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1.
A-Mi Seo Seung-Woo Hong Jae-Sik Shin In-Chul Park Nam-Joo Hong Dae-Jin Kim Won-Keun Lee Wang-Jae Lee Dong-Hoon Jin Myeong-Sok Lee 《Apoptosis : an international journal on programmed cell death》2009,14(7):913-922
Sulindac is a non-steroidal anti-inflammatory agent with anti-tumor activities that include the induction of apoptosis in
various cancer cells and the inhibition malignant transformation. However, the molecular mechanisms underlying these effects
are unclear. Recently, it has been shown that sulindac can inhibit NF-κB activation. Here, we demonstrate that sulindac induces
apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKβ activity. More
specifically, when we compared two different human breast cancer cell lines, Hs578T, which has relatively low basal IKKβ activity,
and MDA-MB231, which has relatively high basal IKKβ activity, we found that MDA-MB231 was markedly more sensitive to sulindac-induced
apoptosis than Hs578T. This was associated with greater caspase-3 and -9 activity in sulindac-treated MDA-MB231 cells. Using
a combination of chemical kinase inhibitors and siRNA-mediated knockdown of specific kinases, we found that sulindac inhibits
IKKβ, which, in turn, leads to the p38 MAPK-dependent activation of JNK1. Together, these findings suggest that sulindac induces
apoptosis in susceptible human breast cancer cells through, at least in part, the inhibition of IKKβ and the subsequent p38
MAPK-dependent activation of JNK1.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
A-Mi Seo and Seoug-Woo Hong have contributed equally. 相似文献
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Hongwei Si Dongmin Liu 《Apoptosis : an international journal on programmed cell death》2009,14(1):66-76
Isoflavone genistein may have beneficial effects on vascular function, but the mechanism is unclear. Here, we investigated
whether genistein protects vascular endothelial cells against apoptosis induced by tumor necrosis factor-α. We show that genistein
significantly inhibited TNF-α-induced apoptosis in human aortic endothelial cells as determined by caspase-3 activation, 7-amino
actinomycin D staining, in situ apoptotic cell detection and DNA laddering. The anti-apoptotic effect of genistein was associated
with an enhanced expression of Bcl-2 protein and its promoter activity. Inhibition of extracellular signal-regulated kinase
1/2, protein kinase A, or estrogen receptors had no effect on the cytoprotective effect of genistein. However, inhibition
of p38 mitogen-activated protein kinase (p38) completely abolished this genistein effect. Accordingly, stimulation of HAECs
with genistein resulted in rapid activation of p38β, but not p38α. These findings provide the evidence that genistein acts
as a survival factor for vascular ECs to protect cells against apoptosis via activation of p38β. Preservation of the functional
integrity of the endothelial monolayer may represent an important mechanism by which genistein exerts its vasculoprotective
effect. 相似文献
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Beauséjour M Noël D Thibodeau S Bouchard V Harnois C Beaulieu JF Demers MJ Vachon PH 《Apoptosis : an international journal on programmed cell death》2012,17(6):566-578
In human intestinal epithelial crypt (HIEC) cells, the PI3-K/Akt-1 pathway is crucial for the promotion of cell survival and
suppression of anoikis. Class I PI3-K consists of a complex formed by a catalytic (C) and regulatory (R) subunit. Three R
(p85α, β, and p55γ) and four C (p110α, β, γ and δ) isoforms are known. Herein, we analyzed the expression of PI3-K isoforms
in HIEC cells and determined their roles in cell survival, as well as in the β1 integrin/Fak/Src-mediated suppression of anoikis.
We report that: (1) the predominant PI3-K complexes expressed by HIEC cells are p110α/p85β and p110α/p55γ; (2) the inhibition
and/or siRNA-mediated expression silencing of p110α, but not that of p110β, γ or δ, results in Akt-1 down-activation and consequent
apoptosis; (3) the expression silencing of p85β or p55γ, but not that of p85α, likewise induces Akt-1 down-activation and
apoptosis; however, the impact of a loss of p55γ on both Akt-1 activation and cell survival is significantly greater than
that from the loss of p85β; and (4) both the p110α/p85β and p110α/p55γ complexes are engaged by β1 integrin/Fak/Src signaling;
however, the engagement of p110α/p85β is primarily Src-dependent, whereas that of p110α/p55γ is primarily Fak-dependent (but
Src-independent). Hence, HIEC cells selectively express PI3-K isoform complexes, translating into distinct roles in Akt-1
activation and cell survival, as well as in a selective engagement by Fak and/or Src within the context of β1 integrin/Fak/Src-mediated
suppression of anoikis. 相似文献
7.
