scholarly journals Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

2006 ◽  
Vol 282 (7) ◽  
pp. 4288-4300 ◽  
Author(s):  
Sasmita Mishra ◽  
Jyoti P. Mishra ◽  
Ashok Kumar
Keyword(s):  
Viral Protein ◽  
Cell Types ◽  
Mitochondrial Pathway ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Monocytic Cells ◽  
Viral Protein R ◽  
Jnk Inhibitors ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Human immunodeficiency virus (HIV) accessory protein viral protein R (Vpr) plays a key role in virus replication and induces cell cycle arrest and apoptosis in various cell types including T cells and neuronal and tumor cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein. The C-terminal Vpr peptide encompassing amino acids 52–96 (Vpr-(52–96)) is required for exerting the apoptotic effects, whereas the N-terminal Vpr-(1–45) peptide is responsible for virus transcription. We demonstrate that Vpr-(52–96) induced apoptosis in human promonocytic THP-1 cells and primary monocytes through the mitochondrial pathway in a caspase-dependent manner. To understand the regulation of Vpr-induced apoptosis, we investigated the signaling pathways, particularly the MAPKs, and the transcription factors involved. Although both Vpr-(52–96) and Vpr-(1–45) peptides induced phosphorylation of all the three members of the MAPKs, Vpr-(52–96)-activated JNK selectively induced apoptosis in monocytic cells through the mitochondrial pathway as determined by using JNK inhibitors SP60025, dexamethasone, curcumin, and JNK-specific small interfering RNAs. Furthermore Vpr-(52–96)-induced apoptosis was mediated by inhibition of downstream antiapoptotic Bcl2 and c-IAP1 genes whose expression could be restored following pretreatment with JNK-specific inhibitors. Overall the results suggest that Vpr-(52–96)-activated JNK plays a key role in inducing apoptosis through the down-regulation of antiapoptotic Bcl2 and c-IAP1 genes.

scholarly journals Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis

2006 ◽  
Vol 203 (1) ◽  
pp. 189-201 ◽  
Author(s):  
Ronit Vogt Sionov ◽  
Orly Cohen ◽  
Shlomit Kfir ◽  
Yael Zilberman ◽  
Eitan Yefenof
Keyword(s):  
T Cell ◽  
Glucocorticoid Receptor ◽  
Cell Lines ◽  
Cell Types ◽  
Thymic Epithelial Cells ◽  
Dependent Manner ◽  
Localization Signal ◽  
Induced Apoptosis ◽  
T Cell Lines

The mechanisms by which glucocorticoid receptor (GR) mediates glucocorticoid (GC)-induced apoptosis are unknown. We studied the role of mitochondrial GR in this process. Dexamethasone induces GR translocation to the mitochondria in GC-sensitive, but not in GC-resistant, T cell lines. In contrast, nuclear GR translocation occurs in all cell types. Thymic epithelial cells, which cause apoptosis of the PD1.6 T cell line in a GR-dependent manner, induce GR translocation to the mitochondria, but not to the nucleus, suggesting a role for mitochondrial GR in eliciting apoptosis. This hypothesis is corroborated by the finding that a GR variant exclusively expressed in the mitochondria elicits apoptosis of several cancer cell lines. A putative mitochondrial localization signal was defined to amino acids 558–580 of human GR, which lies within the NH2-terminal part of the ligand-binding domain. Altogether, our data show that mitochondrial and nuclear translocations of GR are differentially regulated, and that mitochondrial GR translocation correlates with susceptibility to GC-induced apoptosis.

scholarly journals Agaricus blazeiExtract Induces Apoptosis through ROS-Dependent JNK Activation Involving the Mitochondrial Pathway and Suppression of Constitutive NF-κB in THP-1 Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Mun-Ock Kim ◽  
Dong-Oh Moon ◽  
Jin Myung Jung ◽  
Won Sup Lee ◽  
Yung Hyun Choi ◽  
...  
Keyword(s):  
Mitochondrial Pathway ◽  
Ros Generation ◽  
Gene Products ◽  
Oxygen Species ◽  
Agaricus Blazei ◽  
Anti Cancer ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
Apoptotic Effects ◽  
Apoptotic Mechanism

