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Survival Pathways (survival + pathway)
Kinds of Survival Pathways Selected AbstractsEarly growth response 2 regulates the survival of thymocytes during positive selectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2010Victoria J. Lawson Abstract The early growth response (Egr) transcription factor family regulates multiple steps during T-cell development. We examine here the role played by Egr2 in positive selection. In double-positive cells, Egr2 is upregulated immediately following TCR ligation, and its expression requires both the MAPK and calcineurin signaling pathways. Inducible transgenic and knockout mice were generated to cause gain- or loss-of-function of Egr2 in double-positive cells, and had reciprocal effects; more mature single-positive cells were made when Egr2 was overexpressed, and fewer when Egr2 was absent. These defects were associated with changes in the survival of positively selected cells rather than perturbation of positive selection or immediate post-selection signaling. The survival function of Egr2 at least partly depends upon its ability to activate the cytokine-mediated survival pathway, likely through negative regulation of both the IL-7R and suppressor of cytokine signaling 1 (Socs1), the molecular switch whose downregulation normally results in restored responsiveness to cytokine signaling following selection. While gain of Egr2 caused a decrease in Socs1 mRNA, loss of Egr2 resulted in downregulation of IL-7R, upregulation of Socs1, and inhibition of Stat5 phosphorylation and IL-7-mediated survival post-selection. Therefore, expression of Egr2 following positive selection links the initial TCR signaling event to subsequent survival of signaled cells. [source] A stress survival response in retinal cells mediated through inhibition of the serine,/,threonine phosphatase PP2AEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2010Sorcha Finnegan Abstract Cell survival signalling involving the PI3K/Akt survival pathway can be negatively regulated by several phosphatases including PP2A. When retinal-derived 661W cells were subjected to trophic factor deprivation this initiated a survival response through inhibition of the activity of PP2A and subsequent upregulation of the Erk and Akt survival pathways. We show this survival response via inhibition of PP2A activity was due in part to increased reactive oxygen species production when retinal cells were deprived of trophic factors. Inhibition of PP2A activity was mediated by a rapid and transient increase in phosphorylation at Tyr307, accompanied by an increase in demethylation and a decrease in the methylated form. Pre-treatment with N -acetyl- l -cysteine, which is involved in scavenging reactive oxygen species, prevented PP2A inhibition and subsequent upregulation of survival pathways. Pre-treatment with the Src family kinase inhibitor PP2 resulted in approximately 50% reduction in cellular levels of phospho-PP2A in trophic factor-deprived 661W cells, suggesting an Src tyrosine kinase had a role to play in this redox regulation of cell survival. We observed similar events in the rd10 mouse retina where there was an increased survival response prior to retinal cell death mediated through an increase in both phospho-PP2A and phospho-Gsk. Together, these results demonstrate that when retinal cells are stressed there is an initial struggle to survive, mediated through inhibition of PP2A and subsequent upregulation of survival pathways, and that these events occur simultaneously with production of reactive oxygen species, thus suggesting an important cell-signalling role for reactive oxygen species. [source] Molecular and functional characterization of a novel splice variant of ANKHD1 that lacks the KH domain and its role in cell survival and apoptosiscFEBS JOURNAL, Issue 16 2005Melissa C. Miles Multiple ankyrin repeat motif-containing proteins play an important role in protein,protein interactions. ANKHD1 proteins are known to possess multiple ankyrin repeat domains and a single KH domain with no known function. Using yeast two-hybrid system analysis, we identified a novel splice variant of ANKHD1. This splice variant of ANKHD1, which we designated as HIV-1 Vpr-binding ankyrin repeat protein (VBARP), does not contain the signature KH domain, and codes for only a single ankyrin repeat motif. We characterized VBARP by molecular and functional analysis, revealing that VBARP is ubiquitously expressed in different tissues as well as cell lines of different lineage. In