Heregulin-α (HRGα) is a cytokine secreted by the mammary mesenchyme, adjacent to lobuloalveolar structures. To understand
the role of HRGα and its receptors in mammary glands, and the underlying mechanisms, we performed this study to determine
the expression and localization of HRGα and its receptors ErbB2 and ErbB3. We also determined the role of HRGα in the development
of mammary glands, β-casein expression and secretion, Rab3A protein expression and the phosphorylation of HRGα signaling molecules
using confocal laser scanning microscopy, tissue culture, capillary electrophoresis, Western blotting and enzyme-linked immunosorbent
assays. We found that a peak was on pregnancy day 15. Changes of ErbB2 and ErbB3 expression were positively and linearly correlated
with HRGα, indicating that HRGα positively regulates ErbB2 and ErbB3 expression. During pregnancy, HRGα enhanced the phosphorylation
of STAT5, p42/p44, p38, PKC and Rab3A protein expression, stimulated the proliferation and differentiation of the ductal epithelial
cells of mammary glands, and increased and maintained the expression and secretion of β-casein. During lactation, HRGα enhanced
the phosphorylation of STAT5 and p38, inhibited the phosphorylation of PKC and Rab3A protein expression, maintained the morphology
of the mammary glands and increased the secretion of lactoprotein to reduce the expression of β-casein in mammary epithelial
cells. During involution, HRGα induced the phosphorylation of STAT3 and Rab3A protein expression, and inhibited the phosphorylation
of PKC to stimulate the degeneration of mammary epithelial cells. It also inhibited the secretion of β-casein, resulting in
increased levels of β-casein in mammary epithelial cells. 相似文献
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Exposure of p53 mutated estrogen-receptor-negative MDA-MB231 human breast tumor cells to a pharmacological concentration of estradiol enhances liposome-mediated uptake and expression of SV-40 luciferase. Unexpectedly, the effect of estradiol on SV-40 expression is evident even when estradiol exposure occurs after the initial uptake phase; this suggests that estradiol may influence gene expression by mechanisms other than increasing gene uptake alone, such as altering the intracellular distribution of the gene. We determined that while uptake of SV-40 luciferase is increased only three-fold by estradiol, there is a 30-fold increase in the nuclear/cytoplasmic ratio of the gene. In order to demonstrate that the influence of estradiol on gene uptake and expression is translated into a functional response, the effects of estradiol on the function of an exogenous gene, in this case the apoptotic function of p53, were assessed in the p53 mutated MDA-MB231 breast tumor cell. While liposome-mediated delivery of CMV-p53 alone was ineffective in promoting cell death, incubation with estradiol and the liposomal p53 complex resulted in a two-fold increase in cell killing over that observed in cells transfected with the corresponding mock vector (empty vector for p53). Evidence that cell killing was occurring through apoptosis included apoptotic body formation, cell shrinkage and an increase in fluorescence after terminal transferase end-labeling. The capacity of estradiol to promote apoptosis in MDA-MB231 cells by a p53-liposome complex is likely to be related to the preferential redistribution of the gene from the cytoplasm to the nucleus which could occur during both the uptake and post-uptake phases. Consequently, although direct effects on gene expression, and the stability of message and protein cannot be ruled out, the predominant effect of estradiol in this experimental system appears to be to influence DNA translocation from the cytoplasm to the cell nucleus. 相似文献
10.
Mycobacterium avium-intracellulare (MAI) is a ubiquitous environmental pathogen that causes disseminated infection in immunocompromised patients, such as those
with human immunodeficiency virus, interleukin-12 deficiency, or interferon-γ receptor mutation. Colony morphotypes are associated
with MAI pathogenicity. Our previous studies have reported that smooth-transparent (SmT) morphotypes are more virulent and
induce less cytokine (interleukin-1β and tumor necrosis factor-α) production by human monocytes than the smooth-domed (SmD)
morphotypes. Mitogen-activated protein (MAP) kinases such as extracellular-regulated kinase (ERK) are activated by the phagocytosis
of particle antigens in macrophages, and this ERK activation subsequently influences cytokine expression and the control of
intracellular pathogen growth. The influence of MAP kinase activation on MAI replication in human monocytes was examined.
Peripheral blood monocytes isolated from healthy subjects by Ficoll-Hypaque sedimentation were infected with virulent SmT
or avirulent SmD MAI without or with MAP kinase inhibitors. MAP kinase activities were determined by in vitro kinase assay,
intracellular MAI growth by CFU assay, and cytokines by enzyme-linked immunosorbent assay. MAI infection induced ERK and p38
activation. Inhibition of ERK by PD98059, but not p38, significantly increased intracellular MAI growth. Tumor necrosis factor-α
release and interleukin-1β production in response to MAI were reduced by MAP kinase inhibition. p38 inhibition tended to reduce
cytokine production more substantially. These data suggest that ERK activation limits intra-monocytic MAI replication and
enhances monocytic cytokine release, whereas p38 activation influences only cytokine release. The effect of MAP kinases on
MAI growth might thus be mediated by the modulation of cytokine production. 相似文献
11.
