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)

Spontaneous apoptosis was assessed in ten small-cell (SCLC) and five non-small cell (NSCLC) lung carcinoma cell lines by the TUNEL assay and chromatin cleavage. TUNEL staining showed significantly higher apoptotic index (AI) in SCLC (2-20%) compared with NSCLC lines (0.2-1%) in untreated exponentially growing cells. Six out of ten SCLC and none of the NSCLC showed DNA fragmentation when analysed by agarose gel electrophoresis. Field inversion pulse gel electrophoresis was used in a subset of cell lines and showed the presence of high molecular weight fragments in untreated SCLC lines U-1285 and U-1906 cells, but not in the NSCLC line U-1810. Important molecular determinants of apoptosis were studied by Western blot. Bcl-2 was detected at highest level in SCLC. There was no correlation between the ratio Bcl-2/Bax and AI in all tested cell lines. Neither p53 nor c-Myc protein status correlated to AI. Pro-caspase-3 was expressed in all cell lines without correlation to AI and no difference between the SCLC and NSCLC groups was found. In conclusion, this study shows a high degree of spontaneous apoptosis in SCLC lines compared to NSCLC lines unrelated to Bcl-2/Bax ratio.
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PMID:Higher spontaneous apoptotic index in small cell compared with non-small cell lung carcinoma cell lines; lack of correlation with Bcl-2/Bax. 986 2

Expression levels of gangliosides and glycosyltransferase genes responsible for their syntheses in human lung cancer cell lines and a normal bronchial epithelial cell line were analyzed. Both non-small cell lung cancers and small cell lung cancers (SCLCs) mainly expressed G(M2) and G(M1), whereas only SCLCs expressed b-series gangliosides, such as G(D2), G(D1b), and G(T1b). Accordingly, many SCLC cell lines showed up-regulation of the G(D3) synthase gene. Consequently, we introduced G(D3) synthase cDNA into a SCLC line with low expression of b-series gangliosides and analyzed the effects of newly expressed gangliosides on tumor phenotypes. The transfectant cells expressing high levels of G(D2) and G(D3) exhibited markedly increased growth rates and strongly enhanced invasion activities. Addition of anti-G(D2) monoclonal antibodies into the culture medium of these cells resulted in the marked growth suppression of G(D2)-expressing cell lines with reduced activation levels of mitogen-activated protein kinases but not of nonexpressants, suggesting that G(D2) plays important roles in cell proliferation. Moreover, G(D2)-expressing cells treated with anti-G(D2) antibodies showed features of apoptotic cell death at 30 min after addition of antibodies, i.e., shrinkage of cytoplasm, binding of Annexin V, and staining with propidium iodide, followed by DNA fragmentation. This G(D2)-mediated apoptosis was associated with caspase-3 activation and partly inhibited by a caspase inhibitor, z-Val-Ala-Asp-fluoromethyl ketone. The finding that anti-G(D2) antibodies suppressed the cell growth and induced apoptosis of SCLC cells strongly suggested the usefulness of G(D2) as a target for the therapy of disastrous cancer, although the precise mechanisms for apoptosis remain to be clarified.
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PMID:Ganglioside G(D2) in small cell lung cancer cell lines: enhancement of cell proliferation and mediation of apoptosis. 1135 51

All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of G(alphaq) and G(alpha12,13). Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting G(alphaq) and stimulating G(alpha12,13). However, these SPDs had low potency and short half-lives. In this report we show that a bradykinin antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric bradykinin antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two antagonists. CU201 inhibited intracellular Ca2+ release in response to bradykinin, indicating blockage of the G(alphaq) signal, and stimulated c-Jun kinases, indicating stimulation of the G(alpha12,13) pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a "biased agonist" mechanism. 1193 11

The serine/threonine protein kinase C (PKC) has been implicated in the regulation of drug resistance and cell survival in many types of cancer cells. However, the one or more precise mechanisms remain elusive. In this study, we have identified and determined the mechanism by which PKC-epsilon, a novel PKC isoform, modulates drug resistance in lung cancer cells. Western blot analysis demonstrates that expression of PKC-epsilon, but not other PKC isoforms, is associated with the chemo-resistant phenotype of non-small cell lung cancer (NSCLC) cell lines. Northern blotting and nuclear run-on transcription analysis further reveals that the failure of expression of PKC-epsilon in the chemo-sensitive phenotype of small cell lung cancer (SCLC) cells results from transcriptional inactivation of the gene. Importantly, forced expression of PKC-epsilon in NCI-H82 human SCLC cells confers a significant resistance to the chemotherapeutic drugs, etoposide and doxorubicin. Resistance is characterized by a significant reduction in apoptosis in PKC-epsilon-expressing cells. Treatment of NCI-H82 cells with etoposide induces a series of time-dependent events, including the release of cytochrome c from the mitochondria to the cytosol, activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). All of these events are blocked by PKC-epsilon expression. Furthermore, caspase-specific inhibitors, z-VAD-fmk and z-DEVD-fmk, significantly attenuate the accumulation of sub-G(1) population and block the PARP cleavage in response to etoposide. These results suggest that PKC-epsilon prevents cells from undergoing apoptosis through inhibition of the mitochondrial-dependent caspase activation, thereby leading to cell survival. Finally, down-regulation of PKC-epsilon expression by the antisense cDNA in NSCLC cells results in increased sensitivity to etoposide. Taken together, our findings suggest an important role for PKC-epsilon in regulating survival of lung cancer cells.
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PMID:Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. 1212 73

