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)

Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various carcinoma cells and inhibit tumorigenesis in several in vivo models. However, the mechanisms by which they mediate their effects are not yet fully understood. In this study, we show that FOH is an effective inducer of apoptosis in several lung carcinoma cells, including H460. This induction is associated with activation of several caspases and cleavage of poly(ADP-ribose) polymerase (PARP). To obtain insight into the mechanism involved in FOH-induced apoptosis, we compared the gene expression profiles of FOH-treated and control H460 cells by microarray analysis. This analysis revealed that many genes implicated in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1, PDIA4, and PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting that FOH-induced apoptosis involves an ER stress response. This was supported by observations showing that treatment with FOH induces splicing of XBP1 mRNA and phosphorylation of eIF2alpha. FOH induces activation of several mitogen-activated protein kinase (MAPK) pathways, including p38, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, and c-jun NH2-terminal kinase (JNK). Inhibition of MEK1/2 by U0126 inhibited the induction of ER stress response genes. In addition, knockdown of the MEK1/2 and JNK1/2 expression by short interfering RNA (siRNA) effectively inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH. However, only MEK1/2 siRNAs inhibited the induction of ER stress-related genes, XBP1 mRNA splicing, and eIF2alpha phosphorylation. Our results show that FOH-induced apoptosis is coupled to ER stress and that activation of MEK1/2 is an early upstream event in the FOH-induced ER stress signaling cascade.
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PMID:Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response. 1769

New benzyliminoether derivatives [PtCl2{N(H)=C(OMe)CH2Ph}2] of cis (1a, 1b) and trans (2a, 2b) geometry were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques, and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] (1a) was significantly more potent than cisplatin against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia and Lewis lung carcinoma) showed that derivative 1a induced a remarkable antitumor activity in both tumor models, as measured by prolonged survival and reduced tumor mass compared to control groups.
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PMID:Cisplatinum and transplatinum complexes with benzyliminoether ligands; synthesis, characterization, structure-activity relationships, and in vitro and in vivo antitumor efficacy. 1771 97

We have previously shown that reactivation of DLC1, a RhoGAP containing tumor suppressor gene, inhibits tumorigenicity of human non-small cell lung carcinoma cells (NSCLC). After transfection of NSCLC cells with wild type (WT) DLC1, changes in cell morphology were observed. To determine whether such changes have functional implications, we generated several DLC1 mutants and examined their effects on cell morphology, proliferation, migration and apoptosis in a DLC1 deficient NSCLC cell line. We show that WT DLC1 caused actin cytoskeleton-based morphological alterations manifested as cytoplasmic extensions and membrane blebbings in most cells. Subsequently, a fraction of cells exhibiting DLC1 protein nuclear translocation (PNT) underwent caspase 3-dependent apoptosis. We also show that the RhoGAP domain is essential for the occurrence of morphological alterations, PNT and apoptosis, and the inhibition of cell migration. DLC1 PNT is dependent on a bipartite nuclear localizing sequence and most likely is regulated by a serine-rich domain at N-terminal part of the DLC1 protein. Also, we found that DLC1 functions in the cytoplasm as an inhibitor of tumor cell proliferation and migration, but in the nucleus as an inducer of apoptosis. Our analyses provide evidence for a possible link between morphological alterations, PNT and proapoptotic and anti-oncogenic activities of DLC1 in lung cancer.
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PMID:Morphological changes and nuclear translocation of DLC1 tumor suppressor protein precede apoptosis in human non-small cell lung carcinoma cells. 1788 3

Human 8-oxoguanine DNA glycosylase (hOGG1) is the main defense enzyme against mutagenic effects of cellular 7,8-dihydro-8-oxoguanine. In this study, we investigated the biological role of hOGG1 in DNA damage-related apoptosis induced by hydrogen peroxide (H(2)O(2))-derived oxidative stress. The down-regulated expression of hOGG1 by its small interfering RNA prominently triggers the H(2)O(2)-induced apoptosis in human fibroblasts GM00637 and human lung carcinoma H1299 cells via the p53-mediated apoptotic pathway. However, the apoptotic responses were specifically inhibited by hOGG1 overexpression. The p53-small interfering RNA transfection into the hOGG1-deficient GM00637 markedly inhibited the H(2)O(2)-induced activation of p53-downstream target proteins such as p21, Noxa, and caspase-3/7, which eventually resulted in the increased cell viability. Although the cell viability of hOGG1-knockdown H1299 p53 null cells was similar to that of the hOGG1 wild-type H1299, after the overexpression of p53 the hOGG1-knockdown H1299 showed the significantly decreased cell viability compared with that of the hOGG1 wild-type H1299 at the same experimental condition. Moreover, the array comparative genome hybridization analyses revealed that the hOGG1-deficient GM00637 showed more significant changes in the copy number of large regions of their chromosomes in response to H(2)O(2) treatment. Therefore, we suggest that although p53 is a major modulator of apoptosis, hOGG1 also plays a pivotal role in protecting cells against the H(2)O(2)-induced apoptosis at the upstream of the p53-dependent pathway to confer a survival advantage to human fibroblasts and human lung carcinomas through maintaining their genomic stability.
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PMID:Human 8-oxoguanine DNA glycosylase suppresses the oxidative stress induced apoptosis through a p53-mediated signaling pathway in human fibroblasts. 1795 8

