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)

Anticancer effects of the dietary isothiocyanate sulforaphane were investigated in the human pancreatic cancer cell lines MIA PaCa-2 and PANC-1. Sulforaphane-treated cells accumulated in metaphase as determined by flow cytometry [4C DNA content, cyclin A(-), cyclin B1(+), and phospho-histone H3 (Ser(10))(+)]. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-8, loss of mitochondrial membrane potential, and loss of plasma membrane integrity. The initial detection of caspase-3 cleavage occurring in G(2)-M arrest was independent of a change in phospho-cdc2 (Tyr(15)) protein; consequently, sulforaphane treatment combined with UCN-01 had no significant impact on cellular toxicity. Incubations at higher sulforaphane doses (>10 micromol/L) resulted in cleavage of caspase-3 in the G(1) subpopulation, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Cellular toxicity in MIA PaCa-2, and to a greater extent in PANC-1, was positively correlated with a decrease in cellular glutathione levels, whereas sustained increases in glutathione observed in MIA PaCa-2 cells or the simultaneous incubation with N-acetyl-L-cysteine in PANC-1 cells were associated with resistance to sulforaphane-induced apoptosis. Daily sulforaphane i.p. injections (375 micromol/kg/d for 3 weeks) in severe combined immunodeficient mice with PANC-1 s.c. tumors resulted in a decrease of mean tumor volume by 40% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have activity in established pancreatic cancer.
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PMID:The dietary isothiocyanate sulforaphane targets pathways of apoptosis, cell cycle arrest, and oxidative stress in human pancreatic cancer cells and inhibits tumor growth in severe combined immunodeficient mice. 1548 91

Pancreatic cancer remains a highly chemoresistant malignancy. Gemcitabine, the most effective first-line agent available, acts by disrupting cellular replication. Caspases belong to a family of proteases that function as key components of the apoptotic death machinery. We investigated the mechanisms by which gemcitabine blocks proliferation and whether it can induce apoptosis in pancreatic cancer cells. Quiescent pancreatic cancer cells (BxPC-3) were stimulated to proliferate (10% fetal calf serum) with or without gemcitabine, PS-341 (26S proteasome inhibitor), or both. Proliferation was measured by MTT assay and apoptosis by propidium iodine staining. To determine activation of the apoptotic regulatory cell proteins, caspase-3 and cleavage of poly(ADP-ribose)polymerase (PARP) into its 85-kDa fragment were assessed by Western blotting. Gemcitabine at even low doses (10 micromol/L) significantly inhibited cellular proliferation, whereas PS-341 (10 nmol/L) had no effect. With combined treatment, PS-341 potentiated the antiproliferative effects of gemcitabine (P=0.001). At 48 hours, the apoptotic fraction was greatly enhanced by the presence of PS-341 compared with gemcitabine alone. Caspase-3 accumulated as early as 30 minutes and was associated with cleavage of PARP to its apoptotic fragment. Gemcitabine, a nucleoside analogue, may in part exert its antiproliferative effects by directing pancreatic cancer cells to a default pathway of apoptosis. 26S proteasome inhibition potentiates this effect, suggesting its potential clinical value against chemoresistance in pancreatic cancer.
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PMID:Caspase-3 drives apoptosis in pancreatic cancer cells after treatment with gemcitabine. 1558 96