addition, blast searches indicated that orthologs and homologs to VBARP exist in different phyla, suggesting that VBARP might be evolutionarily conserved, and thus may be involved in basic cellular function(s). Furthermore, biochemical analysis revealed the presence of two VBARP isoforms coding for 69 and 49 kDa polypeptides, respectively, that are primarily localized in the cytoplasm. Functional analysis using short interfering RNA approaches indicate that this gene product is essential for cell survival through its regulation of caspases. Taken together, these results indicate that VBARP is a novel splice variant of ANKHD1 and may play a role in cellular apoptosis (antiapoptotic) and cell survival pathway(s). [source] 7-Ketocholesterol-induced apoptosisFEBS JOURNAL, Issue 12 2005Involvement of several pro-apoptotic but also anti-apoptotic calcium-dependent transduction pathways Oxysterols, and particularly 7-ketocholesterol, appear to be strongly involved in the physiopathology of atherosclerosis. These molecules are suspected to be cytotoxic to the cells of the vascular wall and monocytes/macrophages, particularly by inducing apoptosis. Previous studies have demonstrated that 7-ketocholesterol-induced apoptosis is triggered by a sustained increase of cytosolic-free Ca2+, which elicits the mitochondrial pathway of apoptosis by activation of the calcium-dependent phosphatase calcineurin, leading to dephosphorylation of the ,BH3 only' protein BAD. However, thorough study of the results suggests that other pathways are implicated in 7-ketocholesterol-induced cytotoxicity. In this study, we demonstrate the involvement of two other calcium-dependent pathways during 7-ketocholesterol-induced apoptosis. The activation of the MEK,ERK pathway by the calcium-dependent tyrosine kinase PYK 2, a survival pathway which delays apoptosis as shown by the use of the MEK inhibitor U0126, and a pathway involving another pro-apoptotic BH3 only protein, Bim. Indeed, 7-ketocholesterol treatment of human monocytic THP-1 cells induces the release of Bim-LC8 from the microtubule-associated dynein motor complex, and its association with Bcl-2. Therefore, it appears that 7-ketocholesterol-induced apoptosis is a complex phenomenon resulting from calcium-dependent activation of several pro-apoptotic pathways and also one survival pathway. [source] Radiation-induced HIF-1, cell survival pathway is inhibited by soy isoflavones in prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 7 2009Vinita Singh-Gupta Abstract We previously showed that treatment of prostate cancer cells with soy isoflavones and radiation resulted in greater cell killing in vitro, and caused downregulation of NF-,B and APE1/Ref-1. APE1/Ref-1 functions as a redox activator of transcription factors, including NF-,B and HIF-1,. These molecules are upregulated by radiation and implicated in radioresistance of cancer cells. We extended our studies to investigate the role of HIF-1, survival pathway and its upstream Src and STAT3 molecules in isoflavones and radiation interaction. Radiation induced phosphorylation of Src and STAT3 leading to induction of HIF-1,. Genistein, daidzein or a mixture of soy isoflavones did not activate this pathway. These data were observed both in PC-3 (AR-) and C4-2B (AR+) androgen-independent cell lines. Pretreatment with isoflavones inhibited Src/STAT3/HIF-1, activation by radiation and nuclear translocation of HIF-1,. These findings correlated with decreased expression of APE1/Ref-1 and DNA binding activity of HIF-1, and NF-,B. In APE1/Ref-1 cDNA transfected cells, radiation caused a greater increase in HIF-1, and NF-,B activities but this effect was inhibited by pretreatment with soy prior to radiation. Transfection experiments indicate that APE1/Ref-1 inhibition by isoflavones impairs the radiation-induced transcription activity of NF-,B and HIF-1,. This mechanism could result in the inhibition of genes essential for tumor growth and angiogenesis, as demonstrated by inhibition of VEGF production and HUVECs tube formation. Our novel findings suggest that the increased responsiveness to radiation mediated by soy isoflavones could be due to pleiotropic effects of isoflavones blocking cell survival pathways induced by radiation including Src/STAT3/HIF-1,, APE1/Ref-1 and NF-,B. © 2008 Wiley-Liss, Inc. [source] ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2003Stanislav Zelivianski Abstract Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone-refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine- and docetaxel-induced cell