Although benzo(a)pyrene (BP) induces apoptosis in vitro in murine Hepa1c1c7 cells and in vivo indications of apoptosis in rat lung exist, related cellular mechanisms in human cells are not known. p53 protein participates in several apoptotic processes. We found that BP induces cell death in human MCF-7 breast adenocarcinoma cells at 48 and 72h but not in human A549 lung carcinoma cells. BP did not induce measurable caspase-3-like protease activity or internucleosomal DNA fragmentation in either cell types. However, procaspase-7 cleavage in MCF-7 cells by BP-treatment indicates activation of caspase-7 meaning that apoptosis is most likely involved in BP-induced MCF-7 cell death. BP-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adducts and level of p53 protein increased dose-dependently, but more extensively in MCF-7 cells. Phosphorylation of p53 protein at serines 15, 20, 46 and 392 increased in MCF-7 cells. Increase in phosphorylation at serine 392 was clear already at 24h by 1 microM concentration of BP. Increase of phosphorylation at other sites occurred only with higher concentrations or at later time points in relation to the increase of p53 protein. These results suggest that serine 392 phosphorylation is the first stabilizing event of p53 associated with BP exposure and subsequent cell death in MCF-7 cells.
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PMID:Benzo(a)pyrene increases phosphorylation of p53 at serine 392 in relation to p53 induction and cell death in MCF-7 cells. 1844 Jul 33

Tremella mesenterica (TM) is a common food and folk medicine widely used in several Asian countries as a tonic for the lungs. In the present study, we compared the effects of extracellular polysaccharides (EPS), intracellular polysaccharides (IPS), and ethanol extract (EE) of Tremella mesenterica on the induction of apoptosis into human lung carcinoma A549 epithelial cells. The EE, but not the EPS or the IPS, almost completely inhibited the growth of A549 cells. The results of Annexin V-FITC/PI staining and flow cytometric analysis indicated that the percentage of Annexin V(+)/PI(-) cells in EE-treated cells increased to 32.8%. The results of further investigation showed a disruption of mitochondrial transmembrane potential (DeltaPsi(m)), the production of reactive oxygen species (ROS), and the activation of caspase-3 protein in EE-treated cells. These findings suggest that EE can decrease cell viability and induce apoptosis in A549 cell lines by activating a mitochondrial pathway.
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PMID:Induction of apoptosis in human lung carcinoma A549 epithelial cells with an ethanol extract of Tremella mesenterica. 1846 Aug 9

Maspin, a serine protease inhibitor related to the serpin family, can inhibit invasion and metastasis of malignancies although direct evidence of the clinicopathologic significance of cytoplasmic relative to nuclear expression is limited. Here, maspin expression was examined on tissue microarrays containing lung carcinoma (n=155) and adjacent noncancerous tissue (n=20) and also 4 lung carcinoma cell lines (LC-1/Sq, LC-IF, PC-14, and AoI) by immunohistochemistry. Maspin expression was compared with clinicopathologic parameters of the tumors. Maspin expression showed positive nuclear staining in basal cells, LC-IF, and PC-14 cell lines, and also cytoplasmic immunoreactivity in secretory and ciliated cells, LC-1/Sq cell line. Cytoplasmic staining was the lowest in adenocarcinoma (AD) and the highest in squamous cell carcinoma as compared with other types of lung carcinoma (P<0.05), and positively correlated with expression of p53 and caspase-3 (P<0.05). The cytoplasmic one showed stronger immunoreactivity in male carcinoma patients than female ones (P<0.05). The nuclear maspin expression gradually increased through squamous cell carcinoma, AD, large cell carcinoma to small cell carcinoma (P<0.05) and was also positively associated with the levels of vascular epithelial growth factor and extracellular matrix metalloproteinase inducer expression (P<0.05). Kaplan-Meier analysis indicated that the cytoplasmic or nuclear maspin expression was not a good prognostic marker for lung carcinomas overall (P>0.05), but the cytoplasmic pattern pointed to good survival for AD cases (P<0.05). It was concluded that the cytoplasmic and nuclear expression patterns of maspin are involved in the cellular differentiation of normal lung tissue and the histogenesis of different lung carcinomas. The cytoplasmic maspin may play an important role in lung carcinomas by regulating apoptosis and thus is a favorable prognostic marker for AD patients, whereas the nuclear location may be linked to promotion of angiogenesis.
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PMID:Cytoplasmic and nuclear maspin expression in lung carcinomas: an immunohistochemical study using tissue microarrays. 1866 36

