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Scattering of MCF7 Cells by Heregulin ?-1 Depends on the MEK and p38 MAP Kinase Pathway  [PDF]
Rintaro Okoshi, Chung-Li Shu, Sayoko Ihara, Yasuhisa Fukui
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053298
Abstract: Heregulin (HRG) β1 signaling promotes scattering of MCF7 cells by inducing breakdown of adherens and tight junctions. Here, we show that stimulation with HRG-β1 causes the F-actin backbone of junctions to destabilize prior to the loss of adherent proteins and scattering of the cells. The adherent proteins dissociate and translocate from cell–cell junctions to the cytosol. Moreover, using inhibitors we show that the MEK1 pathway is required for the disappearance of F-actin from junctions and p38 MAP kinase activity is essential for scattering of the cells. Upon treatment with a p38 MAP kinase inhibitor, adherens junction complexes immediately reassemble, most likely in the cytoplasm, and move to the plasma membrane in cells dissociated by HRG-β1 stimulation. Subsequently, tight junction complexes form, most likely in the cytoplasm, and move to the plasma membrane. Thus, the p38 MAP kinase inhibitor causes a re-aggregation of scattered cells, even in the presence of HRG-β1. These results suggest that p38 MAP kinase signaling to adherens junction proteins regulates cell aggregation, providing a novel understanding of the regulation of cell–cell adhesion.
Analysis of Safety from a Human Clinical Trial with Pterostilbene  [PDF]
Daniel M. Riche,Corey L. McEwen,Krista D. Riche,Justin J. Sherman,Marion R. Wofford,David Deschamp,Michael Griswold
Journal of Toxicology , 2013, DOI: 10.1155/2013/463595
Abstract: Objectives. The purpose of this trial was to evaluate the safety of long-term pterostilbene administration in humans. Methodology. The trial was a prospective, randomized, double-blind placebo-controlled intervention trial enrolling patients with hypercholesterolemia (defined as a baseline total cholesterol ≥200?mg/dL and/or baseline low-density lipoprotein cholesterol ≥100?mg/dL). Eighty subjects were divided equally into one of four groups: (1) pterostilbene 125?mg twice daily, (2) pterostilbene 50?mg twice daily, (3) pterostilbene 50?mg + grape extract (GE) 100?mg twice daily, and (4) matching placebo twice daily for 6–8 weeks. Safety markers included biochemical and subjective measures. Linear mixed models were used to estimate primary safety measure treatment effects. Results. The majority of patients completed the trial (91.3%). The average age was 54 years. The majority of patients were females (71%) and Caucasians (70%). There were no adverse drug reactions (ADRs) on hepatic, renal, or glucose markers based on biochemical analysis. There were no statistically significant self-reported or major ADRs. Conclusion. Pterostilbene is generally safe for use in humans up to 250?mg/day. 1. Introduction Pterostilbene is a phenol that is chemically related to resveratrol, a possible contributor to the “French Paradox” which associates red wine consumption and lower coronary heart disease [1, 2]. Naturally found in blueberries and grapes, pterostilbene is a phytoalexin, a class of compounds naturally synthesized by plants during pathogen infection. The primary structural difference between pterostilbene and resveratrol is that pterostilbene contains two methoxy groups and one hydroxyl group while resveratrol has three hydroxyl groups. The two methoxy groups cause pterostilbene to be more lipophilic, which increases oral absorption and gives pterostilbene a higher potential for cellular uptake [3]. Pterostilbene has a longer half-life (105 minutes versus 14 minutes) and higher oral bioavailability (80% versus 20%) compared to resveratrol [4–7]. Pterostilbene also has low total body clearance and subsequent Vss which suggests extensive tissue distribution [4]. There has been extensive animal research examining both the safety and efficacy of pterostilbene. Animal studies have demonstrated efficacy in cardiometabolics (e.g., cholesterol and blood glucose), as well as cancer and cognition mediators [8–10]. Substances that are generally recognized as safe (GRAS) are exempt from premarket Food and Drug Administration (FDA) review and may be intentionally added to
Role of Rac1/p38 and ERK-Dependent Cytosolic Phospholipase A2 Activation in Porphyromonas gingivalis-Evoked Induction in Matrix Metalloproteinase-9 (MMP-9) Release by Salivary Gland Cells  [PDF]
Bronislaw L. Slomiany, Amalia Slomiany
Journal of Biosciences and Medicines (JBM) , 2016, DOI: 10.4236/jbm.2016.44010