Recently we observed that pancreatic carcinoma cell lines constitutively express Interleukin-18 (IL-18). Bioactive IL-18 induces Interferon (IFN)-gamma production, Fas Ligand (FasL) expression, and inhibits angiogenesis, raising the issue of anti-tumor effects of a tumor-derived cytokine and motivating a more detailed analysis of IL-18 production in pancreatic carcinoma cells. This analysis included the study of effects of chemotherapeutic drugs (5-fluorouracil [5-FU], gemcitabine, cisplatin) commonly used in the treatment of pancreatic cancer patients on IL-18 production and processing. IL-18 expression and post-translational processing were determined using RT-PCR, immunoblot and ELISA in pancreatic carcinoma cell lines and in tumor tissue and serum samples from pancreatic carcinoma patients in the presence and absence of chemotherapeutic drugs. We describe expression of IL-18 in pancreatic carcinoma cells and tissues associated with significantly elevated IL-18 levels in patients sera. Specifically, Capan-2 pancreatic tumor cells produced and secreted precursor IL-18 with no apparent biological activity. However, the chemotherapeutic agent 5-FU, by inducing Caspase-1 and Caspase-3 activation, induced secretion of proteolytically processed mature and degraded IL-18 species, respectively, in Capan-2 cells. Conditioned medium from 5-FU-treated but not control Capan-2 cells induced IFN-gamma production by activated T cells in an IL-18-dependent manner. Furthermore, adjuvant polychemotherapy including 5-FU significantly increased serum levels of mature, bioactive IL-18 in pancreatic carcinoma patients. Treatment of pancreatic cancer cells with 5-FU induced Caspase-dependent processing of pro-IL18 leading to the secretion of biologically active IL-18. These findings delineate a novel mechanism by which chemotherapeutic agents may modulate local anti-tumor cell-mediated immune responses.
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PMID:Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: implications for anti-tumor immune response. 1568 7

Polyphenols such as epigallocatechin-3-gallate (EGCG) from green tea extract can exert a growth-suppressive effect on human pancreatic cancer cells in vitro. In pursuit of our investigations to dissect the molecular mechanism of EGCG action on pancreatic cancer, we observed that the antiproliferative action of EGCG on pancreatic carcinoma is mediated through programmed cell death or apoptosis as evident from nuclear condensation, caspase-3 activation and poly-ADP ribose polymerase (PARP) cleavage. EGCG-induced apoptosis of pancreatic cancer cells is accompanied by growth arrest at an earlier phase of the cell cycle. In addition, EGCG invokes Bax oligomerization and depolarization of mitochondrial membranes to facilitate cytochrome c release into cytosol. EGCG-induced downregulation of IAP family member X chromosome linked inhibitor of apoptosis protein (XIAP) might be helpful to facilitate cytochrome c mediated downstream caspase activation. On the other end, EGCG elicited the production of intracellular reactive oxygen species (ROS), as well as the c-Jun N-terminal kinase (JNK) activation in pancreatic carcinoma cells. Interestingly, inhibitor of JNK signaling pathway as well as antioxidant N-acetyl-L-cysteine (NAC) blocked EGCG-induced apoptosis. To summarize, our studies suggest that EGCG induces stress signals by damaging mitochondria and ROS-mediated JNK activation in MIA PaCa-2 pancreatic carcinoma cells.
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PMID:Epigallocatechin-3-gallate induces mitochondrial membrane depolarization and caspase-dependent apoptosis in pancreatic cancer cells. 1570 1

Dysregulation of the epidermal growth factor receptor (EGFR) signaling network has been frequently reported in pancreatic cancer. Inhibition of EGFR was associated with antitumor effects in both in vitro and in vivo studies of pancreatic cancer. We have previously reported the isolation and characterization of an EGFR-related protein (ERRP), which seems to be a negative regulator of EGFR. In the present investigation, we tested our hypothesis whether recombinant ERRP could be an effective inhibitor of growth of BxPC3 pancreatic cancer cells. Cell growth and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and apoptosis ELISA assay, respectively, in the presence and absence of recombinant ERRP in BxPC3 cells. To evaluate activation of EGFR and its downstream signaling events, levels of phospho-EGFR, phospho-AKT, and phospho-extracellular signal-regulated kinase (phospho-ERK) were determined by Western blot analysis. NF-kappaB activity was measured by electrophoretic mobility shift assay. Our data show, for the first time, that ERRP inhibits the growth of BxPC3 cells in a dose- and time-dependent manner. The EGF or transforming growth factor (TGF)-alpha-induced stimulation of cell growth and activation of EGFR was also inhibited by ERRP. These changes were accompanied by a concomitant attenuation of activation of mitogen-activated protein (MAP) kinases, AKT, and NF-kappaB. ERRP also induced apoptosis as evidenced by increased poly(ADP-ribose) polymerase cleavage and reduction in procaspase3. From these results, we conclude that ERRP is a potent inhibitor of growth of BxPC-3 pancreatic cancer cells, which could be due to attenuation of EGFR cellular signaling processes. We also suggest that ERRP could be a potential therapeutic agent for pancreatic cancer.
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PMID:Epidermal growth factor receptor-related protein inhibits cell growth and induces apoptosis of BxPC3 pancreatic cancer cells. 1586 87