Antimycin A (AMA) inhibits mitochondrial electron transport between cytochrome b and c. We evaluated the effects of AMA on the growth of human lung cancer cell line, Calu-6. AMA inhibited the growth of Calu-6 cells. AMA induced a G1 phase arrest of the cell cycle in these cells at 72h. AMA increased a cyclin-dependent kinase inhibitor (CDKI), p27 and decreased CDK2, CDK4, and CDK6, as well as cyclin D1 and cyclin E in Calu-6 cells. AMA also induced apoptosis in Calu-6 cells. The apoptotic process in AMA-treated Calu-6 cells was accompanied by the up-regulation of Bax, the loss of mitochondrial membrane potential (DeltaPsi(m)), and the activation of caspase-3 and -8. All of the tested caspase inhibitors, especially pan-caspase inhibitor (Z-VAD), markedly rescued Calu-6 cells from AMA-induced Calu-6 cell death. Inhibitors of pan-caspase and caspase-8 also prevented the loss of mitochondrial membrane potential (DeltaPsi(m)). AMA decreased the intracellular ROS levels but increased the O(2)(*-) levels in Calu-6 cells. In conclusion, AMA as a mitochondrial electron transport inhibitor decreased the growth of lung cancer Calu-6 cell via inducing a G1 arrest of the cell cycle and apoptosis.
Lung Cancer 2009 Aug
PMID:Growth inhibition in antimycin A treated-lung cancer Calu-6 cells via inducing a G1 phase arrest and apoptosis. 1911 65

Osteopontin (OPN) is a multi-functional cytokine involved in cell survival, migration and adhesion which is associated with tumorigenesis, progression and metastasis. However, the role of OPN in chemo-sensitivity of human lung cancer has not yet been elucidated. The purpose of this study is to investigate the role of OPN in chemo-sensitivity of lung cancer cells. We developed a stable OPN transfectant (SBC-3/OPN) and a control transfectant (SBC-3/NEO) from human small cell lung cancer cell line, SBC-3. SBC-3/OPN cells were more resistant to cisplatin than SBC-3/NEO cells. Multi-drug resistance-associated protein (MRP) does not appear to be involved in the development of acquired chemo-resistance, since MRP inhibitor did not alter chemo-sensitivity. After exposure to cisplatin, the apoptotic SBC-3/OPN cells were reduced in number compared to SBC-3/NEO cells. Treatment with cisplatin revealed that the expression of anti-apoptotic protein, bcl-2, was down-regulated in SBC-3/NEO cells, while that of SBC-3/OPN cells was not altered. In contrast, pro-apoptotic protein, bax, was not altered in both SBC-3/OPN and SBC-3/NEO cells, thus bcl-2/bax ratio was decreased in SBC-3/NEO but not altered in SBC-3/OPN cells. Activation of caspase-3 and caspase-9 was increased in SBC-3/NEO cells, but not in SBC-3/OPN cells. Our results suggest that OPN enhances chemo-resistance of cisplatin in SBC-3 cells by suppressing bcl-2 protein down-regulation, thereby blocking the caspase-9- and caspase-3-dependent cell apoptosis.
Lung Cancer 2009 Nov
PMID:Osteopontin is involved in the development of acquired chemo-resistance of cisplatin in small cell lung cancer. 1928 49

The beta-carboline alkaloids are naturally existing plant substances. It is known that these alkaloids have a wide spectrum of neuropharmacological, psychopharmacological, and antitumor effects. Therefore, they have been traditionally used in oriental medicine for the treatment of various diseases including cancers and malaria. In this study, harmol and harmalol, which are beta-carboline alkaloids, were examined for their antitumor effect on human lung carcinoma cell lines, and structure-activity relationship was also investigated. H596, H226, and A549 cells were treated with harmol and harmalol, respectively. Apoptosis was induced by harmol only in H596 cells. In contrast, harmalol had negligible cytotoxicity in three cell lines. Harmol induced caspase-3, caspase-8, and caspase-9 activities and caspase-3 activities accompanied by cleavage of poly-(ADP-ribose)-polymerase. Furthermore, harmol treatment decreased the native Bid protein, and induced the release of cytochrome c from mitochondria to cytosol. The apoptosis induced by harmol was completely inhibited by caspase-8 inhibitor and partially inhibited by caspase-9 inhibitor. The antagonistic antibody ZB4 blocked Fas ligand-induced apoptosis, but had no effect on harmol-induced apoptosis. Harmol had no significant effect on the expression of Fas. In conclusion, our results showed that the harmol could cause apoptosis-inducing effects in human lung H596 cells through caspase-8-dependent pathway but independent of Fas/Fas ligand interaction.
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PMID:Harmol induces apoptosis by caspase-8 activation independently of Fas/Fas ligand interaction in human lung carcinoma H596 cells. 1931 10


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