APOPTOSIS (APOPTOSIS )

Publisher: Springer Verlag

Description

Apoptosis is an international peer-reviewed journal published bimonthly. The Journal is devoted to the rapid publication of innovative basic and clinically-oriented investigations into programmed cell death. It aims to stimulate both research on the basis of mechanisms of apoptosis and on its role in various human disease processes including: cancer autoimmune disease viral infection AIDS cardiovascular disease neurodegenerative disorders osteoporosis and ageing. The Editor-In-Chief recognises the need to encourage the development of clinical therapies against apoptosis-related diseases.

  • Impact factor
    3.95
    Show impact factor history
     
    Impact factor
  • 5-year impact
    4.16
  • Cited half-life
    5.50
  • Immediacy index
    0.63
  • Eigenfactor
    0.01
  • Article influence
    1.24
  • Website
    Apoptosis website
  • Other titles
    Apoptosis (Online)
  • ISSN
    1360-8185
  • OCLC
    37773456
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Springer Verlag

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • Authors own final version only can be archived
    • Publisher's version/PDF cannot be used
    • On author's website or institutional repository
    • On funders designated website/repository after 12 months at the funders request or as a result of legal obligation
    • Published source must be acknowledged
    • Must link to publisher version
    • Set phrase to accompany link to published version (The original publication is available at www.springerlink.com)
    • Articles in some journals can be made Open Access on payment of additional charge
  • Classification
    ​ green

