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Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells.
Dos Santos AA, López-Granero C, Farina M, Rocha JBT, Bowman AB, Aschner M
(2018) Food Chem Toxicol 113: 328-336
MeSH Terms: Animals, Astrocytes, Caspase 3, Caspase 9, Cell Death, Cells, Cultured, Enzyme Activation, Lim Kinases, Methylmercury Compounds, Mice, Inbred C57BL, Myosin-Light-Chain Phosphatase, Oxidative Stress, Phosphorylation, Proteolysis, rho-Associated Kinases
Show Abstract · Added April 11, 2018
Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes. Exposure of cells with 10 μM MeHg decreased cellular viability after 24 h of incubation. This reduction in viability was preceded by a significant increase in intracellular and mitochondrial reactive oxygen species levels, as well as a reduced NAD/NADH ratio. MeHg also induced an increase in mitochondrial-dependent caspase-9 and caspase-3, while the levels of RhoA protein expression were reduced or unchanged. We further found that MeHg induced ROCK-1 cleavage/activation and promoted LIMK1 and MYPT1 phosphorylation, both of which are the best characterized ROCK-1 downstream targets. Inhibiting ROCK-1 and caspases activation attenuated the MeHg-induced cell death. Collectively, these findings are the first to show that astrocytes exposed to MeHg showed increased cleavage/activation of ROCK-1, which was independent of the small GTPase RhoA.
Copyright © 2018. Published by Elsevier Ltd.
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15 MeSH Terms
Preconditioning mesenchymal stem cells with caspase inhibition and hyperoxia prior to hypoxia exposure increases cell proliferation.
Saini U, Gumina RJ, Wolfe B, Kuppusamy ML, Kuppusamy P, Boudoulas KD
(2013) J Cell Biochem 114: 2612-23
MeSH Terms: Amino Acid Chloromethyl Ketones, Animals, Caspase 1, Caspase 3, Caspase 6, Caspase 7, Caspase 9, Cell Hypoxia, Cell Proliferation, Cells, Cultured, Male, Mesenchymal Stem Cells, Rats
Show Abstract · Added February 21, 2015
Myocardial infarction is a leading cause of mortality and morbidity worldwide. Occlusion of a coronary artery produces ischemia and myocardial necrosis that leads to left ventricular (LV) remodeling, dysfunction, and heart failure. Stem cell therapy may decrease infarct size and improve LV function; the hypoxic environment, however, following a myocardial infarction may result in apoptosis, which in turn decreases survival of transplanted stem cells. Therefore, the effects of preconditioned mesenchymal stem cells (MSC) with hyperoxia (100% oxygen), Z-VAD-FMK pan-caspase inhibitor (CI), or both in a hypoxic environment in order to mimic conditions seen in cardiac tissue post-myocardial infarction were studied in vitro. MSCs preconditioned with hyperoxia or CI significantly decreased apoptosis as suggested by TUNEL assay and Annexin V analysis using fluorescence assisted cell sorting. These effects were more profound when both, hyperoxia and CI, were used. Additionally, gene and protein expression of caspases 1, 3, 6, 7, and 9 were down-regulated significantly in MSCs preconditioned with hyperoxia, CI, or both, while the survival markers Akt1, NF-κB, and Bcl-2 were significantly increased in preconditioned MSCs. These changes ultimately resulted in a significant increase in MSC proliferation in hypoxic environment as determined by BrdU assays compared to MSCs without preconditioning. These effects may prove to be of great clinical significance when transplanting stem cells into the hypoxic myocardium of post-myocardial infarction patients in order to attenuate LV remodeling and improve LV function.
© 2013 Wiley Periodicals, Inc.
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13 MeSH Terms
Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.
Ko DC, Gamazon ER, Shukla KP, Pfuetzner RA, Whittington D, Holden TD, Brittnacher MJ, Fong C, Radey M, Ogohara C, Stark AL, Akey JM, Dolan ME, Wurfel MM, Miller SI
(2012) Proc Natl Acad Sci U S A 109: E2343-52
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Apoptosis, Apoptosis Regulatory Proteins, Bone Marrow Cells, Caspase 1, Caspase 9, Deoxyadenosines, Genetic Predisposition to Disease, Genetic Variation, HEK293 Cells, HapMap Project, Humans, Methionine, Mice, Mice, Inbred C57BL, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Salmonella Infections, Salmonella typhimurium, Thionucleosides, Young Adult
Show Abstract · Added April 13, 2017
Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5'-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5'-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology.
