scholarly journals prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2

1996 ◽  
Vol 316 (1) ◽  
pp. 25-28 ◽  
Author(s):  
Miriam J. SMYTH ◽  
David K. PERRY ◽  
Jiandi ZHANG ◽  
Guy G. POIRIER ◽  
Yusuf A. HANNUN ◽  
...  
Keyword(s):  
Cell Death ◽  
Inhibitory Action ◽  
Second Messenger ◽  
The Novel ◽  
Over Expression ◽  
Downstream Target ◽  
Induced Apoptosis ◽  
Insight Into

The novel lipid second messenger, ceramide, specifically induced poly(ADP-ribose) polymerase cleavage through activation of the protease prICE. Over-expression of Bcl-2 inhibited ceramide-induced poly(ADP-ribose) polymerase proteolysis and protected cells from ceramide-induced death. These data provide the first insight into the mechanism by which ceramide mediates apoptosis and suggest a mechanism by which Bcl-2 protects from cell death.

Altered expression of prostaglandin synthases in NSCLC: Therapeutic strategies and targets for intervention

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18083-18083
Author(s):  
M. Cathcart ◽  
K. Gatley ◽  
E. Kay ◽  
G. P. Pidgeon ◽  
K. J. O’ Byrne
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cell Survival ◽  
Lower Grade ◽  
Altered Expression ◽  
Over Expression ◽  
Chemotherapy Drugs ◽  
Dna Laddering ◽  
Induced Apoptosis ◽  
Brdu Assay

18083 Background: Prostacyclin Synthase (PGIS) and Thromboxane synthase (TXS) metabolize PGH(2) into prostacyclin and thromboxane respectively. PGIS over-expression inhibits cancer growth in a mouse model, while over-expression of TXS caused opposite effects. TXS is expressed in a variety of tumours, associated with poor prognosis and increased metastasis. The aim of this study was to examine the expression of PGIS and TXS in NSCLC, the effect of targeted TXS inhibition, and the mechanisms regulating these effects. Methods: A panel of resected human lung tumours were stained for PGIS and TXS expression by IHC and by western analysis. A 170- core tissue microarray was stained for TXS and intensity correlated with tumour grade. Cell survival was examined by BrdU assay in A-549 (adenocarcinoma) and SKMES-1 (squamous cell carcinoma) cells following 24h selective TXS inhibition with Ozagrel (500nM) alone, or in combination with chemotherapy. Multi-parameter apoptosis signalling was examined after TXS inhibition using In Cell Analyser and confirmed by DNA laddering and cell death ELISA. PCR arrays were used to examine genes involved in tumourigenesis following TXS inhibition. Results: PGIS was absent in lung cancer sections. TXS was over-expressed in lung cancer relative to matched normal, with significantly increased expression in lower grade tumours. PGIS was down-regulated or absent, while TXS expression was up-regulated in tumours v’s normal tissue. Ozagrel significantly reduced cell survival and induced apoptosis, determined by both DNA laddering and Cell Death ELISA. Multi-parameter apoptosis analysis revealed enlarged nuclei, decreased f-actin staining and decreased mitochondrial mass potential, while PCR arrays confirmed upregulation of the pro-apoptotic gene BAX following TXS inhibition. Ozagrel in combination with Doxorubicin (10nM) showed greatest efficacy compared to a number of other chemotherapy drugs. Conclusions: Expression of PGIS and TXS are altered in NSCLC. Overexpression of TXS may regulate tumour survival as its inhibition induces apoptosis, potentially through upregulation of pro- apoptotic proteins. Targeting TXS, alone or in combination with chemotherapy is a potential therapeutic strategy for the treatment of NSCLC. No significant financial relationships to disclose.

scholarly journals Down-Regulation of miR-212-5p Facilitates Homocysteine-Induced Hepatocytes Apoptosis Via Targeting PSMD10

2020 ◽  
Author(s):  
Huiping Zhang ◽  
Kun Xiao ◽  
Shengchao Ma ◽  
Long Xu ◽  
Ning Ding ◽  
...  
Keyword(s):  
Liver Injury ◽  
Er Stress ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Down Regulation ◽  
Over Expression ◽  
Direct Binding ◽  
Induced Apoptosis ◽  
Insight Into

