorrhagic necrosis at 48 h. DMBA-induced apoptosis, evaluated by the TUNEL assay, immunohistochemical analysis of activated caspase 3, and the ratio of expression of pro-apoptotic Bax to anti-apoptotic Bcl2, was greater in rats fed NIH-31 diet relative to rats fed 5K96 diet at 24 h after treatment. Four of six DMBA-treated rats fed 5K96 diet had severe adrenal necrosis by 48 h, whereas this lesion was present in only two of six DMBA-treated rats fed NIH-31 diet. DMBA also caused a significant decrease of serum corticosterone relative to controls at 48 h in rats fed 5K96 diet. The present study indicated that diet modulates DMBA-induced adrenal toxicity in female rats, with increased apoptosis early and reduced necrosis later in rats fed a soy-containing diet.
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PMID:Dietary modulation of 7,12-dimethylbenz[a]anthracene (DMBA)-induced adrenal toxicity in female Sprague-Dawley rats. 1577 17

Programmed cell death is a critical process in B lymphocyte development. Premature apoptosis in developing B cells could affect the repertoire and number of mature B cells produced. Of particular concern is the ability of environmentally ubiquitous polycyclic aromatic hydrocarbons (PAH) to induce B cell apoptosis within the bone marrow microenvironment in a clonally nonspecific way. Here, models of bone marrow B cell development were used to assess the role of the "extrinsic" apoptosis pathway in PAH-induced apoptosis and to compare PAH-induced apoptosis with that induced during clonal deletion. As demonstrated previously with a nontransformed pro-/pre-B cell line, primary pro-B cells cultured on bone marrow stromal cells underwent apoptosis after exposure to a prototypic PAH, 7,12-dimethylbenz[a]anthracene (DMBA). Apoptosis was preceded by cleavage of caspase-3 (4-6 h) and caspase-8 (6-8 h) and their respective substrates, alpha-fodrin and Bid. Inhibition of caspase-3 blocked caspase-8 activation and apoptosis. Furthermore, a pan-caspase inhibitor blocked apoptosis and activation of both caspases-3 and -8. Cells from mice defective in tumor necrosis factor (TNF)-alpha, TNF-beta, lymphotoxin-beta, or TNFR1, TNFR2, Fas, or death receptor 6 were as susceptible to apoptosis signaling as wild-type cells. These results suggest a complex death receptor-independent B cell apoptosis pathway in which caspase-8 is activated downstream of caspase-3.
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PMID:Environmental chemical-induced bone marrow B cell apoptosis: death receptor-independent activation of a caspase-3 to caspase-8 pathway. 1601 77


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