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25 MeSH Terms
Co-treatment with ginsenoside Rh2 and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation, bax translocation, and cytochrome c release.
Li Q, Li Y, Wang X, Fang X, He K, Guo X, Zhan Z, Sun C, Jin YH
(2011) Mol Carcinog 50: 760-9
MeSH Terms: Antineoplastic Agents, Phytogenic, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Blotting, Western, Caspase 3, Caspase 8, Caspase 9, Cell Line, Tumor, Cell Survival, Cytochromes c, Dose-Response Relationship, Drug, Drug Synergism, Enzyme Activation, Flow Cytometry, Ginsenosides, HeLa Cells, Hep G2 Cells, Humans, Molecular Structure, Neoplasms, Pentacyclic Triterpenes, Poly(ADP-ribose) Polymerases, Protein Transport, RNA Interference, Triterpenes, bcl-2-Associated X Protein
Show Abstract · Added July 28, 2015
We provide evidence for the first time, that two natural compounds ginsenoside Rh2 (G-Rh2) and betulinic acid (Bet A) synergistically induce apoptosis in human cervical adenocarcinoma (HeLa), human lung cancer A549, and human hepatoma HepG2 cells. G-Rh2 and Bet A cooperated to induce Bax traslocation to mitochondria and cytochrome c release. Co-treatment of G-Rh2 and Bet A resulted in enhanced cleavage of caspase-8 and Bid. Moreover, specific inhibition of caspase-8 by siRNA technology effectively reduced caspase-9 processing, poly (ADP-ribose) polymerase (PARP) cleavage, caspase-3 activation, and apoptosis in co-treated cells, which indicated that the caspase-8 feedback amplification pathway may have been involved in the apoptosis process. A previous study has shown that G-Rh2 induces cancer cell apoptosis via a Bcl-2 and/or Bcl-xL-independent mechanism, and Bet A induces apoptosis mainly through a mitochondrial pathway with tumor specificity. Since the antiapoptotic Bcl-2 and Bcl-xL are frequently overexpressed in human cancer cells, combined treatment with G-Rh2 and Bet A may be a novel strategy to enhance efficacy of anticancer therapy. © 2011 Wiley-Liss, Inc.
Copyright © 2011 Wiley-Liss, Inc.
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26 MeSH Terms
Inhibition of Mdm2 sensitizes human retinal pigment epithelial cells to apoptosis.
Bhattacharya S, Ray RM, Chaum E, Johnson DA, Johnson LR
(2011) Invest Ophthalmol Vis Sci 52: 3368-80
MeSH Terms: Adult, Apoptosis, Blotting, Western, Caspase 3, Caspase 9, Cell Line, Cell Proliferation, DNA Fragmentation, Humans, Imidazoles, Piperazines, Protein Binding, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Retinal Pigment Epithelium, Transfection, Tumor Suppressor Protein p53, bcl-X Protein
Show Abstract · Added June 11, 2018
PURPOSE - Because recent studies indicate that blocking the interaction between p53 and Mdm2 results in the nongenotoxic activation of p53, the authors sought to investigate whether the inhibition of p53-Mdm2 binding activates p53 and sensitizes human retinal epithelial cells to apoptosis.
METHODS - Apoptosis was evaluated by the activation of caspases and DNA fragmentation assays. The Mdm2 antagonist Nutlin-3 was used to dissociate p53 from Mdm2 and, thus, to increase p53 activity. Knockdown of p53 expression was accomplished by using p53 siRNA.
RESULTS - ARPE-19 and primary RPE cells expressed high levels of the antiapoptotic proteins Bcl-2 and Bcl-xL. Exposure of these cells to camptothecin (CPT) or TNF-α/ cycloheximide (CHX) failed to induce apoptosis. In contrast, treatment with the Mdm2 antagonist Nutlin-3 in the absence of CPT or TNF-α/CHX increased apoptosis. Activation of p53 in response to Nutlin-3 also increased levels of Noxa, p53-upregulated modulator of apoptosis (PUMA), and Siva-1, decreased expression of Bcl-2 and Bcl-xL, and simultaneously increased caspases-9 and -3 activities and DNA fragmentation. Knockdown of p53 decreased the basal expression of p21Cip1 and Bcl-2, inhibited the Nutlin-3-induced upregulation of Siva-1 and PUMA expression, and consequently inhibited caspase-3 activation.