Agaricus blazeiis widely accepted as a traditional medicinal mushroom, and it has been known to exhibit immunostimulatory and anti-cancer activity. However, the apoptotic mechanism in cancer cells is poorly understood. In this study, we have investigated whetherA. blazeiextract (ABE) exerts antiproliferative and apoptotic effects in human leukemic THP-1 cells. We observed that ABE-induced apoptosis is associated with the mitochondrial pathway, which is mediated by reactive oxygen species (ROS) generation and prolonged c-Jun N-terminal kinase (JNK) activation. In addition, the ABE treatment resulted in the accumulation of cytochromecin the cytoplasm, an increase in caspase activity, and an upregulation of Bax and Bad. With those results in mind, we found that ABE decreases constitutive NF-κB activation and NF-κB-regulated gene products such as IAP-1 and -2. We concluded that ABE induces apoptosis with ROS-dependent JNK activation and constitutive activated NF-κB inhibition in THP-1 cells.

scholarly journals Ethanol Extract ofDianthus chinensisL. Induces Apoptosis in Human Hepatocellular Carcinoma HepG2 CellsIn Vitro

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Kyoung Jin Nho ◽  
Jin Mi Chun ◽  
Ho Kyoung Kim
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Chromatin Condensation ◽  
Ethanol Extract ◽  
Mitochondrial Pathway ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Caspase Inhibitor ◽  
Caspase Activation ◽  
Apoptotic Effects

Dianthus chinensisL. is used to treat various diseases including cancer; however, the molecular mechanism by which the ethanol extract ofDianthus chinensisL. (EDCL) induces apoptosis is unknown. In this study, the apoptotic effects of EDCL were investigated in human HepG2 hepatocellular carcinoma cells. Treatment with EDCL significantly inhibited cell growth in a concentration- and time-dependent manner by inducing apoptosis. This induction was associated with chromatin condensation, activation of caspases, and cleavage of poly (ADP-ribose) polymerase protein. However, apoptosis induced by EDCL was attenuated by caspase inhibitor, indicating an important role for caspases in EDCL responses. Furthermore, EDCL did not alter the expression of bax in HepG2 cells but did selectively downregulate the expression of bcl-2 and bcl-xl, resulting in an increase in the ratio of bax:bcl-2 and bax:bcl-xl. These results support a mechanism whereby EDCL induces apoptosis through the mitochondrial pathway and caspase activation in HepG2 cells.

Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD

2012 ◽  
Vol 302 (6) ◽  
pp. E615-E625 ◽  
Author(s):  
Yuria Saito ◽  
Yuko Tanaka ◽  
Yuichi Aita ◽  
Kiyo-aki Ishii ◽  
Tatsuhiko Ikeda ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pc12 Cells ◽  
Kinase Inhibitor ◽  
Active Agent ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Downstream Effectors ◽  
Apoptotic Effect ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors (VEGFRs). Very recently, sunitinib has been shown to be an active agent for the treatment of malignant pheochromocytomas. However, it is unclear whether sunitinib acts only through an antiangiogenic mechanism or whether it may also directly target tumor cells. Sunitinib markedly induced apoptosis of PC12 cells in a dose-dependent and time-dependent manner. Furthermore, in support of these findings, we found that sunitinib induced a reduction in the expression of the antiapoptotic molecule Bcl-2 as well as dephosphorylation of the proapoptotic molecule BAD, which results in the activation of BAD in these cells. Consistent with these apoptotic effects, our results showed that sunitinib inhibited phosphorylation of Akt and mTOR and was followed by a reduction of S6K1, which is a well-known target of mTOR. Knockdown of VEGFR-2 attenuated the sunitinib-induced effects, including apoptosis and inhibition of signaling pathways such as the phosphorylation of Akt as well as mTOR, and Bcl-2, which confirmed that these effects could be mediated by VEGFR-2. In addition, silencing of S6K1 induced apoptosis accompanied by a decrease in the phosphorylation of BAD and Bcl-2, similar to that observed with sunitinib treatment. Thus, these results together suggest that sunitinib initially exerts its apoptotic effect through the inhibition of VEGFR-2, which, when followed by reduction of its downstream effectors, including Akt/mTOR/S6K1, may lead to inhibition of the antiapoptotic molecule Bcl-2 and activation of the proapoptotic molecule BAD in PC12 cells. However, PC12 cells do not precisely reflect the pathogenesis of malignant cells. Therefore, we confirmed the key findings by replicating these experiments in human neuroblastoma SK-N-SH cells.