Publications in this journal

  • [show abstract] [hide abstract]
    ABSTRACT: Licochalcone A (LicA), an estrogenic flavonoid, induces apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of LicA were investigated in HepG2 human hepatocellular carcinoma cells. LicA induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by CHOP knockdown or treatment with the ER stress inhibitors, salubrinal and 4-phenylbutyric acid, reduced LicA-induced cell death. LicA also induced reactive oxygen species (ROS) accumulation and the anti-oxidant N-acetylcysteine reduced LicA-induced cell death and CHOP expression. In addition, LicA increased the levels of cytosolic Ca2+, which was blocked by 2-aminoethoxydiphenyl borate (an antagonist of inositol 1,4,5-trisphosphate receptor) and BAPTA-AM (an intracellular Ca2+ chelator). 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited LicA-induced cell death. Interestingly, LicA induced phosphorylation of phospholipase Cγ1 (PLCγ1) and inhibition of PLCγ1 reduced cell death and ER stress. Moreover, the multi-targeted receptor tyrosine kinase inhibitors, sorafenib and sunitinib, reduced LicA-induced cell death, ER stress, and cytosolic Ca2+ and ROS accumulation. Finally, LicA induced phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and c-Met receptor and inhibition of both receptors by co-transfection with VEGFR2 and c-Met siRNAs reversed LicA-induced cell death, Ca2+ increase, and CHOP expression. Taken together, these findings suggest that induction of ER stress via a PLCγ1-, Ca2+-, and ROS-dependent pathway may be an important mechanism by which LicA induces apoptosis in HepG2 hepatocellular carcinoma cells.
    APOPTOSIS 01/2013;
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    ABSTRACT: Dracorhodin perchlorate has been recently shown to induce apoptotic cell death in cancer cells. However, the molecular mechanisms underlying these effects are unknown in human gastric tumor cells. In this study, effects of Dracorhodin perchlorate on cell viability, cell cycle, and apoptosis were investigated in SGC-7901 cells. The results showed that Dracorhodin perchlorate induced cellular and DNA morphological changes and decreased the viability of SGC-7901 cells. Dracorhodin perchlorate-mediated cell cycle arrest was associated with a marked decrease in protein levels of phosphorylated retinoblastoma and E2F1. Dracorhodin perchlorate-induced apoptosis is mediated via upregulation of p53, inhibiting the activation of PI3K-Akt, and NF-κB, thereby decreasing the expression of the anti-apoptotic proteins, Bcl-2 and Bcl-XL. Interestingly, we also found that Dracorhodin perchlorate significantly suppressed the IGF-1-induced phosphorylation of Akt in the stably expressing EGFP-Akt recombinant CHO-hIR cells and inhibited TNF-induced NF-κB transcriptional activity in the NF-κBp65-EGFP recombinant U2OS cells, indicating that inhibition of PI3K/Akt and NF-κB may provide a molecular basis for the ability of Dracorhodin perchlorate to induce apoptosis. Dracorhodin perchlorate induced up-regulation of p53, thereby resulting in the activation of its downstream targets p21 and Bax following the dissipation of mitochondrial membrane potential and activation of caspase-3 and its substrate, PARP. Moreover, Dracorhodin perchlorate dramatically enhanced the wortmannin- and TNF-induced apoptosis in SGC-7901 cells. These results reveal functional interplay among the PI3K/AKT, p53 and NF-κB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by Dracorhodin perchlorate could result in efficacious and selective killing of cancer cells.
    APOPTOSIS 05/2012;
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    ABSTRACT: TRAIL (TNF-related apoptosis-inducing ligand) has been shown to induce apoptosis by binding to TRAIL-R1 and -R2 death receptors, but not to TRAIL-R3 or -R4, its decoy receptors that lack the internal death domain. Osteoclasts (Ocs) are sensitive to TRAIL-induced apoptosis, and modulation of these receptors may change Oc sensitivity to TRAIL. Using human Oc cultures, we first investigated the gene expression profile of these receptors (TNFRSF10 -A, -B, -C, -D encoding TRAIL-Rs 1-4) by real time PCR after adding osteotropic factors during the last week of Oc cultures. We observed a significant decrease in the expression of TNFRSF10-A after the addition of TGFβ, and an increase in that of TNFRSF10-A and -B post-PTH stimulation. Protein expression of TRAIL-R1 and -R3 was upregulated in the presence of MIP-1α, but down-regulated in the presence of TGFβ (R1), TRAIL (R2) or OPG (R3). The percentage of Ocs expressing the TRAIL-R1 and/or -R2 at their surface was increased by MIP-1α and TRAIL, increased (R2) or decreased (R1) by TGFβ, and the percentage expressing TRAIL-R3 was increased by MIP-1α, TRAIL and RANKL. Although significant, the magnitude of all these changes was of about 10-15%. While a direct correlation between these changes and TRAIL-induced Oc apoptosis was less clear, a protective effect was observed in Ocs that had been treated with OPG, and an additive effect in Ocs pre-treated with TRAIL or TGFβ increased TRAIL sensitivity.
    APOPTOSIS 02/2012; 17(2):121-31.
  • APOPTOSIS 01/2012; 17:278.
  • [show abstract] [hide abstract]
    ABSTRACT: One of the impeding factors in the effective treatment of metastatic renal cell carcinoma (RCC) is their intrinsic and acquired resistance to chemotherapeutics. Many studies have shown that drug resistance, at least in part, is mediated by the upregulation of anti-apoptotic (Bcl-2) and multidrug resistance molecules (MDR-1 and MRP-1) by the transcription factor nuclear factor kappa B (NF-kappaB). Combining NF-kappaB inhibitors with conventional chemotherapeutics could overcome resistance of cancer cells. In this study, we examined the synergistic effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, and cisplatin, on two human metastatic RCC cell lines ACHN and SN12K1. Individual non-toxic concentrations of PDTC and cisplatin, when combined, synergistically induced a significant increase in apoptosis of the two RCC cell lines. In ACHN cells, the groups with nuclear translocation of NF-kappaB showed resistance to apoptosis, but in SN12K1 cells, the groups with NF-kappaB translocation were susceptible to apoptosis. The combination treatment significantly decreased the transcription activity of all NF-kappaB subunits in both cell lines. Anti-apoptotic proteins Bcl-2 and Bcl-(XL) were significantly decreased in the combination therapy group of both cell lines, but MDR-1 was decreased only in the ACHN cells. No changes in MRP-1 were observed in any of the treatment groups. The results demonstrate the potential of PDTC to be an adjunct therapeutic agent. The major mechanism of the synergistic effect appears to be mediated by the inhibition of transcription activity of NF-kappaB rather than its expression, and the resultant decrease in the anti-apoptotic proteins Bcl-2 and Bcl-(XL).