CONCLUSIONS - These results indicate that the normally available pool of intracellular p53 is predominantly engaged in the regulation of cell cycle checkpoints by p21Cip1 and does not trigger apoptosis in response to DNA-damaging agents. However, the blockage of p53 binding to Mdm2 frees a pool of p53 that is sufficient, even in the absence of DNA-damaging agents, to increase the expression of proapoptotic targets and to override the resistance of RPE cells to apoptosis.
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MeSH Terms
Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells.
Li Y, He K, Huang Y, Zheng D, Gao C, Cui L, Jin YH
(2010) Mol Carcinog 49: 630-40
MeSH Terms: Antineoplastic Agents, Phytogenic, Apoptosis, Apoptosis Regulatory Proteins, Caspase 3, Caspase 7, Caspase 9, Cell Line, Tumor, Cell Survival, Cytochromes c, HeLa Cells, Hep G2 Cells, Humans, Intracellular Signaling Peptides and Proteins, K562 Cells, Mitochondria, Mitochondrial Proteins, Neoplasms, Triterpenes, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Show Abstract · Added July 28, 2015
We examined whether betulin, a naturally abundant compound, has anticancer functions in human cancer cells. The results showed that betulin significantly inhibited cell viability in cervix carcinoma HeLa cells, hepatoma HepG2 cells, lung adenocarcinoma A549 cells, and breast cancer MCF-7 cells with IC(50) values ranging from 10 to 15 microg/mL. While betulin exhibited only moderate anticancer activity in other human cancer cells such as hepatoma SK-HEP-1 cells, prostate carcinoma PC-3, and lung carcinoma NCI-H460, with IC(50) values ranging from 20 to 60 microg/mL, it showed minor growth inhibition in human erythroleukemia K562 cells (IC(50) > 100 microg/mL). We further investigated the mechanism of anticancer activity by betulin, using HeLa cells as an experimental model. Betulin (10 microg/mL) induces apoptotic cell death, as evidenced by morphological characteristics such as membrane phosphatidylserine translocation, nuclear condensation/fragmentation, and apoptotic body formation. A kinetics analysis showed that the depolarization of mitochondrial membrane potential and the release of mitochondrial cytochrome c occurred as early as 30 min after treatment with betulin. Betulin, unlike its chemical derivative betulinic acid, did not directly trigger mitochondrial cytochrome c release in isolated mitochondria. Importantly, Bax and Bak were rapidly translocated to the mitochondria 30 min after betulin treatment. The sequential activation of caspase-9 and caspase-3/-7 and the cleavage of poly(ADP-ribose) polymerase (PARP) were observed behind those mitochondrial events. Furthermore, specific downregulation of either caspase-9, Bax, or Bak by siRNA effectively reduced PARP cleavage and caspase-3 activation. Taken together, the lines of evidence demonstrate that betulin triggers apoptosis of human cancer cells through the intrinsic apoptotic pathway.
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20 MeSH Terms
Optimization of the PiggyBac transposon system for the sustained genetic modification of human T lymphocytes.