scholarly journals Relationship between the Regulation of Caspase-8-Mediated Apoptosis and Radioresistance in Human THP-1-Derived Macrophages

2018 ◽  
Vol 19 (10) ◽  
pp. 3154 ◽  
Author(s):  
Hironori Yoshino ◽  
Haruka Konno ◽  
Koya Ogura ◽  
Yoshiaki Sato ◽  
Ikuo Kashiwakura
Keyword(s):  
Cell Types ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Dna Double Strand Breaks ◽  
Differentiated Cells ◽  
Pathways Analysis ◽  
Radiation Induced ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Related Proteins

Radiosensitivity varies depending on the cell type; highly differentiated cells typically exhibit greater radioresistance. We recently demonstrated that human macrophages derived from THP-1 monocytic cells, which lack TP53, are highly resistant to radiation-induced apoptosis compared with undifferentiated THP-1 cells. However, the mechanisms by which THP-1 cells acquire radioresistance during differentiation remain unknown. Herein, we investigated the mechanisms by which THP-1-derived macrophages develop p53-independent radioresistance by analyzing DNA damage responses and apoptotic pathways. Analysis of γ-H2AX foci, which indicates the formation of DNA double-strand breaks (DSB), suggested that a capacity to repair DSB of macrophages is comparable to that of radiosensitive THP-1 cells. Furthermore, treatment with inhibitors against DSB repair-related proteins failed to enhance radiation-induced apoptosis in THP-1-derrived macrophages. Analysis of the apoptotic pathways showed that radiosensitive THP-1 cells undergo apoptosis through the caspase-8/caspase-3 cascade after irradiation, whereas this was not observed in the macrophages. Caspase-8 protein expression was lower in macrophages than in THP-1 cells, whereas mRNA expressions were comparable between both cell types. Co-treatment with a proteasome inhibitor and ionizing radiation effectively induced apoptosis in macrophages in a caspase-8-dependent manner. Results suggest that the regulation of caspase-8-mediated apoptosis during differentiation plays a role in the p53-independent radioresistance of THP-1-derived macrophages.

Involvement of mitochondrial pathway in benzo[a]pyrene-induced neuron apoptosis

2013 ◽  
Vol 33 (3) ◽  
pp. 240-250 ◽  
Author(s):  
J-S Nie ◽  
H-M Zhang ◽  
J Zhao ◽  
H-J Liu ◽  
Q Niu
Keyword(s):  
Cytochrome C ◽  
Learning And Memory ◽  
B Cell Lymphoma ◽  
Mitochondrial Pathway ◽  
Dependent Manner ◽  
Cerebral Neurons ◽  
Induced Neuron ◽  
Induced Apoptosis ◽  
Dose Dependent ◽  
Different Doses

Benzo[a]pyrene (B[a]P), a well-known carcinogen, is widespread in the environment. Although the neurotoxic effect of B[a]P has not drawn much attention, toxic effects of B[a]P on learning and memory have been reported. Since it is well known that neuronal apoptosis plays a major role in impairment of learning and memory triggered by many stimuli, an effort has been made to examine whether the B[a]P-induced neurotoxicity occurs through mitochondria-mediated apoptosis. Cultured newborn rat cerebral neurons were used to clarify the apoptosis induced by B[a]P in the study. After incubating with different doses of B[a]P in presence of S9 for 40 h, the apoptotic rates of B[a]P-treated neurons increased in a dose-dependent manner. Further analysis showed that B[a]P-induced apoptosis was accompanied by loss of mitochondrial membrane potential, release of cytochrome c from mitochondria to the cytosol, downregulation of antiapoptotic protein B-cell lymphoma-2 (Bcl-2) levels with concurrent upregulation in proapoptotic Bcl-2-associated X protein (Bax) levels, and increase in the levels and activities of caspases-9 and -3. However, there was no difference in the activity of caspase-8 between B[a]P-exposed neurons and controls. Collectively, these results showed that B[a]P upregulates Bax and downregulates Bcl-2 expression in cultured cerebral neurons, which leads to mitochondrial release of cytochrome c, caspase-3 activation and neuronal apoptotic death.

