Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of aspirin is associated with a lower risk of many cancer types. However, there are few reports about cervical cancer. The proto-oncogene ErbB2 is overexpressed in cervical cancer, and considered as a therapeutic target. In the present study, we investigated whether aspirin had therapeutic value in cervical cancer and examined the effects of aspirin on the amplification and expression of ErbB2. To investigate the effects of aspirin on apoptosis and proliferation, we tested apoptosis by Hoechst 33258 staining and Annexin V-FITC/PI method; MTT assay and colony formation assay were used to detect proliferation. Induction of apoptosis and inhibition of proliferation were observed in HeLa cells incubated with aspirin. Western blot and immunocytochemical staining showed that aspirin induced a dose- and time-dependent reduction of ErbB2 expression that was due to proteosome-mediated degradation of this protein. To further investigate the underlying mechanism by which aspirin exerts its apoptosis effects, we studied the ErbB2 downstream cell survival signaling pathways and the expression of anti-apoptosis gene Bcl-2. We found that aspirin inhibited the activation of extracellular signal-regulated kinase (ERK) and AKT. The inhibition of Bcl-2 expression was also observed. These data reveal that aspirin significantly induces apoptosis and inhibits proliferation, which maybe via inhibiting ErbB2 downstream cell survival signaling pathways. Taken together, our article describes a novel mechanism of action for anti-tumor activity of aspirin and implicates aspirin as a novel agent for cervical cancer.
 ...
PMID:Aspirin inhibits ErbB2 to induce apoptosis in cervical cancer cells. 1942 77

To investigate the anti-cancer effects and molecular mechanism of deguelin on the human leukemia HL-60 cells, to explore the expression and clinical significance of p-AKT, survivin and Bcl-2 in leukemia cell line HL-60 cell. Cell growth rate was assessed by MTT assay. Apoptotic index was evaluated by TUNEL staining. Apoptosis was detected by Annexin V-FITC Apoptosis Detection Kit and transmission electron microscopy (TEM), expression of p-Akt, Bcl-2 and surviving in HL-60 cells was checked by Western blot. Deguelin presented striking proliferation inhibition potency on HL-60 cells in vitro, with the I(C50) value for 48 h being 20.14 nM, and induced apoptosis in HL-60 in a concentration-time-dependent manner. Apoptotic bodies and cell shrinkage and fragmentation were observed by TUNEL and TEM. Deguelin-induced cells morphological changes and degraded several kinase proteins, including Bcl-2 and survivin (members of lap). The degradation of these kinases blocked PI3K/Akt survival signal pathways, inducing apoptosis. Deguelin may induce HL-60 cell apoptosis through depletion of multiple kinase proteins and blockage of survival signal pathways of HL-60 cells.
 ...
PMID:Deguelin blocks cells survival signal pathways and induces apoptosis of HL-60 cells in vitro. 1945 92

Autoimmunity affects a substantial fraction of our population. In patients with autoimmune disease, the immune system recognizes self-tissues as foreign. Common autoimmune diseases include rheumatoid arthritis, diabetes mellitus, lupus and multiple sclerosis. Though different target organs may be affected in different autoimmune diseases, aberrations in adaptive or innate immunity underlie all of these diseases. Abnormal functioning, differentiation and/or activation of T-cells, B-cells and myeloid cells have been documented in various autoimmune diseases. More recent studies have also detailed anomalous activation of various signaling axes including various MAPK, AKT, NF-kappaB, Bcl-2 family members, and JAK/STAT molecules in these cells, in the context of systemic autoimmunity. Among these, one molecular pathway that appears to be particularly attractive for therapeutic targeting is the PI3K/AKT/mTOR axis. In this review, we summarize how the AKT axis affects multiple molecular processes in autoimmune diseases and discuss the potential of targeting this axis in these diseases.
 ...
PMID:The AKT axis as a therapeutic target in autoimmune diseases. 1951 64