growth suppression of androgen-independent prostate cancer cells. In androgen-independent C-81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl-2 by increasing phosphorylated Bcl-2 by more than 6-fold and Bax expression by 3-fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl-2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl-2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel-induced growth suppression in PC-3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone-refractory prostate cancer. © 2003 Wiley-Liss, Inc. [source] Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt-mediated HIF-1, up-regulation and MMP9 activationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Gang Song Abstract Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein. OPN has been shown to facilitate the progression and metastasis of malignancies and has prognostic value in several types of cancer, including gastric cancer. However, the functional mechanism of OPN mediated metastatic growth in gastric cancer remains unclear. Here, using multiple in vitro and in vivo models, we report that OPN strongly promoted the progression and metastasis of gastric cancer. Immunohistochemical staining revealed that OPN, matrix metalloproteinase (MMP)9 and hypoxia-inducible factor (HIF)-1, have statistically significant different expression patterns between well- and poorly differentiated tissue samples (P < 0.05). Correlations existed between OPN and MMP9, and between OPN and HIF-1, (r1= 0.872, p1 < 0.01 and r2= 0.878, p2 < 0.01). Furthermore, OPN dramatically increased colony formation and invasion of gastric cancer cells in vitro and promoted tumour growth and metastasis in vivo. In addition, OPN potently protected gastric cancer cells from serum depletion-induced apoptosis. Further study shows that OPN activated phosphoinositide 3-kinase/Akt survival pathway and up-regulated HIF-1,via binding to ,v,3 integrins in gastric cancer cells. Moreover, we found that OPN could activate MMP9 and up-regulate MMP2. Taken together, our results suggest that the survival-promoting function is crucial for OPN to promote the development of gastric cancer, and HIF-1, and MMP9 may play key roles during this process. Thus, targeting OPN and its related signalling network may develop an effective therapeutic approach for the management of gastric cancer. [source] Mahanine inhibits growth and induces apoptosis in prostate cancer cells through the deactivation of Akt and activation of caspases,THE PROSTATE, Issue 12 2006Swati Sinha Abstract BACKGROUND The present study was undertaken to evaluate anti-proliferative and -apoptotic activities of mahanine, a plant derived carbazole alkaloid, in prostate cancer cells and to determine its molecular mechanism by which it induces apoptotic cell death. METHODS The growth inhibitory and apoptotic inductive effect of mahanine on prostate cancer cells were examined by measuring cell proliferation and BrdU labeling, caspase activity, DNA fragmentation, and Western blot analyses. RESULTS Mahanine inhibited growth of PC3 and LNCaP prostate cancer cells in a dose and time-dependent manner. Mechanistically, mahanine inhibited cell-survival pathway by dephosphorylation of PIP3 dependent kinase 1 (PDK1) thereby deactivation of Akt and downregulation of Bcl-xL. In addition, mahanine activated caspase pathway (caspases 9 and 3) and eventually cleavage of DNA repair enzyme, PARP resulting DNA fragmentation and apoptosis. CONCLUSIONS Mahanine inhibits growth and induces apoptosis in both androgen-responsive, LNCaP and androgen-independent, PC3 cells by targeting cell survival pathway. Prostate © 2006 Wiley-Liss, Inc. [source] Expression and function of the adaptor protein Gads in murine B,cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2005Thomas Abstract Nearly all hematopoietic receptors are dependent on adaptor proteins for the activation of downstream signaling pathways. The Gads adaptor protein is expressed in many hematopoietic tissues, including bone marrow, lymph node, and spleen. Using intracellular staining, we detected Gads protein in a number cells, including B,cells, T,cells, NK cells, monocytes, and plasmacytoid DC, but not in macrophages, neutrophils, or monocyte-derived DC. In the B,cell compartment, Gads was first expressed after immature B,cells leave the bone marrow and was down-regulated after B,cell antigen receptor (BCR) ligation. Female Gads,/, mice had increased numbers of splenic B,cells, as compared to female Gads+/+ mice, suggesting a role for Gads in B,cell homeostasis. Although