scholarly journals Rapid Apoptosis Induced by Shiga Toxin in HeLa Cells

2003 ◽  
Vol 71 (5) ◽  
pp. 2724-2735 ◽  
Author(s):  
Jun Fujii ◽  
Takashi Matsui ◽  
Daniel P. Heatherly ◽  
Kailo H. Schlegel ◽  
Peter I. Lobo ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
Hela Cells ◽  
Shiga Toxin ◽  
Specific Inhibitor ◽  
Mitochondrial Pathway ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Mitochondrial Membranes ◽  
Caspase 9 ◽  
Induced Apoptosis

ABSTRACT Apoptosis was induced rapidly in HeLa cells after exposure to bacterial Shiga toxin (Stx1 and Stx2; 10 ng/ml). Approximately 60% of HeLa cells became apoptotic within 4 h as detected by DNA fragmentation, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and electron microscopy. Stx1-induced apoptosis required enzymatic activity of the Stx1A subunit, and apoptosis was not induced by the Stx2B subunit alone or by the anti-globotriaosylceramide antibody. This activity was also inhibited by brefeldin A, indicating the need for toxin processing through the Golgi apparatus. The intracellular pathway leading to apoptosis was further defined. Exposure of HeLa cells to Stx1 activated caspases 3, 6, 8, and 9, as measured both by an enzymatic assay with synthetic substrates and by detection of proteolytically activated forms of these caspases by Western immunoblotting. Preincubation of HeLa cells with substrate inhibitors of caspases 3, 6, and 8 protected the cells against Stx1-dependent apoptosis. These results led to a more detailed examination of the mitochondrial pathway of apoptosis. Apoptosis induced by Stx1 was accompanied by damage to mitochondrial membranes, measured as a reduced mitochondrial membrane potential, and increased release of cytochrome c from mitochondria at 3 to 4 h. Bid, an endogenous protein known to permeabilize mitochondrial membranes, was activated in a Stx1-dependent manner. Caspase-8 is known to activate Bid, and a specific inhibitor of caspase-8 prevented the mitochondrial damage. Although these data suggested that caspase-8-mediated cleavage of Bid with release of cytochrome c from mitochondria and activation of caspase-9 were responsible for the apoptosis, preincubation of HeLa cells with a specific inhibitor of caspase-9 did not protect against apoptosis. These results were explained by the discovery of a simultaneous Stx1-dependent increase in endogenous XIAP, a direct inhibitor of caspase-9. We conclude that the primary pathway of Stx1-induced apoptosis and DNA fragmentation in HeLa cells is unique and includes caspases 8, 6, and 3 but is independent of events in the mitochondrial pathway.

scholarly journals Polypeptide Fraction fromArca subcrenataInduces Apoptosis and G2/M Phase Arrest in HeLa Cells via ROS-Mediated MAPKs Pathways

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Xianjing Hu ◽  
Zhang Zhang ◽  
Ting Liu ◽  
Liyan Song ◽  
Jianhua Zhu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Hela Cells ◽  
Underlying Mechanism ◽  
Cyclin B1 ◽  
Mitochondrial Pathway ◽  
Dependent Manner ◽  
Phase Arrest ◽  
M Phase ◽  
Induced Apoptosis ◽  
High Level

Arca subcrenatais documented in the literature of marine Traditional Chinese Medicine. Polypeptide fraction fromA. subcrenata, coded as P2, was demonstrated to possess significant antitumor activity in our previous study. However, the underlying mechanism remains undefined. The present study was carried out to investigate the underlying antitumor mechanism of P2 in human cervical cancer HeLa cells by MTT, FCM, LSCM, and western blot assays. The results revealed that P2 significantly induced apoptosis of HeLa cells in a concentration- and time-dependent manner. High level of ROS was provoked by P2, which was in turn responsible for induction of apoptosis through activation of intrinsic mitochondrial pathway and JNK1/2, p38 MAPK pathways, as well as inhibition of ERK1/2 pathway, as evidenced by the abrogation of P2’s effect on HeLa cells preincubated with the ROS scavenger NAC. P2 also was observed to display significant effect on G2/M phase arrest by downregulating the expression of cyclin B1/cdc2 complex and upregulating the expression of p21. These findings demonstrate that P2 induces apoptosis and G2/M phase arrest in HeLa cells through ROS-mediated MAPKs pathways, suggesting that P2 would be worth investigating as a promising agent within the scope of marine drugs for treatment of cervical cancer.