Abstract Background: Increasing evidences supported that elevated homocysteine (Hcy) levels contribute to cell apoptosis is implicated in the pathogenesis of liver injury, it correlates with liver disease severity. However, the underlying mechanism of apoptosis in Hcy-mediated liver injury remains obscure. Results: In this study, we found that homocysteine increases ER stress-mediated apoptosis and aggravates liver injury through up-regulation of PSMD10 expression in cbs+/- mice mice fed with high methionine diet and hepatocytes treated with homocysteine in vitro. Knockdown of PSMD10 expression remarkably reduced ER stress or apoptosis-associated protein in hepatocytes exposed to homocysteine. Moreover, bioinformatics analysis revealed that PSMD10 is a potential target gene of miR-212-5p, and luciferase reporter assay also confirmed that miR-212-5p negatively regulated PSMD10 expression by direct binding to its 3’-UTR regions. Subsequently, over-expression of miR-212-5p inhibited ER stress-mediated hepatocytes apoptosis though targeting PSMD10, all of which were abrogated by knockdown of miR-212-5p expression. Further study showed that the interaction between PSMD10 and GRP78 accelerated ER stress-mediated hepatic apoptosis induced by homocysteine. Conclusion: Taken together, these results demonstrated that down-regulation of miR-212-5p facilitates homocysteine-induced hepatocytes apoptosis via targeting PSMD10, which provides novel insight into the mechanism of homocysteine induced apoptosis in liver injury.

scholarly journals Transforming growth factor β1 attenuates ceramide-induced CPP32/Yama activation and apoptosis in human leukaemic HL-60 cells

1997 ◽  
Vol 327 (3) ◽  
pp. 663-667 ◽  
Author(s):  
Min-Liang KUO ◽  
Chien-Wei CHEN ◽  
Shiou-Hwa JEE ◽  
Shuang-En CHUANG ◽  
Ann-Lii CHENG
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Second Messenger ◽  
Transforming Growth Factor Β1 ◽  
Cellular Functions ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis ◽  
Tgf Β1

Ceramide, a product of sphingomyelin turnover, is a novel lipid second messenger that mediates important cellular functions including proliferation, differentiation and apoptosis. This study demonstrates that the CPP32/Yama protease was activated during apoptosis induced by the membrane-permeable second messenger C2-ceramide in HL-60 cells. We also found that the addition of a specific tetrapeptide inhibitor of CPP32/Yama, Ac-DEVD-CHO, provided an effective protection against ceramide-induced cell death. These results suggested that CPP32/Yama has a central role in ceramide-mediated apoptosis. Furthermore a wide variety of cytokines were examined for their effect on ceramide-induced apoptosis. Only transforming growth factor β1 (TGF-β1) (1 ng/ml) exerted significant prevention of apoptosis induced by C2-ceramide, or by sphingomyelinase (increases intracellular ceramide). Consistently, TGF-β1 abrogated the cleavage of poly(ADP-ribose) polymerase and the production of the CPP32/Yama active subunit, p17. However, TGF-β1 treatment did not cause growth inhibition or alter the level of cyclin-dependent kinase inhibitor p27. It suggests that the preventive effect of TGF-β1 is not mediated by growth arrest. Interestingly, we found that TGF-β1 prevented the C2-ceramide-caused decrease of Bcl-2 protein. We thus propose that TGF-β1 rescues ceramide-induced cell death, possibly by maintaining the constant level of Bcl-2, thereby abolishing CPP32/Yama protease activation.

scholarly journals Inhibition of FOXO1-Mediated Autophagy Promotes Paclitaxel-Induced Apoptosis in MDA-MB-231 Cell Lines

2021 ◽  
Author(s):  
Kaixiang Xu ◽  
Wanyun Zhu ◽  
Anyong Xu ◽  
Zhe Xiong ◽  
Heng Zhao ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Apoptotic Cell ◽  
Target Therapy ◽  
Breast Cancers ◽  
Tumor Cell Death ◽  
Downstream Target ◽  
Induced Apoptosis ◽  
Aggressive Subtype

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and often produces resistance to paclitaxel (PTX) therapy. Autophagy plays an important cytoprotective role in PTX-induced tumor cell death and targeting autophagy is promising to improve the efficacy of tumor chemotherapy in recent years. Here, we reported that PTX induced both apoptosis and autophagy of MDA-MB-231 cells, and inhibition of autophagy enable to promote apoptotic cell death. Furthermore, we found that FOXO1 enhanced PTX-induced autophagy by a transcriptional activation pattern in MDA-MB-231 cells, which was associated with its downstream target genes ATG5, VPS34, BECN1 and MAP1LC3B. The knockdown of FOXO1 attenuated the survival of MDA-MB-231 cells under the PTX treatment. These findings will be beneficial to improve the treatment efficacy of PTX and to develop the autophagic target therapy of TNBC.