Nakazawa Y, Huye LE, Dotti G, Foster AE, Vera JF, Manuri PR, June CH, Rooney CM, Wilson MH
(2009) J Immunother 32: 826-36
MeSH Terms: Apoptosis, Cancer Vaccines, Caspase 9, Cells, Cultured, DNA Transposable Elements, Genetic Engineering, Genetic Vectors, Humans, Immunotherapy, Adoptive, Interleukin-15, T-Lymphocytes, Transgenes
Show Abstract · Added August 22, 2013
Optimal implementation of adoptive T-cell therapy for cancer will likely require multiple and maintained genetic modifications of the infused T cells and their progeny so that they home to tumor sites and recognize tumor cells, overcome tumor immune evasion strategies, and remain safe. Retroviral vectors readily transduce T cells and integrate into the host cell genome, but have a limited capacity for multigene insertion and cotransduction and are prohibitively expensive to produce at clinical grade. Genetic modification of T cells using transposons as integrating plasmids is an attractive alternative because of the increased simplicity and cost of production. Of available transposons, piggyBac has the higher transposase activity and larger cargo capacity, and we now evaluate piggyBac for potential adoptive therapies with primary T cells. PiggyBac transposons mediated stable gene expression in approximately 20% of primary T cells without selection. Treatment and maintenance of T cells with interleukin-15 increased stable transgene expression up to approximately 40% and expression was sustained through multiple logs of expansion for over 9 weeks in culture. We demonstrate simultaneous integration of 2 independent transposons in 20% of T cells, a frequency that could be increased to over 85% by selection of a transgenic surface marker (truncated CD19). PiggyBac could also deliver transposons of up to 13 kb with 10,000-fold expansion of transduced T cells in culture and finally we demonstrate delivery of a functional suicide gene (iCasp9). PiggyBac transposons may thus be used to express the multiple integrated transgenes that will likely be necessary for the broader success of T-cell therapy.
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12 MeSH Terms
Diallyl disulfide causes caspase-dependent apoptosis in human cancer cells through a Bax-triggered mitochondrial pathway.
Nagaraj NS, Anilakumar KR, Singh OV
(2010) J Nutr Biochem 21: 405-12
MeSH Terms: Allyl Compounds, Anticarcinogenic Agents, Antineoplastic Agents, Phytogenic, Apoptosis, Apoptotic Protease-Activating Factor 1, Caspase 3, Caspase 9, Caspase Inhibitors, Cell Line, Tumor, Chemoprevention, Cystatin B, Cytochromes c, Disulfides, Fas-Associated Death Domain Protein, Garlic, Gene Expression Regulation, Neoplastic, Humans, Mitochondria, Neoplasms, Plant Roots, Protein Transport, Signal Transduction, bcl-2-Associated X Protein
Show Abstract · Added June 14, 2013
Diallyl disulfide (DADS), an important component of garlic (Allium sativum) derivative, has been demonstrated to exert a potential molecular target against human cancers. We investigated DADS-induced expressions of Apaf1, cystatin B, caspase-3 and FADD (fas-associated protein with death domain) in breast, prostate and lung cancer cells. These showed coincident data when further examined by quantitative reverse transcription-polymerase chain reaction and Western blot analysis. Furthermore, DADS induced a marked amount of Bax translocation, cytochrome c release and activation of caspase-3 and caspase-9. DADS-treated tumor cells triggered mitochondria-mediated signaling pathways that led to a significant increase in apoptosis induction. Further studies with caspase-3 and caspase-9 inhibitors (zDEVD-fmk and zLEHD-fmk, respectively) proved that DADS induces apoptosis through a caspase-3-dependent pathway. DADS is only an agent used in the study. The molecular mechanism presented therefore provides strong additional support to the hypothesis that DADS is a strong inducer of apoptosis through a Bax-triggered mitochondria-mediated and caspase-3-dependent pathway. This study shows clearly that DADS causes caspase-dependent apoptosis in human cancer cells through a Bax-triggered mitochondrial pathway. Therefore, the mitochondrial pathway might be the target for cancer chemoprevention and/or chemotherapy by DADS.
Published by Elsevier Inc.
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23 MeSH Terms
t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism.