    APOPTOSIS 01/2010;
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    ABSTRACT: The molecular subversion of cell death is acknowledged as a principal contributor to the development and progression of cancer. The p53 tumor suppressor protein is among the most commonly altered proteins in human cancer. The p53 protein mediates critical functions within cells including the response to genotoxic stress, differentiation, senescence, and cell death. Loss of p53 function can result in enhanced rates of cell proliferation, resistance to cell death stimuli, genomic instability, and metastasis. The community of cancer scientists is now in possession of a vast repository of information regarding the frequency, specific mechanisms, and clinical context of cell death deregulation in cancer. This information has enabled the design of therapeutic agents to target proteins, including p53. The feasibility and impact of targeting cell death signaling proteins has been established in preclinical models of human cancer. The appropriate application of these targeted agents is now being established in clinical trials.
    APOPTOSIS 03/2009; 14(4):336-347.
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    ABSTRACT: Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid that exerts potent anti-cancer effects in vitro and in vivo, but is non toxic to untransformed cells. In our previous study we observed that BetA consistently induced cell death in a broad panel of tumor cell lines. Apoptosis induced by BetA involves activation of caspases, PARP cleavage and DNA fragmentation and was suggested to depend on the mitochondrial pathway. However, conflicting results have been reported with respect to the role of the pro- and anti-apoptotic members of the Bcl-2 family, which are often aberrantly regulated in tumors and thereby confer growth and survival advantages. Here we show that BetA-induced apoptosis critically depends on the release of cytochrome c from the mitochondria and formation of the apoptosome. Nevertheless, over-expression of Bcl-2 or Bcl-XL only provides limited protection against BetA-induced apoptosis. More importantly, Bax/Bak deficient cells are as sensitive to BetA as their wild-type counterparts, suggesting that cytochrome c is released in a non-classical fashion. In agreement, pre-incubation with cyclosporin A indicated a crucial role for the mitochondrial permeability transition pore (PT) in the induction of apoptosis. Our observations therefore indicate that BetA affects mitochondria and induces cytochrome c release directly via PT Pore. This is only temporarily prevented by anti-apoptotic members of the Bcl-2 family, but independent of Bax and Bak. These findings help to explain the remarkable broad efficacy of BetA against tumor cells of different origin and its effect in tumor cells that are resistant to other chemotherapeutic agents.
    APOPTOSIS 01/2009; 14(2):191-202.
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    ABSTRACT: Rottlerin, a compound reported to be a PKC δ-selective inhibitor, has been shown to induce growth arrest or apoptosis of human cancer cell lines. In our study, rottlerin dose-dependently induced apoptotic cell death in colon carcinoma cells. Treatment of HT29 human colon carcinoma cells with rottlerin was found to induce a number of signature ER stress markers; phosphorylation of eukaryotic initiation factor-2α (eIF-2α), ER stress-specific XBP1 splicing, and up-regulation of glucose-regulated protein (GRP)-78 and CCAAT/enhancer-binding protein-homologous protein (CHOP). However, suppression of PKC δ expression by siRNA or overexpression of WT-PKC δ and DN-PKC δ did not abrogate the rottlerin-mediated induction of CHOP. These results suggest that rottlerin induces up-regulation of CHOP via PKC δ-independent pathway. Furthermore, down-regulation of CHOP expression using CHOP siRNA attenuated rottlerin-induced apoptosis. Taken together, the present study thus provides strong evidence to support an important role of ER stress response in mediating the rottlerin-induced apoptosis.
    APOPTOSIS 10/2008; 13(11):1378-1385.
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    ABSTRACT: Yeast-based functional screening of a human glioblastoma cDNA library identified ras-related nuclear protein (Ran) as a novel suppressor of Bcl-2-associated X protein (Bax), a pro-apoptotic member of the Bcl-2 family of proteins. Yeast cells that expressed human Ran were resistant to Bax-induced cell death. In U373MG glioblastoma cells, stable overexpression of Ran significantly attenuated apoptotic cell death induced by the chemotherapeutic agent paclitaxel. FACS analysis demonstrated that Ran is involved in paclitaxel-induced cell cycle arrest. Stable overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2 by paclitaxel, and inhibited the translocation of Bax, the release of cytochrome c and activation of caspase-3. Paclitaxel-induced phosphorylation of c-JUN N-terminal kinase (JNK), but not p38, extracellular signal-regulated kinase and Akt, was markedly suppressed in U373MG cells that stably expressed Ran. These results suggest that Ran suppresses paclitaxel-induced cell death through the downregulation of JNK-mediated signal pathways.
    APOPTOSIS 09/2008; 13(10):1223-1231.