Abstract: Matrix metalloproteinase-9 (MMP-9) is a highly glycosylated endopeptidase implicated in a wide rage of oral mucosal inflammatory and neoplastic diseases, including chronic periodontitis, a persistent mucosal inflammation attributed primarily to infection by oral anaerobe, P. gingivalis. In this study, we explored the role of Rac1 and mitogen-activated protein kinases (MAPKs) in the processes of MMP-9 release in sublingual salivary gland cells exposed to P. gingivalis key endotoxin, cell wall lipopolysaccharide (LPS). We demonstrate that the LPS-elicited induction in the acinar cell MMP-9 release is associated with MAPK, ERK and p38 activation, and occurs with the involvement of Rac1 and cytosolic phospholipase A2 (cPLA2). Further, we reveal that the LPS-induced MMP-9 release involves ERK-mediated phosphorylation of cPLA2 on Ser505 that is essential for its membrane translocation with Rac1, and that this process requires p38 activation. Moreover, we show that phosphorylation and membrane localization of p38 with Rac1-GTP play a pivotal role in cPLA2-dependent induction in MMP-9 release. Thus collectively, our findings infer that P. gingivalis LPS-induced up-regulation in the acinar cell MMP-9 release requires ERK-dependent recruitment of cPLA2 to the membrane localized Rac1/p38 complex.
Expression and function of heregulin-α and its receptors in the mouse mammary gland
LiJing Geng,QingZhang Li
Science China Life Sciences , 2010, DOI: 10.1007/s11427-010-4042-0
Abstract: 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.
Identification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrol
Zhiqiang Pan, Ameeta K Agarwal, Tao Xu, Qin Feng, Scott R Baerson, Stephen O Duke, Agnes M Rimando
BMC Medical Genomics , 2008, DOI: 10.1186/1755-8794-1-7
Abstract: S. cerevisiae strain S288C was exposed to pterostilbene at the IC50 concentration (70 μM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and S. cerevisiae mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene.Transcript profiling studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment.Using transcript profiling, we have identified the cellular pathways targeted by pterostilbene, an analog of resveratrol. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties, and the induction of mitochondrial genes is consistent with its demonstrated role in apoptosis in human cancer cell lines. Furthermore, our data show that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound.Pterostilbene is a naturally-occurring phytoalexin identified in several plant species. It belongs to a group of phenolic compounds known as stilbenes, and is found in the heartwood of sandalwood (Pterocarpus santalinus) [1] and P. marsupium [2]. It was also identified in the leaves of Vitis vinifera [3], in infected grape berries of var. Chardonnay and Gamay [4], and in healthy and immature berries of var. Pinot Noir and Gamay [5]. Pterostilbene has al
Ethanol Extracts of Fruiting Bodies of Antrodia cinnamomea Suppress CL1-5 Human Lung Adenocarcinoma Cells Migration by Inhibiting Matrix Metalloproteinase-2/9 through ERK, JNK, p38, and PI3K/Akt Signaling Pathways
Ying-Yi Chen,Fon-Chang Liu,Pei-Yu Chou,Yi-Chung Chien,Wun-Shaing Wayne Chang,Guang-Jhong Huang,Chieh-Hsi Wu,Ming-Jyh Sheu
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/378415
Abstract: Cancer metastasis is a primary cause of cancer death. Antrodia cinnamomea (A. cinnamomea), a medicinal mushroom in Taiwan, has shown antioxidant and anticancer activities. In this study, we first observed that ethanol extract of fruiting bodies of A. cinnamomea (EEAC) exerted a concentration-dependent inhibitory effect on migration and motility of the highly metastatic CL1-5 cells in the absence of cytotoxicity. The results of a gelatin zymography assay showed that A. cinnamomea suppressed the activities of matrix metalloproteinase-(MMP-) 2 and MMP-9 in a concentration-dependent manner. Western blot results demonstrated that treatment with A. cinnamomea decreased the expression of MMP-9 and MMP-2; while the expression of the endogenous inhibitors of these proteins, that is, tissue inhibitors of MMP (TIMP-1 and TIMP-2) increased. Further investigation revealed that A. cinnamomea suppressed the phosphorylation of ERK1/2, p38, and JNK1/2. A. cinnamomea also suppressed the expressions of PI3K and phosphorylation of Akt. Furthermore, treatment of CL1-5 cells with inhibitors specific for PI3K (LY 294002), ERK1/2 (PD98059), JNK (SP600125), and p38 MAPK (SB203580) decreased the expression of MMP-2 and MMP-9. This is the first paper confirming the antimigration activity of this potentially beneficial mushroom against human lung adenocarcinoma CL1-5 cancer cells.