B,cell production and turnover of splenic B,cell subsets appeared normal in Gads,/, mice, homeostatic proliferation was significantly impaired in Gads,/, B,cells. Whereas BCR ligation can induce apoptosis in wild-type transitional stage 1 (T1) B,cells, Gads,/, T1 B,cells were resistant to BCR-induced apoptosis. Gads,/, B,cells also showed increased BCR-mediated calcium mobilization. We conclude that Gads may have a negative regulatory role in signaling through survival pathways, and is necessary for normal homeostatic proliferation in B,cells. [source] A stress survival response in retinal cells mediated through inhibition of the serine,/,threonine phosphatase PP2AEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2010Sorcha Finnegan Abstract Cell survival signalling involving the PI3K/Akt survival pathway can be negatively regulated by several phosphatases including PP2A. When retinal-derived 661W cells were subjected to trophic factor deprivation this initiated a survival response through inhibition of the activity of PP2A and subsequent upregulation of the Erk and Akt survival pathways. We show this survival response via inhibition of PP2A activity was due in part to increased reactive oxygen species production when retinal cells were deprived of trophic factors. Inhibition of PP2A activity was mediated by a rapid and transient increase in phosphorylation at Tyr307, accompanied by an increase in demethylation and a decrease in the methylated form. Pre-treatment with N -acetyl- l -cysteine, which is involved in scavenging reactive oxygen species, prevented PP2A inhibition and subsequent upregulation of survival pathways. Pre-treatment with the Src family kinase inhibitor PP2 resulted in approximately 50% reduction in cellular levels of phospho-PP2A in trophic factor-deprived 661W cells, suggesting an Src tyrosine kinase had a role to play in this redox regulation of cell survival. We observed similar events in the rd10 mouse retina where there was an increased survival response prior to retinal cell death mediated through an increase in both phospho-PP2A and phospho-Gsk. Together, these results demonstrate that when retinal cells are stressed there is an initial struggle to survive, mediated through inhibition of PP2A and subsequent upregulation of survival pathways, and that these events occur simultaneously with production of reactive oxygen species, thus suggesting an important cell-signalling role for reactive oxygen species. [source] Radiation-induced HIF-1, cell survival pathway is inhibited by soy isoflavones in prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 7 2009Vinita Singh-Gupta Abstract We previously showed that treatment of prostate cancer cells with soy isoflavones and radiation resulted in greater cell killing in vitro, and caused downregulation of NF-,B and APE1/Ref-1. APE1/Ref-1 functions as a redox activator of transcription factors, including NF-,B and HIF-1,. These molecules are upregulated by radiation and implicated in radioresistance of cancer cells. We extended our studies to investigate the role of HIF-1, survival pathway and its upstream Src and STAT3 molecules in isoflavones and radiation interaction. Radiation induced phosphorylation of Src and STAT3 leading to induction of HIF-1,. Genistein, daidzein or a mixture of soy isoflavones did not activate this pathway. These data were observed both in PC-3 (AR-) and C4-2B (AR+) androgen-independent cell lines. Pretreatment with isoflavones inhibited Src/STAT3/HIF-1, activation by radiation and nuclear translocation of HIF-1,. These findings correlated with decreased expression of APE1/Ref-1 and DNA binding activity of HIF-1, and NF-,B. In APE1/Ref-1 cDNA transfected cells, radiation caused a greater increase in HIF-1, and NF-,B activities but this effect was inhibited by pretreatment with soy prior to radiation. Transfection experiments indicate that APE1/Ref-1 inhibition by isoflavones impairs the radiation-induced transcription activity of NF-,B and HIF-1,. This mechanism could result in the inhibition of genes essential for tumor growth and angiogenesis, as demonstrated by inhibition of VEGF production and HUVECs tube formation. Our novel findings suggest that the increased responsiveness to radiation mediated by soy isoflavones could be due to pleiotropic effects of isoflavones blocking cell survival pathways induced by radiation including Src/STAT3/HIF-1,, APE1/Ref-1 and NF-,B. © 2008 Wiley-Liss, Inc. [source] From anchorage dependent proliferation to survival: Lessons from redox signallingIUBMB LIFE, Issue 