Transducer of ErbB-2 (TOB) is a member of the TOB/Btg gene family. A role for TOB in the suppression of human tumorigenesis has been proposed, based on the observations that TOB-knockout mice spontaneously form tumors and TOB expression is lost in human lung and thyroid cancers. However, the role of TOB in human breast cancer remains unknown. To evaluate the this role, we screened a panel of breast cancer cell lines for TOB expression levels and found that they are inversely correlated with the tumorigenicity and metastatic potential of the cell lines. In addition, we demonstrated for the first time that TOB expression is inversely correlated with breast cancer progression in clinical specimens. These results strongly indicate that the loss of TOB expression plays a role in breast cancer progression. We have also provided the first evidence that TOB functions as a tumor suppressor in breast cancer MCF-7 cells, using gain-of-function and loss-of-function approaches to manipulate TOB expression. Cell-cycle analysis further revealed that TOB can prolong the G1-S phase transition by inducing arrest at G1-S phase. Moreover, upregulation of the cyclin-dependent kinase inhibitor p27 and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-XL were observed in MCF7/TOB transfectants. Conversely, opposite results were observed in shRNA-TOB transfectants. Furthermore, decreased activity of Erk2, AKT, CrkL, PDK1, and Smads were observed in TOB-overexpressing cells. Taken together, these data provide evidence that TOB can function as a tumor suppressor in breast cancer through modulation and regulation of multiple signaling pathways.
 ...
PMID:TOB suppresses breast cancer tumorigenesis. 1956 30

Interleukin (IL)-10, a prototypical anti-inflammatory cytokine, has been shown to provide beneficial effects in neuronal injury in vivo but the full range of actions has not been established. In order to understand the neuronal mechanisms underlying IL-10-mediated neuroprotection, we examined the effect of IL-10 on primary neurons in culture. We found that IL-10 exerted a direct trophic influence on spinal cord neurons, and that activation of the neuronal IL-10 receptor provided trophic support and survival cues to overcome the neurotoxic effects of glutamate in vitro. IL-10 treatment resulted in activation of janus-associated kinases/signal transducers and transcription factors and phosphatidylinositol 3-kinase-AKT pathways in neurons to enhance expression of Bcl-2 and Bcl-x(L); under stress conditions IL-10 blocks cytochrome c release and caspase cleavage. IL-10 activation of the canonical nuclear factor kappaB pathway enhanced translocation of p50 and p65 and enhanced their binding to kappaB DNA sequences, with p50 playing a more prominent role in neuronal survival. These data indicate that in addition to known anti-inflammatory effects through astroglia in other inflammatory cells, IL-10 has direct neuronal effects with important implications for development and neuroprotection.
 ...
PMID:Interleukin-10 provides direct trophic support to neurons. 1957 7

Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to promote apoptosis in cancer cells. However, the role of EGCG in endothelial cells following ischemia/reperfusion (I/R) injury remains unclear. In the present study, we investigated the mechanisms by which EGCG enhances I/R-induced cell growth inhibition and apoptosis in human umbilical vein endothelial cells (HUVECs). Our results showed that EGCG treatment caused cell proliferation inhibition during I/R injury, and this effect was associated with increased p27 and p21 levels and reduced cyclin D1 level. Moreover, treatment of cells with EGCG resulted in increase of caspase-3 and Bax and decrease of Bcl-2, enhancing I/R-induced apoptosis. Interestingly, EGCG decreased I/R-induced phosphorylation of AKT and its downstream substrates Foxo1 and Foxo3a and ERK1/2. In contrast, EGCG increased JNK1/2 and c-Jun phosphorylation. Furthermore, both wortamannin (PI3K inhibitor) and U0126 (MEK1/2 inhibitor) markedly enhanced EGCG-induced apoptosis during I/R, whereas SP600125 (JNK inhibitor) attenuated the action of EGCG. Taken together, our study for the first time suggest that EGCG is able to enhance growth arrest and apoptosis of HUVECs during I/R injury, at least in part, through inhibition of AKT and ERK1/2 and activation of JNK1/2 signaling pathways.
 ...
PMID:Epigallocatechin-3-gallate enhances ischemia/reperfusion-induced apoptosis in human umbilical vein endothelial cells via AKT and MAPK pathways. 1966 89

The role of PI-3-K in the regulation of mitochondrial functions is becoming a field that draws attentions from cancer as well as metabolic diseases. In this review, we focus on the action of the major downstream target of PI-3-K, the serine/threonine kinase AKT, a proto-oncoprotein. We reviewed the functions of AKT in the mitochondrial intrinsic apoptosis pathway. We analyzed how AKT regulates the different factors in the Bcl-2 family of anti- and pro-apoptotic factors either directly or indirectly. We further reviewed the role of AKT in regulating mitochondrial coupled glycolysis through hexokinase II and VDAC. This review is focused on the function of PI-3-K and AKT at the mitochondrial. These interactions between the mitogenic PI-3-K/AKT and the mitochondrial function may provide clues on how tumors overcome the ongoing need for nutrient supply. Such characterizations can provide new targets for drug discoveries targeted at blocking tumor progression.
 ...
PMID:PI-3-K and AKT: Onto the mitochondria. 1972 99

Lovastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. Its inhibitory action on HMG-CoA reductase leads to depletion of isoprenoids, which inhibits post-translational modification of RAS. In this study, we investigated the effect of combining lovastatin with gefitinib on gefitinib-resistant human non-small cell lung cancer (NSCLC) cell lines with K-Ras mutations. Antitumor effects were measured by growth inhibition and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Effects on apoptosis were determined by flow cytometry, DNA fragmentation, and immunoblots. Protein levels of RAS, AKT/pAKT, and RAF/ERK1/2 in cancer cells were analyzed by immunoblot. Compared with gefitinib alone, a combination of gefitinib with lovastatin showed significantly enhanced cell growth inhibition and cytotoxicity in gefitinib-resistant A549 and NCI-H460 human NSCLC cells. In addition, lovastatin combination treatment significantly increased gefitinib-related apoptosis, as determined by fluorescence microscopy and flow cytometric analysis. These effects correlated with up-regulation of cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), and Bax and down-regulation of Bcl-2. The combination of lovastatin and gefitinib effectively down-regulated RAS protein and suppressed the phosphorylation of RAF, ERK1/2, AKT, and EGFR in both cell lines. Taken together, these results suggest lovastatin can overcome gefitinib resistance, in NSCLC cells with K-Ras mutations, by down regulation of RAS protein, which leads to inhibition of both RAF/ERK and AKT pathways.
 ...
PMID:Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations. 1976 Jan 59

Apoptosis and proliferation are two dynamically and tightly regulated processes that together maintain the homeostasis of renewable tissues. Anoikis is a subtype of apoptosis induced by detachment of adherent cells from the extracellular matrix. By using the defined mTeSR1 medium and collecting freshly detached cells, we found here that human pluripotent stem (PS) cells including embryonic stem (ES) cells and induced pluripotent stem cells are subject to constant anoikis in culture, which is escalated in the absence of basic fibroblast growth factor (bFGF). Withdrawal of bFGF also promotes apoptosis and differentiation of the remaining adherent cells without affecting their cell cycle progression. Insulin-like growth factor 2 (IGF2) has previously been reported to act downstream of FGF signaling to support self-renewal of human ES cells. However, we found that IGF2 cannot substitute bFGF in the TeSR1-supported culture, although endogenous IGF signaling is required to sustain self-renewal of human ES cells. On the other hand, all of the bFGF withdrawal effects observed here can be markedly prevented by the caspase inhibitor z-VAD-FMK. We further demonstrated that the bFGF-repressed anoikis is dependent on activation of ERK and AKT and associated with inhibition of Bcl-2-interacting mediator of cell death and the caspase-ROCK1-myosin signaling. Anoikis is independent of pre-detachment apoptosis and differentiation of the cells. Because previous studies of human PS cells have been focused on attached cells, our findings revealed a neglected role of bFGF in sustaining self-renewal of human PS cells: preventing them from anoikis via inhibition of caspase activation.
 ...
PMID:Inhibition of caspase-mediated anoikis is critical for basic fibroblast growth factor-sustained culture of human pluripotent stem cells. 1982 53

Sarcomas are a group of heterogeneous tumors that arise from mesenchymal tissue and account for approximately 1% of all adult solid malignancies diagnosed, although its incidence approaches 20% in pediatric cancers. Characterization of molecular abnormalities in patients with sarcomas, in particular the up-regulation of the receptor tyrosine kinase and the PI3K-AKT-mTOR pathway, loss or deletions of retinoblastoma (Rb) and p53 gene, increased VEGF expression and angiogenesis, dysregulation of apoptosis through Bcl-2 overexpression, along with oncogene mutations and activations, such as c-KIT in Gastrointestinal stromal tumors (GISTs), makes treatment with novel biological therapies a promising option. This review focuses on the molecular heterogeneity of soft tissue and bone sarcomas, novel biological therapies currently in clinical trials to target the various molecular pathways, and the potential biological agents in pre-clinical and early clinical development.
 ...
PMID:Targeting sarcomas: novel biological agents and future perspectives. 1986 Jun 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>