Angiotensin II induces NF-κB, JNK and p38 MAPK activation in monocytic cells and increases matrix metalloproteinase-9 expression in a PKC- andRho kinase-dependent manner
Yaghooti, H.;Firoozrai, M.;Fallah, S.;Khorramizadeh, M.R.;
Brazilian Journal of Medical and Biological Research , 2011, DOI: 10.1590/S0100-879X2011007500008
Abstract: angiotensin ii (ang ii), the main effector of the renin-angiotensin system, is implicated in endothelial permeability, recruitment and activation of the immune cells, and also vascular remodeling through induction of inflammatory genes. matrix metalloproteinases (mmps) are considered to be important inflammatory factors. elucidation of ang ii signaling pathways and of possible cross-talks between their components is essential for the development of efficient inhibitory medications. the current study investigates the inflammatory signaling pathways activated by ang ii in cultures of human monocytic u-937 cells, and the effects of specific pharmacological inhibitors of signaling intermediates on mmp-9 gene (mmp-9) expression and activity. mmp-9 expression was determined by real-time pcr and supernatants were analyzed for mmp-9 activity by elisa and zymography methods. a multi-target elisa kit was employed to evaluate iκb, nf-κb, jnk, p38, and stat3 activation following treatments. stimulation with ang ii (100 nm) significantly increased mmp-9 expression and activity, and also activated nf-κb, jnk, and p38 by 3.8-, 2.8- and 2.2-fold, respectively (p < 0.01). ang ii-induced mmp-9 expression was significantly reduced by 75 and 67%, respectively, by co-incubation of the cells with a selective inhibitor of protein kinase c (gf109203x, 5 μm) or of rho kinase (y-27632, 15 μm), but not with inhibitors of phosphoinositide 3-kinase (wortmannin, 200 nm), tyrosine kinases (genistein, 100 μm) or of reactive oxygen species (α-tocopherol, 100 μm). thus, protein kinase c and rho kinase are important components of the inflammatory signaling pathways activated by ang ii to increase mmp-9 expression in monocytic cells. both signaling molecules may constitute potential targets for effective management of inflammation.
HER2 Oncogenic Function Escapes EGFR Tyrosine Kinase Inhibitors via Activation of Alternative HER Receptors in Breast Cancer Cells  [PDF]
Anthony Kong, Véronique Calleja, Pierre Leboucher, Adrian Harris, Peter J. Parker, Banafshé Larijani
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002881
Abstract: Background The response rate to EGFR tyrosine kinase inhibitors (TKIs) may be poor and unpredictable in cancer patients with EGFR expression itself being an inadequate response indicator. There is limited understanding of the mechanisms underlying this resistance. Furthermore, although TKIs suppress the growth of HER2-overexpressing breast tumor cells, they do not fully inhibit HER2 oncogenic function at physiological doses. Methodology and Principal Findings Here we have provided a molecular mechanism of how HER2 oncogenic function escapes TKIs' inhibition via alternative HER receptor activation as a result of autocrine ligand release. Using both F?rster Resonance Energy Transfer (FRET) which monitors in situ HER receptor phosphorylation as well as classical biochemical analysis, we have shown that the specific tyrosine kinase inhibitors (TKIs) of EGFR, AG1478 and Iressa (Gefitinib) decreased EGFR and HER3 phosphorylation through the inhibition of EGFR/HER3 dimerization. Consequent to this, we demonstrate that cleavage of HER4 and dimerization of HER4/HER2 occur together with reactivation of HER3 via HER2/HER3, leading to persistent HER2 phosphorylation in the now resistant, surviving cells. These drug treatment–induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2. Whereas an anti-betacellulin antibody in combination with Iressa increased the anti-proliferative effect in resistant cells, ligands such as heregulin and betacellulin rendered sensitive SKBR3 cells resistant to Iressa. Conclusions and Significance These results demonstrate the role of drug-induced autocrine events leading to the activation of alternative HER receptors in maintaining HER2 phosphorylation and in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) in breast cancer cells, and hence specify treatment opportunities to overcome resistance in patients.
Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells
Quanri Jin, Linda X Yuan, Delphine Boulbes, Jong Min Baek, Ying Nai Wang, Daniel Gomez-Cabello, David H Hawke, Sai Ching Yeung, Mong Hong Lee, Gabriel N Hortobagyi, Mien Chie Hung, Francisco J Esteva
Breast Cancer Research , 2010, DOI: 10.1186/bcr2777
Abstract: Using mass spectrometry, we identified FASN as one of the proteins that is dephosphorylated by lapatinib in SKBR3 breast cancer cells. Immunofluorescence, immunoprecipitation, Western blotting, a kinase assay, a FASN enzymatic activity assay, an invasion assay, a cell viability assay and zymography were used to determine the role of FASN phosphorylation in invasion of SKBR3 and BT474 cells. The FASN inhibitor C75 and small interfering RNA were used to downregulate FASN expression and/or activity.Our data demonstrated that FASN is phosphorylated when it is in complex with HER2. FASN phosphorylation was induced by heregulin in HER2-overexpressing SKBR3 and BT474 breast cancer cells. Heregulin-induced FASN phosphorylation resulted in increased FASN enzymatic activity, which was inhibited by lapatinib. The FASN inhibitor C75 suppressed FASN activity by directly inhibiting HER2 and FASN phosphorylation. Blocking FASN phosphorylation and activity by lapatinib or C75 suppressed the activity of matrix metallopeptidase 9 and inhibited invasion of SKBR3 and BT474 cells.FASN phosphorylation by HER2 plays an important role in breast cancer progression and may be a novel therapeutic target in HER2-overexpressing breast cancer cells.The human epidermal growth factor receptor 2 (HER2) gene encodes a 185-kDa transmembrane protein that belongs to the type I family of growth factor receptors, which also includes the epidermal growth factor receptor (EGFR), HER3 and HER4. HER2 is overexpressed in 20 to 25% of invasive breast cancers, and patients with those cancers have worse overall survival and time to relapse than patients whose tumors express normal levels of HER2 [1]. This strong link between HER2 activity and the malignant process has made this protein an excellent target for studies focusing on the development of new cancer therapies [2]. The monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib are the first two HER2-targeted therapies appr
中国科学 生命科学 , 2009,
Abstract: 为阐明Heregulin-α(HRG-α)及其受体对乳腺发育、泌乳及退化的调控作用及其机制,本实验采用激光扫描共聚焦显微技术,组织培养,毛细管电泳,Western Blot,ELISA等方法对小鼠乳腺发育、泌乳及退化阶段HRG-α及其受体ErbB2和ErbB3的表达、定位及其对乳腺形态发育、β-酪蛋白表达和分泌、Rab3A蛋白表达、HRG-α信号转导途径信号分子的磷酸化状态的影响进行了系统研究.结果表明,HRG-α及其受体ErbB2,ErbB3在妊娠期15d乳腺中表达到达高峰,退化期9d时又出现另一小高峰;HRG-α及其受体ErbB2,ErbB3主要在乳腺脂肪细胞、导管上皮细胞以及围绕导管的基膜中检测到,在青春期、妊娠期和退化期呈特异性表达;ErbB2和ErbB3的表达变化趋势与HRG-α的表达变化趋势相似,呈显著线性正相关.妊娠期,HRG-α能够促进STAT5,p42/p44,p38和PKC的磷酸化以及Rab3A蛋白表达,刺激乳腺上皮细胞的增殖和分化,增加并维持β-酪蛋白的表达和分泌;泌乳期,HRG-α能够促进STAT5,p38的磷酸化并抑制PKC磷酸化和Rab3A蛋白表达,维持泌乳期乳腺形态,促进乳蛋白的...
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