5 2008Paola Chiarugi Abstract Anchorage to extracellular matrix (ECM) is essential for the execution of the mitotic program of nontransformed cells as they need simultaneous signals starting from mitogenic molecules, as growth factors (GFs), and adhesive agents belonging to ECM. Reactive oxygen species play a key function during both GF and integrin receptor signalling and are therefore recognised to have a synergistic function with several others transducers for anchorage-dependent growth (ADG). Indeed, redox-regulated proteins include protein tyrosine phosphatases, protein tyrosine kinases, small GTPases, cytoskeleton proteins, as well as several transcription factors. In this review, we focus on the role of reactive oxygen species (ROS) as key second messengers granting a proper executed mitosis for anchorage-dependent cells through redox regulation of several downstream targets. Besides, redox signals elicited by ECM contact assure a protection from anoikis, a specific apoptosis induced by lack of anchorage. Cancer cells frequently show a deregulation of ROS production and a constitutive oxidative stress has been associated to the achievement of an invasive phenotype. Hence, in cancer cells, the constitutive deregulation of both mitogenic and survival pathways, likely mimicking autocrine/adhesive signals, helps to guide the transformed cells to escape the innate apoptotic response to abolish the signals started by cell/ECM contact, thus sustaining the spreading of anchorage-independent cancer cells and the metastases growth. © 2008 IUBMB IUBMB Life, 60(5): 301,307, 2008 [source] Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cellsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2008Sheng-Huei Yang Abstract N,-(11H-indolo[3,2-c]quinolin-6-yl)- N,N -dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective antitumor agent in human leukemia cells. In the present study, treatment with IQDMA inhibited phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr-Abl, and Janus-activated kinase (JAK2) in a time-dependent manner. IQDMA also degraded JAK2 protein. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling were also blocked by IQDMA. However, IQDMA did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt and extracellular signal-regulated kinase 1/2. Furthermore, IQDMA upregulated the expression of p21 and p27 and downregulated the expression of cyclin D1, myeloid cell leukemia-1(Mcl-1), Bcl-XL, and vascular endothelial growth factor (VEGF). Taken together, these results indicate that IQDMA causes significant induction of apoptosis in K562 cells via downregulation of EGFR, Src, Bcr-Abl, JAK2, and STAT5 signaling and modulation of p21, p27, cyclin D1, Mcl-1, Bcl-XL, and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukemia K562 cells. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:396,404, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20254 [source] Apoptosis evasion: The role of survival pathways in prostate cancer progression and therapeutic resistanceJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Shaun McKenzie Abstract The ability of a tumor cell population to grow exponentially represents an imbalance between cellular proliferation and cellular attrition. There is an overwhelming body of evidence suggesting the ability of tumor cells to avoid programmed cellular attrition, or apoptosis, is a major molecular force driving the progression of human tumors. Apoptotic evasion represents one of the true hallmarks of cancer and appears to be a vital component in the immunogenic, chemotherapeutic, and radiotherapeutic resistance that characterizes the most aggressive of human cancers [Hanahan and Weinberg, 2000]. The challenges in the development of effective treatment modalities for advanced prostate cancer represent a classic paradigm of the functional significance of anti-apoptotic pathways in the development of therapeutic resistance. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] The radical scavenger CR-6 protects SH-SY5Y neuroblastoma cells from oxidative stress-induced apoptosis: effect on survival pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 3 2006Nuria Sanvicens Abstract Reactive oxygen species (ROS) and oxidative stress have long been linked to cell death of neurons in many neurodegenerative conditions. However, the exact molecular mechanisms triggered by oxidative stress in neurodegeneration are at present unclear. In the current work we have used the human neuroblastoma SH-SY5Y cell line as a model for studying the molecular events occurring after inducing apoptosis with H2O2. We show that treatment of SH-SY5Y cells with H2O2 up-regulates survival pathways during early stages of apoptosis. Subsequently, the decline of anti-apoptotic protein levels leads to the activation of the calcium-dependent proteases calpains and the cysteine proteases caspases. Additionally, we demonstrate that CR-6 (3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran) acts as a scavenger of ROS and prevents apoptosis by enhancing and prolonging up-regulation of survival pathways. Furthermore, we show that pre-treatment of SH-SY5Y cells with a cocktail containing CR-6, the pan-caspase inhibitor zVAD-fmk (zVal-Ala-Asp-fluoro-methylketone) and the calpain inhibitor SJA6017 confers almost total protection against apoptosis. In summary, the present work characterizes the molecular mechanisms involved in oxidative stress-induced apoptosis in SH-SY5Y cells. Our findings highlight the relevance of CR-6, alone or in combination with other drugs, as potential therapeutic strategy for the treatment of neurodegenerative diseases. [source] Alcohol in Moderation, Cardioprotection, and Neuroprotection: Epidemiological Considerations and Mechanistic StudiesALCOHOLISM, Issue 2 2009Michael A. Collins In contrast to many years of important research and clinical attention to the pathological effects of alcohol (ethanol) abuse, the past several decades have seen the publication of a number of peer-reviewed studies indicating the beneficial effects of light-moderate, nonbinge consumption of varied alcoholic beverages, as well as experimental demonstrations that moderate alcohol exposure can initiate typically cytoprotective mechanisms. A considerable body of epidemiology associates moderate alcohol consumption with significantly reduced risks of coronary heart disease and, albeit currently a less robust relationship, cerebrovascular (ischemic) stroke. Experimental studies with experimental rodent models and cultures (cardiac myocytes, endothelial cells) indicate that moderate alcohol exposure can promote anti-inflammatory processes involving adenosine receptors, protein kinase C (PKC), nitric oxide synthase, heat shock proteins, and others which could underlie cardioprotection. Also, brain functional comparisons between older moderate alcohol consumers and nondrinkers have received more recent epidemiological study. In over half of nearly 45 reports since the early 1990s, significantly reduced risks of cognitive loss or dementia in moderate, nonbinge consumers of alcohol (wine, beer, liquor) have been observed, whereas increased risk has been seen only in a few studies. Physiological explanations for the apparent CNS benefits of moderate consumption have invoked alcohol's cardiovascular and/or hematological effects, but there is also experimental evidence that moderate alcohol levels can exert direct "neuroprotective" actions,pertinent are several studies in vivo and rat brain organotypic cultures, in which antecedent or preconditioning exposure to moderate alcohol neuroprotects against ischemia, endotoxin, ,-amyloid, a toxic protein intimately associated with Alzheimer's, or gp120, the neuroinflammatory HIV-1 envelope protein. The alcohol-dependent neuroprotected state appears linked to activation of signal transduction processes potentially involving reactive oxygen species, several key protein kinases, and increased heat shock proteins. Thus to a certain extent, moderate alcohol exposure appears to trigger analogous mild stress-associated, anti-inflammatory mechanisms in the heart, vasculature, and brain that tend to promote cellular survival pathways. [source] Intracellular survival pathways in the liverLIVER INTERNATIONAL, Issue 10 2006Tom Luedde Abstract: Recent studies have drawn attention to cytokines as important modulators of hepatocyte cell death during acute and chronic liver disease. Through interaction with cell surface receptors, they activate specific intracellular pathways that influence cell fate in different manners. For example, tumor necrosis factor not only induces proapoptotic signals via the caspase cascade but also activates intracellular survival pathways, namely the nuclear factor (NF)-,B pathway. In this article, we will focus on the function of the NF-,B pathway in liver physiology and pathology. Especially, recent data based on experiments with genetically modified mice will be discussed, which demonstrated important and controversial functions of this pathway e.g. in cytokine-mediated hepatocyte apoptosis, ischemia-reperfusion injury, liver