The effects of the nuclear factor (NF)-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), combined with tumor necrosis factor (TNF)-alpha were evaluated in PK-8 pancreatic cancer cells. NF-kappaB was activated by TNF-alpha; however, the administration of DHMEQ abrogated its transcriptional activity. The addition of DHMEQ to TNF-alpha markedly induced apoptosis in PK-8 cells with down-regulation of anti-apoptotic c-FLIP and survivin. Combined treatment significantly suppressed cell viability in vitro, and the anti-tumor effect of DHMEQ was also significant in vivo. We investigated the apoptosis signaling pathway involved in these cell killing effects. Truncated Bid was produced by activated caspase-8, and the subsequent depolarization of the mitochondrial membrane potential (Delta Psi m) peaked at 6 h. Then, the activity of caspase-3 was up-regulated 8-fold. Z-VAD-fmk (a pan-caspase inhibitor) perfectly inhibited the up-regulation of caspase-3 but failed to reverse the cell viability. The above findings indicated that the growth inhibitory effect of combined treatment largely depended on mitochondria-associated caspase-independent apoptosis. The intracellular behavior of apoptosis-inducing factor (AIF) following depolarization of Delta Psi m suggested that AIF executed such a caspase-independent apoptosis. Interestingly, caspase-dependent apoptosis appeared within 6 h, whereas the caspase-independent apoptosis lagged. Thus, the addition of DHMEQ to TNF-alpha was capable of inducing caspase-independent apoptosis in pancreatic cancer cells. Once caspase-independent apoptosis was induced, the apoptosis demonstrated powerful cytotoxicity. Therefore, DHMEQ in combination with TNF-alpha may be a promising treatment for pancreatic cancer.
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PMID:Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-kappaB inhibitor. 1621 Dec 19

3,3'-Diindolylmethane (DIM), ring-substituted DIMs and 1,1-bis(3'-indolyl)-1-(p-substitutedphenyl)methanes (C-DIMs) inhibit growth of Panc-1 and Panc-28 pancreatic cancer cells. Although DIMs (diarylmethanes) and selected C-DIMs (triarylmethanes), such as the p-t-butyl derivative (DIM-C-pPhtBu), activate the aryl hydrocarbon receptor and peroxisome proliferator-activated receptor gamma, respectively, this study shows that both DIM and DIM-C-pPhtBu induce common receptor-independent pathways. Both DIM and DIM-C-pPhtBu increased endoplasmic reticulum (ER) staining and ER calcium release in Panc-1 cells, and this was accompanied by increased expression of glucose related protein 78 and C/EBP homologous transcription factor (CHOP/GADD153) proteins. Similar results were observed after treatment with thapsigargin (Tg), a prototypical inducer of ER stress. The subsequent downstream effects of DIM/DIM-C-pPhtBu- and Tg-induced ER stress included CHOP-dependent induction of death receptor DR5 and subsequent cleavage of caspase 8, caspase 3, Bid and PARP. Activation of both receptor-dependent and receptor-independent (ER stress) pathways by DIM and DIM-C-pPhtBu in pancreatic cancer cells enhances the efficacy and potential clinical importance of these compounds for cancer chemotherapeutic applications.
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PMID:3,3'-diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. 1633 27