New Insight into 2-Methoxyestradiol- a Possible Physiological Link between Neurodegeneration and Cancer Cell Death

2016 ◽  
Vol 23 (15) ◽  
pp. 1513-1527 ◽  
Author(s):  
Magdalena Gorska ◽  
Alicja Kuban-Jankowska ◽  
Jaroslaw Slawek ◽  
Michal Wozniak
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Cancer Cell Death ◽  
Insight Into

Poly-L-arginine: Enhancing Cytotoxicity and Cellular Uptake of Doxorubicin and Necrotic Cell Death

2019 ◽  
Vol 18 (10) ◽  
pp. 1448-1456 ◽  
Author(s):  
Bahareh Movafegh ◽  
Razieh Jalal ◽  
Zobeideh Mohammadi ◽  
Seyyede A. Aldaghi
Keyword(s):  
Cell Death ◽  
Cellular Uptake ◽  
Combined Treatment ◽  
Annexin V ◽  
Cell Penetrating Peptides ◽  
Short Exposure ◽  
Dependent Manner ◽  
Du145 Cells ◽  
Induced Apoptosis ◽  
Resistance To Doxorubicin

Objective: Cell resistance to doxorubicin and its toxicity to healthy tissue reduce its efficiency. The use of cell-penetrating peptides as drug delivery system along with doxorubicin is a strategy to reduce its side effects. In this study, the influence of poly-L-arginine on doxorubicin cytotoxicity, its cellular uptake and doxorubicin-induced apoptosis on human prostate cancer DU145 cells are assessed. Methods: The cytotoxicity of doxorubicin and poly-L-arginine, alone and in combination, in DU145 cells was evaluated at different exposure times using MTT assay. The influence of poly-L-arginine on doxorubicin delivery into cells was evaluated by fluorescence microscopy and ultraviolet spectroscopy. DAPI and ethidium bromide- acridine orange stainings, flow cytometry using annexin V/propidium iodide, western blot analysis with anti-p21 antibody and caspase-3 activity were used to examine the influence of poly-L-arginine on doxorubicininduced cell death. Results: Poly-L-arginine had no cytotoxicity at low concentrations and short exposure times. Poly-L-arginine increased the cytotoxic effect of doxorubicin in DU145 cells in a time-dependent manner. But no significant reduction was found in HFF cell viability. Poly-L-arginine seems to facilitate doxorubicin uptake and increase its intracellular concentration. 24h combined treatment of cells with doxorubicin (0.5 µM) and poly-L-arginine (1 µg ml-1) caused a small increase in doxorubicin-induced apoptosis and significantly elevated necrosis in DU145 cells as compared to each agent alone. Conclusion: Our results indicate that poly-L-arginine at lowest and highest concentrations act as proliferationinducing and antiproliferative agents, respectively. Between these concentrations, poly-L-arginine increases the cellular uptake of doxorubicin and its cytotoxicity through induction of necrosis.

The Monk

2016 ◽  
Author(s):  
Matthew Lewis
Keyword(s):  
French Revolution ◽  
English Literature ◽  
Young Girl ◽  
The Novel ◽  
Reading Public ◽  
Ghost Stories ◽  
Gothic Fiction ◽  
Black Magic ◽  
Insight Into ◽  
Profound Insight

‘He was deaf to the murmurs of conscience, and resolved to satisfy his desires at any price.’ The Monk (1796) is a sensational story of temptation and depravity, a masterpiece of Gothic fiction and the first horror novel in English literature. The respected monk Ambrosio, the Abbot of a Capuchin monastery in Madrid, is overwhelmed with desire for a young girl; once having abandoned his monastic vows he begins a terrible descent into immorality and violence. His appalling fall from grace embraces blasphemy, black magic, torture, rape, and murder, and places his very soul in jeopardy. Lewis’s extraordinary tale drew on folklore, legendary ghost stories, and contemporary dread inspired by the terrors of the French Revolution. Its excesses shocked the reading public and it was condemned as obscene. The novel continues to beguile and shock readers today with its gruesome catalogue of iniquities, while at the same time giving a profound insight into the deep anxieties experienced by British citizens during one of the most turbulent periods in the nation’s history.

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