Belkhiri A, Dar AA, Zaika A, Kelley M, El-Rifai W
(2008) Cancer Res 68: 395-403
MeSH Terms: Activating Transcription Factor 1, Carcinoma, Caspase 3, Caspase 9, Cell Survival, Cyclic AMP Response Element-Binding Protein, Cytochromes c, DNA-Binding Proteins, Dopamine and cAMP-Regulated Phosphoprotein 32, Gene Expression Regulation, Neoplastic, Genes, bcl-2, Humans, Membrane Potential, Mitochondrial, Nuclear Proteins, Oncogene Protein v-akt, Phosphorylation, Protein Isoforms, RNA, Messenger, Regulatory Factor X Transcription Factors, Signal Transduction, Stomach Neoplasms, Transcription Factors, Tumor Cells, Cultured, Up-Regulation
Show Abstract · Added March 5, 2014
t-Darpp is a cancer-related truncated isoform of Darpp-32 (dopamine and cyclic-AMP-regulated phosphoprotein of M(r) 32,000). We detected overexpression of t-Darpp mRNA in two thirds of gastric cancers compared with normal samples (P = 0.004). Using 20 micromol/L ceramide treatment as a model for induction of apoptosis in AGS cancer cells, we found that expression of t-Darpp led to an increase in Bcl2 protein levels and blocked the activation of caspase-3 and caspase-9. The MitoCapture mitochondrial apoptosis and cytochrome c release assays indicated that t-Darpp expression enforces the mitochondrial transmembrane potential and protects against ceramide-induced apoptosis. Interestingly, the expression of t-Darpp in AGS cells led to >or=2-fold increase in Akt kinase activity with an increase in protein levels of p-Ser(473) Akt and p-Ser(9) GSK3 beta. These findings were further confirmed using tetracycline-inducible AGS cells stably expressing t-Darpp. We also showed transcriptional up-regulation of Bcl2 using the luciferase assay with Bcl2 reporter containing P1 full promoter, quantitative reverse transcription-PCR, and t-Darpp small interfering RNA. The Bcl2 promoter contains binding sites for cyclic AMP-responsive element binding protein CREB/ATF1 transcription factors and using the electrophoretic mobility shift assay with a CREB response element, we detected a stronger binding in t-Darpp-expressing cells. The t-Darpp expression led to an increase in expression and phosphorylation of CREB and ATF-1 transcription factors that were required for up-regulating Bcl2 levels. Indeed, knockdown of Akt, CREB, or ATF1 in t-Darpp-expressing cells reduced Bcl2 protein levels. In conclusion, the t-Darpp/Akt axis underscores a novel oncogenic potential of t-Darpp in gastric carcinogenesis and resistance to drug-induced apoptosis.
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24 MeSH Terms
Low multiplicity of infection of Helicobacter pylori suppresses apoptosis of B lymphocytes.
Bussiere FI, Chaturvedi R, Asim M, Hoek KL, Cheng Y, Gainor J, Scholz A, Khan WN, Wilson KT
(2006) Cancer Res 66: 6834-42
MeSH Terms: Animals, Apoptosis, B-Lymphocytes, Caspase 3, Caspase 9, Caspases, Cell Growth Processes, Cell Survival, Enzyme Activation, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Membrane Potentials, Mice, Mice, Inbred C57BL, Mitochondrial Membranes, Proto-Oncogene Proteins c-bcl-2, Spleen, T-Lymphocytes
Show Abstract · Added March 5, 2014
Helicobacter pylori infection of the human stomach causes chronic gastritis that can lead to gastric cancer. Because activated lymphocytes persist in the gastric mucosa, and because a high multiplicity of infection (MOI) of H. pylori is needed to induce apoptosis in vitro, we speculated that resistance of lymphocytes to apoptosis is an important feature of the immune response to H. pylori. Freshly isolated mouse splenocytes underwent substantial spontaneous apoptosis and displayed a biphasic response to H. pylori, in which low MOI (1-10) markedly inhibited apoptosis, whereas high MOI (> or =75) potentiated apoptosis. Low MOI reduced mitochondrial membrane depolarization, caspase-3 and caspase-9 activation, and cytochrome c release and increased Bcl-2 levels. Low MOI also induced cellular proliferation. When cells were subjected to fluorescence-activated cell sorting after coculture with H. pylori, CD19+ B cells were found to be protected from apoptosis and undergoing proliferation at low MOI, whereas CD3+ T cells did not exhibit this pattern. The protective effect of low MOI on apoptosis persisted even when B cells were isolated before activation. Immunophenotyping showed that all B-cell subsets examined were protected from apoptosis at low MOI. Additionally, gastric infection with H. pylori resulted in protection of splenic B cells from spontaneous apoptosis. Our results suggest that the low levels of H. pylori infection that occur in vivo are associated with B-cell survival and proliferation, consistent with their potential to evolve into mucosa-associated lymphoid tissue lymphoma.
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19 MeSH Terms