regeneration and the development of hepatocellular carcinoma. Moreover, the role of the interleukin-6 pathway and its possible protective function in the context of liver failure will be summarized. [source] Quantitative mass spectrometry to investigate epidermal growth factor receptor phosphorylation dynamicsMASS SPECTROMETRY REVIEWS, Issue 1 2008Sven Schuchardt Abstract Identifying proteins of signaling networks has received much attention, because an array of biological processes are entirely dependent on protein cross-talk and protein,protein interactions. Protein posttranslational modifications (PTM) add an additional layer of complexity, resulting in complex signaling networks. Of particular interest to our working group are the signaling networks of epidermal growth factor (EGF) receptor, a transmembrane receptor tyrosine kinase involved in various cellular processes, including cell proliferation, differentiation, and survival. Ligand binding to the N -terminal residue of the extracellular domain of EGF receptor induces conformational changes, dimerization, and (auto)-phosphorylation of intracellular tyrosine residues. In addition, activated EGF receptor may positively affect survival pathways, and thus determines the pathways for tumor growth and progression. Notably, in many human malignancies exaggerated EGF receptor activities are commonly observed. An understanding of the mechanism that results in aberrant phosphorylation of EGF receptor tyrosine residues and derived signaling cascades is crucial for an understanding of molecular mechanisms in cancer development. Here, we summarize recent labeling methods and discuss the difficulties in quantitative MS-based phosphorylation assays to probe for receptor tyrosine kinase (RTK) activity. We also review recent advances in sample preparation to investigate membrane-bound RTKs, MS-based detection of phosphopeptides, and the diligent use of different quantitative methods for protein labeling. © 2007 Wiley Periodicals, Inc., Mass Spec Rev 27:51,65, 2008 [source] Cooperative inhibitory effect of ZD1839 (Iressa) in combination with 17-AAG on glioma cell growth,MOLECULAR CARCINOGENESIS, Issue 5 2006Daniel R. Premkumar Abstract ZD1839 ("Iressa") is an orally active, selective epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor. We evaluated the antitumor activity of ZD1839 in combination with HSP90 antagonist, 17-AAG in malignant human glioma cell lines. ZD1839 independently produced a dose-dependent inhibition of cellular proliferation in glioma cells grown in culture with time- and dose-dependent accumulation of cells in G1 phase of the cell cycle on flow cytometric analysis, although the concentrations required for optimal efficacy were at or above the limits of clinically achievable levels. Because the heat shock protein (HSP) is involved in the conformational maturation of a number of signaling proteins critical to the proliferation of malignant glioma cells, we hypothesized that the HSP90 inhibitor 17-AAG would potentiate ZD 1839-mediated glioma cytotoxicity by decreasing the activation status of EGF receptor, as well as downregulating the levels of other relevant signaling effectors. We, therefore, examined the effects of ZD1839 and 17-AAG, alone and in combination, on signal transduction and apoptosis in a series of malignant glioma cell lines. Simultaneous exposure to these inhibitors significantly induced cell death and quantitative analysis revealed that interaction between ZD1839 and 17-AAG-induced cytotoxicity was synergistic, leading to a pronounced increase in active caspase-3 and PARP cleavage. No significant growth inhibition or caspase activation was seen in control cells. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and a significant downregulation of EGFR receptor, Raf-1 and mitogen activated protein kinase (MAPK). Cells exposed to 17-AAG and ZD1839 displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that ZD1839, an EGF receptor tyrosine kinase inhibitor, plays a critical role in regulating the apoptotic response to 17-AAG and that multi-site targeting of growth signaling and cell survival pathways could provide a potent strategy to treat patients with malignant gliomas. © 2006 Wiley-Liss, Inc. [source] Proteomic and SAGE profiling of murine melanoma progression indicates the reduction of proteins responsible for ROS degradationPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2006Gustavo A. de Souza Abstract Using 2-DE of total cell protein extracts, we compared soluble proteins from murine melanoma lines Tm1 