Eveline S. J. M. de Bont Anita E. Niemarkt Rienk Y. J. Tamminga Jan L. L. Kimpen Willem A. Kamps Lou H. M. F. de Leij 《Histochemistry and cell biology》1996,106(6):593-598
Lipopolysaccharide (LPS) can induce monocytes to produce various cytokines such as tumor necrosis factor α (TNFα) and interleukin
1β (IL-1β). In the present study, the kinetics of both intracellular and extracellular accumulation of TNFα and IL-1β in LPS
stimulated mononuclear cell (MNC) cultures has been determined. A three-color-immunofluorescence technique was used to detect
intracellular accumulation of cytokines. Intracellular accumulation of TNFα in monocytes starts shortly after initiation of
the culture; i.e., TNFα is detectable after 1 h, reaching a peak level after 3–4 hours with 50–65% of monocytes staining positive.
In parallel with its increased intracellular presence, TNFα was also found in the culture supernatant. The intracellular accumulation
of IL-1β in monocytes became detectable after 2 h of culture in the presence of LPS. After 4 h, a plateau was reached, with
90% of the monocytes being positive. In parallel, but with a little delay, IL-1β could be detected in the culture supernatant.
TNFα and IL-1β can be produced simultaneously in the same monocytes as was shown by a three-color-immunofluorescence technique.
It is concluded that TNFα and IL-1β are good parameters for the early measurement of monocyte activation and that both the
intracellular accumulation in monocytes and the amount of secreted cytokines can be used for such a purpose. The intracellular
accumulation in monocytes can be measured by the three-color-immunofluorescence technique described.
Accepted: 27 August 1996 相似文献
12.
Hong Zhao Jinmin Zhu Kemi Cui Xiaoyin Xu Megan O'Brien Kelvin K Wong Santosh Kesari Weiming Xia Stephen TC Wong 《Cancer cell international》2009,9(1):15
Background
Cancer and Alzheimer's disease (AD) are two seemingly distinct diseases and rarely occur simultaneously in patients. To explore molecular determinants differentiating pathogenic routes towards AD or cancer, we investigate the role of amyloid β protein (Aβ) on multiple tumor cell lines that are stably expressing luciferase (human glioblastoma U87; human breast adenocarcinoma MDA-MB231; and mouse melanoma B16F). 相似文献13.
Cannino G Ferruggia E Luparello C Rinaldi AM 《Journal of inorganic biochemistry》2008,102(8):1668-1676
It was reported that cadmium is able to exert a cytotoxic effect on tumor MDA-MB231 cells, which shows signs of “non-classical” apoptosis and is characterized by drastic changes in gene expression pattern. In this study, we have extended our knowledge of metal-breast cancer cell interactions by analyzing some mitochondria-related aspects of the stress response to CdCl2 at either 5 or 50 μM 24- or 96-h exposure, by cytochemical, conventional PCR and Northern/Western blot techniques. We demonstrated that (i) no modification of the mitochondrial mass was detectable due to CdCl2 exposure; (ii) the respiration activity appeared to be increased after 96-h exposures, while the production of reactive oxygen species was significantly induced, as well; (iii) hsp60, hsp70, COXII and COXIV expressions were dependent on the duration of Cd exposure; (iv) a different hsp60 protein distribution was observed in mitochondrial and post-mitochondrial extracts and (v) 96-h exposure induced the over-expression of hsc/hsp70 proteins and, conversely, the down-regulation of cytochrome oxidase subunits II and IV. These observations, in addition to providing more information on the cellular and molecular aspects of the interaction between CdCl2 and MDA-MB231 breast tumor cells, contribute to the comprehension of the intracellular molecular mechanisms implicated in the regulation of some mitochondrial proteins. 相似文献
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Transforming growth factor (TGF)-beta1, a crucial molecule in metastatic bone cancer, stimulates collagenase-3 expression in the human breast cancer cell line, MDA-MB231. Cycloheximide inhibited this stimulation, indicating that de novo protein synthesis was essential for this response. We examined whether mitogen-activated protein kinase (MAPK) and/or Smad pathways are involved in TGF-beta1-stimulated collagenase-3 expression in MDA-MB231 cells. Biochemical blockade of extracellular regulated kinase-1/2 and p38 MAPK pathways partially abolished TGF-beta1-stimulated collagenase-3 mRNA expression; whereas overexpression of a dominant negative form of Smad3 completely blocked the TGF-beta1-response. These data indicate that TGF-beta1-induced MAPK and Smad pathways are involved in TGF-beta1-stimulated collagenase-3 expression in MDA-MB231 cells. 相似文献
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Michael Hoffmann Mathias Schmidt Winfried Wels 《Cancer immunology, immunotherapy : CII》1998,47(3):167-175
Tumor necrosis factor (TNF)-α has a broad range of biological activities, which depend heavily on cell type and physiological
condition. In a panel of human tumor cell lines we analyzed expression of the receptor tyrosine kinases EGFR, ErbB2 and ErbB3,
and the response to TNF-α. Among the cell lines tested those resistant to TNF-α were found to express high levels of either
EGFR, or ErbB2 and ErbB3. In TNF-sensitive breast and cervical carcinoma cells activation of EGFR or ErbB2 by the exogenous
growth factors EGF and heregulin β1 resulted in a significant increase in the number of cells surviving TNF-α treatment. In
contrast, inhibition of EGFR activation in TNF-resistant breast carcinoma cells by the novel antagonistic anti-EGFR antibody
14E1 sensitized the cells to the cytotoxic effects of TNF-α. A bacterially expressed fusion protein consisting of a 14E1 single-chain
(sc) Fv antibody fragment linked to human TNF-α retained TNF-α activity. This scFv(14E1)-TNF-α molecule localized specifically
to EGFR on the surface of tumor cells and activated the NF-κB pathway in co-cultured T cells, as demonstrated by electrophoretic
mobility shift assays.