p120 RasGTPase-activating protein (RasGAP), the main regulator of Ras GTPase family members, is cleaved at low caspase activity into an N-terminal fragment that triggers potent anti-apoptotic signals via activation of the Ras/PI-3 kinase/Akt pathway. When caspase activity is increased, RasGAP fragment N is further processed into two fragments that effectively potentiate apoptosis. Expression of RasGAP protein and its cleavage was assessed in human lung cancer cells with different histology and responsiveness to anticancer drug-induced apoptosis. Here we show that therapy-sensitive small lung carcinoma cell (SCLC) lines have lower RasGAP expression levels and higher spontaneous cleavage with formation of fragment N compared to therapy-resistant non-small cell lung carcinoma cell (NSCLC) lines. The first RasGAP cleavage event strongly correlated with the increased level of spontaneous apoptosis in SCLC. However, generation of protective RasGAP fragment N also related to the potency of SCLC to develop secondary therapy-resistance. In response to etoposide (ET), RasGAP fragment N was further cleaved in direct dependence on caspase-3 activity, which was more pronounced in NSCLC cells. Caspase inhibition, while effectively preventing the second cleavage of RasGAP, barely affected the first cleavage of RasGAP into fragment N that was always detectable in NSCLC and SCLC cells. These findings suggest that different levels of RasGAP and fragment N might play a significant role in the biology and different clinical course of both subtypes of lung neoplasms. Furthermore, constitutive formation of RasGAP fragment N can potentially contribute to primary resistance of NSCLC to anticancer therapy by ET but also to secondary therapy-resistance in SCLC.
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PMID:RasGTPase-activating protein is a target of caspases in spontaneous apoptosis of lung carcinoma cells and in response to etoposide. 1474 24

The effect of the depletion or oxidation of cellular GSH on cytotoxicity of MG132 was assessed. Viability loss and decrease in GSH contents in small cell lung cancer (SCLC) cells treated with MG132 was attenuated by caspase inhibitors (z-IETD.fmk, z-LEHD.fmk and z-DQMD.fmk). Thiol compounds (N-acetylcysteine and N-(2-mercaptopropionyl)glycine) and free radical scavengers reduced MG132-induced cell death. Antioxidants, including N-acetylcysteine, inhibited the MG132-induced nuclear damage, loss in mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c and caspase-3 activation. Depletion of GSH due to buthionine sulfoxime did not affect the cell viability loss, ROS formation and GSH depletion due to MG132 in SCLC cells. A thiol oxidant monochloramine, p-chloromercuribenzoate and N-ethylmaleiamide also did not affect cytotoxicity of MG132. The results suggest that the toxicity of MG132 on SCLC cells is mediated by activation of caspase-8, -9 and -3. Removal of free radicals and recovery of GSH contents may attenuate MG132-induced apoptotic cell death. Nevertheless, depletion or oxidation of cellular GSH may not affect toxicity of MG132.
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PMID:Differential response of MG132 cytotoxicity against small cell lung cancer cells to changes in cellular GSH contents. 1527 73

Previous studies have shown that sigma receptors are overexpressed in tumor cells. However, the role of sigma receptors remains enigmatic. Recently, we and others have demonstrated that sigma-1 receptor modulates K+ channels in pituitary. In the present report, patch-clamp and Western blot assays were used in small cell lung cancer (SCLC, NCI-H209, and NCI-H146) and leukemic (Jurkat) cell lines to investigate the effects of sigma ligands on voltage-gated K+ channels and cell proliferation. The sigma ligands (+)-pentazocine, igmesine, and 1,3-di(2-tolyl)guanidine (DTG) all reversibly inhibited voltage-activated K+ currents in both cell lines. The potency of sigma ligand-induced inhibition (10 microM) was igmesine = (+)-pentazocine > DTG, pointing to the involvement of sigma-1 receptors. Addition of the K+ channel blockers tetraethylammonium (TEA) and 4-aminopyridin or one of cited sigma ligands in the culture media reversibly inhibited Jurkat cell growth. Interestingly, K+ channel blockers and sigma ligands caused an accumulation of the cyclin-dependent kinase inhibitor p27kip1 and a decrease in cyclin A expression in Jurkat and SCLC cells, whereas no effect could be detected on p21cip1. Moreover, sigma ligands and TEA had no effect on caspase 3 activity. Accordingly, incubation of cells with sigma ligands did not provoke DNA laddering. These data demonstrate that sigma ligands and voltage-dependent channel blockers inhibit cell growth through a cell cycle arrest in the G1 phase but not via an apoptotic mechanism. Altogether, these results indicate that the sigma-1 receptor-induced inhibition of the cell cycle is, at least in part, the consequence of the inhibition of K+ channels.
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PMID:Inhibition of tumor cell proliferation by sigma ligands is associated with K+ Channel inhibition and p27kip1 accumulation. 1527 83