and Tm5 with proteins from the nontumoral cell melan-a from which they were derived. Seventy-one of the 452 spots (average) detected with CBB were differentially accumulated, i.e., increased or decreased twofold. Forty-four spots were identified by PMF/MALDI-TOF, 15 with increased and 29 with decreased protein levels. SAGE showed that 17/34 (50%) of the differentially accumulated proteins, pI range 4,7, presented similar differences at the mRNA level. Major reductions in protein were observed in tumor cells of proteins that degrade reactive oxygen species (ROS). Decreases of , twofold in GST, superoxide dismutase, aldehyde dehydrogenase, thioredoxin, peroxiredoxin 2, and peroxiredoxin 6 protein were observed. SAGE indicated the reduction of other proteins involved in ROS degradation. As expected, the accumulation of exogenous peroxides was significantly higher in the tumor cells while the levels of glutathionylation were two times lower in the tumor cells compared to melan-a. The differential accumulation of proteins involved in oncogene/tumor suppressor pathways was observed. Melanoma cells can favor survival pathways activated by ROS by inhibiting p53 pathways and activation of Ras and c-myc pathways. [source] YB-1 is upregulated during prostate cancer tumor progression and increases P-glycoprotein activityTHE PROSTATE, Issue 3 2004Pepita Giménez-Bonafé Abstract BACKGROUND Currently, the main obstacle to curing advanced prostate cancer is development of androgen independence (AI), where malignant cells acquire the ability to survive in the absence of androgens. Our initial experimental approach used cDNA microarrays to characterize changes in gene expression in the LNCaP human prostate tumor model during progression to AI. The transcription factor Y-box binding protein (YB-1) was shown to be one of the genes upregulated. We focused on increased YB-1 expression during progression in clinical specimens, and further examined one of its downstream targets, P-glycoprotein (P-gp). METHODS Northern blot analysis was performed on LNCaP tumor series, as well as immunohistochemical analyses of human prostate cancer tissue samples. YB-1 was transiently transfected and transport analysis were performed to analyze P-gp efflux activity. RESULTS YB-1 expression is markedly increased during benign to malignant transformation and further following androgen ablation. In addition, increased YB-1 expression after castration in the LNCaP model is linked to upregulation of P-gp. We demonstrate that YB-1 upregulates P-gp activity resulting in a 40% intracellular decrease in the P-gp substrate vinblastine. We have also found that P-gp increases the efflux of the endogenous androgen, dihydrotestosterone (DHT), from prostate cells and leads to decreased androgen regulated gene expression. CONCLUSIONS We hypothesize that early in prostate cancer progression, increased expression of YB-1 may increase P-gp activity which may in turn lower androgen levels in the prostate tumor cells. Suppression of androgen levels may activate cell survival pathways and lead to an adaptive survival advantage of androgen independent prostate cancer cells following androgen ablation therapy. © 2004 Wiley-Liss, Inc. [source] Curcumin in Cancer Chemoprevention: Molecular Targets, Pharmacokinetics, Bioavailability, and Clinical TrialsARCHIV DER PHARMAZIE, Issue 9 2010Adeeb Shehzad Abstract Curcumin (diferuloylmethane), a derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Abundant sources provide interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. The pleiotropic role of this dietary compound includes the inhibition of several cell signaling pathways at multiple levels, such as transcription factors (NF-,B and AP-1), enzymes (COX-2, MMPs), cell cycle arrest (cyclin D1), proliferation (EGFR and Akt), survival pathways (,-catenin and adhesion molecules), and TNF. Curcumin up-regulates caspase family proteins and down-regulates anti-apoptotic genes (Bcl-2 and Bcl-XL). In addition, cDNA microarrays analysis adds a new dimension for molecular responses of cancer cells to curcumin at the genomic level. Although, curcumin's poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies. Currently, sufficient data has been shown to advocate phase II and phase III clinical trials of curcumin for a variety of cancer conditions including multiple myeloma, pancreatic, and colon cancer. [source] Molecular targets of lithium actionACTA NEUROPSYCHIATRICA, Issue 6 2003B Corbella Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1). [source] | ||||||||||||||||