The mouse breast cancer cell lines 4T1, 4T07, and 67NR are highly tumorigenic but vary in metastatic potential: 4T1 widely disseminates, resulting in secondary tumors in the lung, liver, bone, and brain; 4T07 spreads to the lung and liver but is unable to establish metastatic nodules; 67NR is unable to metastasize. The Bcl-2/adenovirus E1B 19 kDa interacting protein-3 (Bnip-3) was recently shown to be absent after hypoxia in pancreatic cancer cell lines whereas its overexpression restored hypoxia-induced cell death. We found that Bnip-3 expression increased after 6 hours of hypoxia in all cell lines tested but was highest in the nonmetastatic 67NR cells and lowest in the highly metastatic 4T1 cells. Hypoxia-induced expression of Bnip-3 in the disseminating but nonmetastatic 4T07 cells was intermediate compared with 4T1 and 67NR cells. Cleaved caspase-3, a key downstream effector of cell death, increased after 6 hours of hypoxia in the 67NR and 4T07 cells by 1.9- and 2.5-fold, respectively. Conversely, cleaved caspase-3 decreased by 45% in the highly metastatic 4T1 cells after hypoxia. Small interfering RNA oligonucleotides targeting endogenous Bnip-3 blocked cell death and increased clonigenic survival after hypoxic challenge in vitro and increased primary tumor size and enabled metastasis to the lung, liver, and sternum of mice inoculated with 4T07 cells in vivo. These data inversely correlate the hypoxia-induced expression of the cell death protein Bnip-3 to metastatic potential and suggest that loss of Bnip-3 expression is critical for malignant and metastatic evasion of hypoxia-induced cell death.
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PMID:Bcl-2/adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver, and bone. 1635 80

Gemcitabine is the only available chemotherapeutic treatment of pancreatic cancers. It is, however, moderately effective, showing a tumor response rate of only 12%. The aim of this work was to identify new pathways involved in the resistance of pancreatic cancer cells to gemcitabine, in the hope of developing new adjuvant strategies to enhance its therapeutic efficacy. Comparison of gene expression patterns of five human pancreatic cancer cell lines showing different degrees of resistance to gemcitabine revealed specific overexpression of several genes in the most resistant. One of them encoded the antiapoptotic p8 protein. We found that (a) knocking down p8 expression in gemcitabine-resistant cells promoted cell death and increased caspase-3 activity; (b) forced overexpression of p8 in gemcitabine-sensitive cells increased their resistance to gemcitabine-induced apoptosis; and (c) gemcitabine down-regulated p8 mRNA expression. These results suggest that, in pancreatic cancer cells, a large part of gemcitabine-induced apoptosis results from the inhibition of the constitutive antiapoptotic activity of p8. Hence, targeting the p8-associated pathway could be a new adjuvant therapy improving the response of patients with pancreatic cancer to gemcitabine treatment.
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PMID:p8 is a new target of gemcitabine in pancreatic cancer cells. 1639 47

Pancreatic cancer exhibits profound chemoresistance resulting either from pre-existing (intrinsic) mechanisms, or from anticancer drug treatment itself (acquired chemoresistance). To identify molecular alterations leading to acquired chemoresistance, the chemosensitive pancreatic carcinoma cell line PT45-P1 was exposed to low-dose treatment with etoposide for 6 weeks. Afterwards, these cells (PT45-P1res) were much more resistant to high-dose treatment with anticancer drugs than parental cells. Among several differentially expressed genes in PT45-P1res cells, IL-1beta was most significantly upregulated, a finding in line with our previous observation that IL-1beta accounts for intrinsic chemoresistance of pancreatic carcinoma cells. Elevated IL-1beta expression in PT45-P1res cells was confirmed by real-time PCR and ELISA, and treatment with the IL-1 receptor antagonist restored drug-induced apoptosis. The increased IL-1beta secretion was accompanied by an elevated formation of nitric oxide (NO) and a NO-dependent inhibition of the etoposide-induced caspase-3/-7/-8/-9 activity. Caspase activation was restored either by the iNOS inhibitor 1400W, the reducing agent dithiothreitol or the IL-1 receptor antagonist, resulting in greater sensitivity towards anticancer drug treatment. Conversely, IL-1beta or the NO-donor SNAP decreased caspase activation and apoptosis in etoposide-treated PT45-P1 cells. These data confirm IL-1beta and NO as determinants of chemoresistance in pancreatic cancer, and indicate that the intrinsic and acquired chemoresistance rely to some extent on common molecular targets beneficial for improved therapeutical strategies.
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PMID:Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1beta and NO lead to inactivation of caspases. 1647 45


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