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    ABSTRACT: We have investigated the interrelationship between two anti-apoptotic factors, XIAP and Akt, and their role in chemoresistance of uterine cancer cells. We used one cervical cancer cell line (HeLa) and two endometrial cancer cell lines (KLE and Ishikawa) as a model. The three drugs decreased Akt and XIAP content and induced apoptosis in P-Akt-negative HeLa cells. In P-Akt1/3-positive Ishikawa cells apoptosis induction correlated with XIAP decrease. P-Akt1/2/3-positive KLE cells showed maximum chemoresistance as XIAP and Akt levels/phosphorylation remained stable in response to the three drugs, and only cisplatin could significantly induce apoptosis. We found that XIAP and Akt were functionally linked in uterine cancer cells, as downregulation of XIAP with RNAi decreased P-Akt levels, and inhibition of PI3-K/Akt activity using LY294002 decreased XIAP content. Overexpression of constitutively active Akt isoforms in HeLa cells induced isoform-specific sensitivity to doxorubicin and taxol but not cisplatin. XIAP RNAi increased the cell-specific sensitivity to cisplatin and doxorubicin but not taxol. Finally, we found P-Akt immunoreactivity in epithelial cells from multiple human endometrial carcinoma tumors, suggesting that Akt may also regulate chemosensitivity in uterine cancers in vivo. Altogether these results highlight an intertwined role for specific Akt isoforms and XIAP in chemoresistance of uterine cancer cells.
    APOPTOSIS 03/2008; 13(2):259-71.
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    ABSTRACT: Although multiple mechanisms have been implicated in chemoresistance, recent evidence has suggested that the attachment of cells to extracellular matrix proteins such as fibronectin (FN) may mediate the signals that participate in cell survival and resistance to apoptosis. We established previously that human ovarian cancer cells and breast cancer cells adhering to FN acquire a survival advantage through activation of the PI3-kinase/Akt2 pathway. However, the mechanism by which Akt2 regulates chemoresistance in adherent cells is unknown. In the present study, we have investigated the role of the interaction between the Akt2/survivin survivial pathway and the ASK1/p38 apoptotic pathway in the phenomenon of resistance to docetaxel. We show here that the resistance of FN-adhered A2780 or MDA-MB-231 cells to docetaxel requires survivin, and we present evidence that attenuation of the antiapoptotic activity of survivin is p38-dependent. The activation of p38 kinase in response to docetaxel, on the other hand, is abolished by FN adhesion. We further demonstrate that FN adhesion-mediated inhibition of p38 activation was governed by Akt2 via the promotion of direct protein association of ASK1 with p38. Our results indicate for the first time that p38 plays a critical role in FN adhesion-mediated resistance to docetaxel. The present findings may help us to understand the formation of FN adhesion-mediated chemoresistance and facilitate development of novel antineoplastic strategies.
    APOPTOSIS 03/2008; 13(2):213-23.
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    ABSTRACT: The simultaneous expression of human papillomavirus type 16 (HPV16) E6 and E7 oncogenes is pivotal for malignant transformation and maintenance of malignant phenotypes. Silencing these oncogenes is considered to be applicable in molecular therapies of human cervical cancer. However, it remains to be determined whether HPV16 E6 and E7 could be both silenced to obtain most efficient antitumor activity by using RNA interference (RNAi) technology. Herein, we designed a small interfering RNA (siRNA) targeting HPV16-E7 region to degrade either E6, or truncated E6 (E6*) and E7 mRNAs and to simultaneously knockdown both E6 and E7 expression. Firstly, the sequence targeting HPV16-E7 region was inserted into the shRNA packing vector pSIREN-DNR, yielding pSIREN-16E7 to stably express corresponding shRNA. HPV16-transformed SiHa and CaSki cells were used as a model system; RT-PCR, Western Blotting, MTT assay, TUNEL staining, Annexin V apoptosis assay and flow cytometry were applied to examine the effects of pSIREN-16E7. Our results indicated that HPV16-E7 specific shRNA (16E7-shRNA) induced selective degradation of E6 and E7 mRNAs and proteins. E6 silencing induced accumulation of cellular p53 and p21. In contrast, E7 silencing induced hypophosphorylation of retinoblastoma (Rb) protein. The loss of E6 and E7 reduced cell growth and ultimately resulted in massive apoptotic cell death selectively in HPV-positive cancer cells, compared with the HPV-negative ones. We demonstrated that 16E7-shRNA can induce simultaneous E6 and E7 suppression and lead to striking apoptosis in HPV16-related cancer cells by activating cellular p53, p21 and Rb. Therefore, RNAi using E7 shRNA may have the gene-specific therapy potential for HPV16-related cancers.
    APOPTOSIS 03/2008; 13(2):273-81.
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    ABSTRACT: CD45 is a type I transmembrane molecule with phosphatase activity which comprises up to 10% of the cell surface area in nucleated haematopoietic cells. We have previously demonstrated the absence of nuclear apoptosis in CD45-negative T cells after chemical-induced apoptosis. The aim of this study was to characterize the role of CD45 in nuclear apoptosis. In contrast to wild type CD45-positive T cells, the CD45-deficient T cell lines are resistant to the induction of DNA fragmentation and chromatin condensation following tributyltin (TBT) or H2O2 exposure, but not to cycloheximide-induced apoptosis. CD45 transfection in deficient cell lines led to the restoration of chromatin condensation and DNA fragmentation following TBT exposure. In both CD45-positive and negative T cell lines, TBT exposure mediates intracellular calcium mobilization, caspase-3 activation and DFF45 cleavage. Moreover, DNA fragmentation was also induced by TBT in cells deficient in expression of p56lck, ZAP-70 and SHP-1. Subcellular partitioning showed a decrease in nuclear localisation of caspase-3 and DFF40. Together, these results demonstrate for the first time, that CD45 expression plays a key role in internucleosomal DNA fragmentation and chromatin condensation processes during apoptosis. CD45 activity or its substrates' activity, appears to be located downstream of caspase-3 activation and plays a role in retention of DFF40 in the nucleus.
    APOPTOSIS 03/2008; 13(2):197-212.

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