The effect of GSH depletion on mitochondrial damage and cell death due to mitomycin c (MMC) was assessed in small cell lung cancer (SCLC) cells. Cytotoxicity of MMC was attenuated by Tempol and dicumarol, inhibitors of the enzymatic reduction, and increased by xanthine oxidase. The MMC-induced cell death and decrease in the GSH contents in SCLC cells were inhibited by caspase inhibitors (z-DQMD.fmk, z-IETD.fmk and z-LEHD.fmk) and antioxidants (N-acetylcysteine, dithiothreitol and N-(2-mercaptopropionyl)glycine, melatonin, rutin and carboxy-PTIO). Thiol compounds, melatonin and rutin attenuated the MMC-induced nuclear damage, decrease in mitochondrial transmembrane potential, release of cytochrome c and activation of caspase-3. Treatment of MMC caused a significant decrease in GSH contents in SCLC cells, which was followed by increase in the formation of reactive oxygen species. Depletion of GSH due to L-buthionine sulfoximine enhanced the MMC-induced activation of caspase-3 and cell death in SCLC cells. Antioxidants, including N-acetylcysteine, depressed formations of nitric oxide, malondialdehyde and carbonyls due to MMC in SCLC cells. The results show that the reductive activation of MMC may cause cell death in SCLC cells by inducing mitochondrial dysfunction, leading to caspase-3 activation, and by activation of caspase-8. The MMC-induced change in the mitochondrial membrane permeability, followed by cell death, in SCLC cells may be significantly enhanced by decrease in the intracellular GSH contents due to oxidative attack of free radicals.
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PMID:Effect of change in cellular GSH levels on mitochondrial damage and cell viability loss due to mitomycin c in small cell lung cancer cells. 1545 Sep 51

Histone deacetylase inhibitors modulate the transcription of target genes and represent a new class of anticancer agents. The histone deacetylase inhibitor FR901228 has been reported to show antiproliferative and apoptotic effects in various malignancies including small cell lung cancer (SCLC) in vitro; however, the underlying mechanism is not fully understood. BCL-2 and BCL-XL are antiapoptotic proteins, of which overexpression has been reported to confer resistance to anticancer agents. High levels of BCL-2 and BCL-XL are frequently expressed in SCLC tumors. The present study was designed to clarify the apoptotic pathway of FR901228 in SCLC cells in vitro. FR901228 induced apoptosis in three SCLC cell lines after 24 hours of treatment. FR901228 activated caspase-9 and caspase-3 but not caspase-8, and the caspase-3 inhibitor Z-DEVD-fmk blocked the cytotoxicity of FR901228. FR901228 down-regulated the expression of bcl-2 and bcl-xL mRNA through de novo protein synthesis and suppressed the expression of BCL-2 and BCL-XL proteins. In addition, the combination of bcl-2 antisense oligonucleotides with FR901228 enhanced FR901228-induced caspase-3 activity and cytotoxicity. These findings suggest that FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway. Considering the possible contributions of BCL-2 and BCL-XL to multidrug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary SCLC tumors.
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PMID:The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells. 1554 78

Proteolytic activation of protein kinase C delta (PKCdelta) has been associated with apoptosis induced by the DNA damaging agent cisplatin. In cells undergoing apoptosis, caspase-3 cleaves PKCdelta at the site DMQD downward arrowN to generate a 40-kDa catalytic fragment. We have previously shown that the PKC signal transduction pathway regulates sensitivity of human small cell lung cancer H69 cells to cisplatin. In the present study, we have investigated if proteolytic activation of PKCdelta is essential for cisplatin-induced apoptosis in H69 cells. The caspase cleavage-resistant mutant PKCdelta (DMQA) was generated by mutating the aspartate residue at the site of proteolysis DMQD downward arrowN to alanine (D330A), and the wild-type and mutant PKCdelta were introduced into H69 cells. Cisplatin induced a substantial increase in PKCdelta catalytic fragment in H69 cells overexpressing PKCdelta (H69/delta, and the level of PKCdelta catalytic fragment in H69 cells expressing DMQA mutant (H69/DMQA) was equivalent to that in H69 cells. However, the cleavage of poly(ADP-ribose) polymerase (PARP), another substrate for caspase-3, was similar in cells overexpressing wild-type PKCdelta and DMQA mutant PKCdelta. The ability of cisplatin to induce mitochondrial depolarization and cell death was also equivalent among the cell lines tested. These results suggest that the proteolytic fragment of PKCdelta does not play a critical role in the induction of apoptosis in H69 cells.
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PMID:Involvement of proteolytic activation of PKCdelta in cisplatin-induced apoptosis in human small cell lung cancer H69 cells. 1594 54


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