Prevention of cytokine withdrawal-induced apoptosis by Mcl-1 requires interaction between Mcl-1 and Bim

2010 ◽  
Vol 88 (5) ◽  
pp. 809-818 ◽  
Author(s):  
Sarwat Jamil ◽  
Shih Wei Wang ◽  
Lise Bondy ◽  
Shadi Mojtabavi ◽  
Vincent Duronio
Keyword(s):  
Normal Growth ◽  
Growth Conditions ◽  
Mitochondrial Pathway ◽  
Hemopoietic Cells ◽  
Primary Bone ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Mutant Forms ◽  
Pest Region ◽  
Primary Bone Marrow

Growth factor withdrawal from hemopoietic cells results in activation of the mitochondrial pathway of apoptosis. Members of the Bcl-2 family regulate this pathway, with anti-apoptotic members counteracting the effects of pro-apoptotic members. We investigated the effect on Mcl-1 function of mutation at a conserved threonine 163 residue (T163) in its proline, glutamate, serine, and threonine rich (PEST) region. Under normal growth conditions, Mcl-1 half-life increased with alteration of T163 to glutamic acid, but decreased with mutation to alanine. However, both T163 mutants exhibited greater pro-survival effects compared with the wild type, which can be explained by an increased stability of the T163A mutant in cytokine-starved conditions. Both the mutant forms exhibited prolonged binding to pro-apoptotic Bim in cytokine-deprived cells. The extent to which Mcl-1 mutants were able to exert their anti-apoptotic effects correlated with their ability to associate with Bim. We further observed that primary bone marrow derived macrophages survived following cytokine withdrawal as long as Bim and Mcl-1 remained associated. In our study, we were unable to detect a role for GSK-3-mediated regulation of Mcl-1 expression. Based on these results we propose that upon cytokine withdrawal, survival of hemopoietic cells depends on association between Mcl-1 and Bim. Furthermore, alteration of T163 of Mcl-1 may change the protein such that its association with Bim is affected, resulting in prolonged association and increased survival.

Pyrrolo-1,5-benzoxazepines: a new class of apoptotic agents

2001 ◽  
Vol 29 (6) ◽  
pp. 704-706 ◽  
Author(s):  
D. M. Zisterer ◽  
M. M. McGee ◽  
G. Campiani ◽  
A. Ramunno ◽  
C. Fattorusso ◽  
...  
Keyword(s):  
Cellular Response ◽  
Caspase 3 ◽  
Signal Transduction Pathway ◽  
Benzodiazepine Receptor ◽  
Cell Types ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
Leukaemia Cell Line ◽  
Apoptotic Activity ◽  
Induced Apoptosis

Some members of a series of novel pyrrolo-1,5-benzoxazepines (PBOXs) potently induce apoptosis in a number of human cancerous cell lines including HL-60 cells and the drug-resistant chronic myelogenous leukaemia cell line, K562. The apoptotic induction seems to be independent of the mitochondrial peripheral-type benzodiazepine receptor (PBR), which binds these PBOXs with high affinity, due to a lack of correlation between their affinities for the receptor and their apoptotic potencies and their high apoptotic activity in PBR-deficient cells. PBOX-6, a potent member of the series, induces a transient activation of c-Jun N-terminal kinase (JNK) in a dose-dependent manner, which correlates with induction of apoptosis. Expression of a cytoplasmic inhibitor of the JNK signal transduction pathway, Jip-1, prevents JNK activity and significantly reduces the extent of apoptosis induced by PBOX-6. This demonstrates the requirement for JNK in the cellular response to this apoptotic agent. In addition, PBOX-6 activates caspase-3-like proteases in K562 and HL-60 cells. The caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethylketone (z-DEVD-fmk), blocks caspase-3-like protease activity in both cell types but only prevents PBOX-6-induced apoptosis in HL-60 cells, suggesting that the requirement for caspase-3-like proteases in the apoptotic pathway is dependent on the cell type.

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