Received: 6 May 1998 / Accepted: 16 July 1998 相似文献
18.
Cadmium (Cd) is a widely-disseminated metal which can be imported and accumulated in living cells thereby drastically interfering with their biological mechanisms. Increasing interest has been recently focused on the elucidation of the cellular and molecular aspects of Cd-dependent regulation of gene expression and signal transduction pathways in different model system. Concerning breast cancer, very limited studies have been produced so far on the role played by Cd on estrogen receptor-negative human breast cancer cells, that are expected to be insensitive to the already-proven metallo-estrogenic effect exerted by Cd on the estrogen receptor-positive cell counterparts. Here, we have examined the effects of long-term (96h) exposure of estrogen receptor-negative MDA-MB231 malignant adenocarcinoma cells to CdCl(2) at 5muM concentration, corresponding to the IC(50) for this time of incubation, by evaluating the expression levels of genes coding for stress response factors (e.g. heat shock proteins and metallothioneins), and for apoptosis-related factors and enzymes. In parallel, we tested the gene expression pattern of immortalized HB2 breast epithelial cells, taken as non-tumoral counterpart, after the same exposure to the metal which instead did not exert any change in their cell number with respect to controls. Our cumulative results indicate that, whilst HB2 cells appear to activate defense mechanisms against metal stress principally via metallothionein massive up-regulation and appearance of the spliced form of XBP-1 message, MDA-MB231 cells seem to couple the onset of a protective reaction (e.g. up-regulation of hsp27 and metallothioneins) to the switching-on of new intracellular pathways directing cells to a kind of death which shares several aspects with the apoptotic program, such as down-regulation of Bcl-2 and over-expression of Dap kinase and several caspases. 相似文献
19.
The microvasculature of the corpus luteum (CL), which comprises greater than 50% of the total number of cells in the CL, is
thought to be the first structure to undergo degeneration via apoptosis during luteolysis. These studies compared the apoptotic
potential of various cytokines (tumor necrosis factor α, TNFα; interferon gamma, IFNγ; soluble Fas ligand, sFasL), a FAS activating
antibody (FasAb), and the luteolytic hormone prostaglandin F2α (PGF2α) on CL-derived endothelial (CLENDO) cells. Neither sFasL, FasAb nor PGF2α had any effect on CLENDO cell viability. Utilizing morphological and biochemical parameters it was evident that TNFα and
IFNγ initiated apoptosis in long-term cultures. However, TNFα was the most potent stimulus for CLENDO cell apoptosis at early
time points. Unlike many other studies described in non-reproductive cell types, TNFα induced apoptosis of CLENDO cells occurs
in the absence of inhibitors of protein synthesis. TNFα-induced death is typically associated with acute activation of distinct
intracellular signaling pathways (e.g. MAPK and sphingomyelin pathways). Treatment with TNFα for 5–30 min activated MAPKs (ERK, p38, and JNK), and increased ceramide
accumulation. Ceramide, a product of sphingomyelin hydrolysis, can serve as an upstream activator of members of the MAPK family
independently in numerous cell types, and is a well-established pro-apoptotic second messenger. Like TNFα, treatment of CLENDO
cells with exogenous ceramide significantly induced endothelial apoptosis. Ceramide also activated the JNK pathway, but had
no effect on ERK and p38 MAPKs. Pretreatment of CLENDO cells with glutathione (GSH), an intracellular reducing agent and known
inhibitor of reactive oxygen species (ROS) or TNFα-induced apoptosis, significantly attenuated TNFα-induced apoptosis. It
is hypothesized that TNFα kills CLENDO cells through elevation of reactive oxygen species, and intracellular signals that
promote apoptosis. 相似文献