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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.
Rellinger EJ, Padmanabhan C, Qiao J, Appert A, Waterson AG, Lindsley CW, Beauchamp RD, Chung DH
(2017) Biochem Biophys Res Commun 491: 463-468
MeSH Terms: Antigens, CD, Antineoplastic Agents, Apoptosis, Cadherins, Caspase 3, Cell Cycle, Cell Line, Tumor, Drug Synergism, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Humans, Isoxazoles, Mesenchymal Stem Cells, Niacinamide, Poly(ADP-ribose) Polymerases, Sarcoma, Ewing, Signal Transduction, Small Molecule Libraries, TNF-Related Apoptosis-Inducing Ligand, Vimentin
Show Abstract · Added March 14, 2018
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Incidence and early outcomes associated with pre-transplant antivimentin antibodies in the cardiac transplantation population.
Young RK, Dale B, Russell SD, Zachary AA, Tedford RJ
(2015) Clin Transplant 29: 685-8
MeSH Terms: Adult, Autoantibodies, Baltimore, Female, Follow-Up Studies, Graft Rejection, Graft Survival, Heart Diseases, Heart Transplantation, Humans, Incidence, Male, Postoperative Complications, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, Vimentin
Show Abstract · Added September 7, 2017
BACKGROUND - In cardiac transplant recipients, the development of antibodies to the endothelial intermediate filament protein vimentin (antivimentin antibodies, AVA) has been associated with rejection and poor outcomes. However, the incidence of these antibodies prior to transplantation and their association with early rejection has not been investigated.
METHODS - Pre-transplant serum was analyzed from 50 patients who underwent de novo cardiac transplant at Johns Hopkins Hospital from 2004 to 2012. Demographic, one-yr rejection, and survival data were obtained from the transplant database.
RESULTS - The incidence of pre-transplant AVA was 34%. AVA-positive patients were younger (p = 0.03), and there was an a trend toward incidence in females (p = 0.08). Demographic data were similar among both groups. AVA positivity did not predict rejection in the first year post-transplant. There was no difference in rejection-free graft survival (53 vs. 52%, p = 0.85) at one yr. Similarly, there was no difference in graft survival at one yr (82 vs. 88%, p = 0.56) or graft survival at a median follow-up of 23 and 26 months, respectively (76 vs. 85%, p = 0.41).
CONCLUSIONS - AVA is common in the cardiac pre-transplant population with a higher incidence in the young. The presence of detectable AVA did not correlate with early post-transplant rejection or graft survival.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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18 MeSH Terms
High spatial resolution imaging mass spectrometry of human optic nerve lipids and proteins.
Anderson DM, Spraggins JM, Rose KL, Schey KL
(2015) J Am Soc Mass Spectrom 26: 940-7
MeSH Terms: Amino Acid Sequence, Hemoglobins, Humans, Lipids, Microscopy, Middle Aged, Molecular Sequence Data, Nerve Tissue Proteins, Optic Nerve, Peptide Fragments, Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Vimentin
Show Abstract · Added February 15, 2016
The human optic nerve carries signals from the retina to the visual cortex of the brain. Each optic nerve is comprised of approximately one million nerve fibers that are organized into bundles of 800-1200 fibers surrounded by connective tissue and supportive glial cells. Damage to the optic nerve contributes to a number of blinding diseases including: glaucoma, neuromyelitis optica, optic neuritis, and neurofibromatosis; however, the molecular mechanisms of optic nerve damage and death are incompletely understood. Herein we present high spatial resolution MALDI imaging mass spectrometry (IMS) analysis of lipids and proteins to define the molecular anatomy of the human optic nerve. The localization of a number of lipids was observed in discrete anatomical regions corresponding to myelinated and unmyelinated nerve regions as well as to supporting connective tissue, glial cells, and blood vessels. A protein fragment from vimentin, a known intermediate filament marker for astrocytes, was observed surrounding nerved fiber bundles in the lamina cribrosa region. S100B was also found in supporting glial cell regions in the prelaminar region, and the hemoglobin alpha subunit was observed in blood vessel areas. The molecular anatomy of the optic nerve defined by MALDI IMS provides a firm foundation to study biochemical changes in blinding human diseases.
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13 MeSH Terms
Stromal matrix metalloproteinase 2 regulates collagen expression and promotes the outgrowth of experimental metastases.
Bates AL, Pickup MW, Hallett MA, Dozier EA, Thomas S, Fingleton B
(2015) J Pathol 235: 773-83
MeSH Terms: Actins, Animals, Cell Proliferation, Coculture Techniques, Collagen, Female, Fibroblasts, Gene Expression Profiling, Humans, Lung Neoplasms, Mammary Neoplasms, Experimental, Matrix Metalloproteinase 2, Mice, Inbred C57BL, Mice, Knockout, Spheroids, Cellular, Stromal Cells, Time Factors, Transfection, Transforming Growth Factor beta1, Vimentin
Show Abstract · Added January 20, 2015
Breast cancer survival rates decrease from 99% for patients with local disease to 25% for those with distant metastases. Matrix metalloproteinases (MMPs), including MMP2, are associated with metastatic progression. We found that loss of host MMP2 reduces the proliferation of experimental metastases in the lungs and identified fibroblasts in tumour-bearing lungs as the major source of MMP2. In vitro, spheroidal mammary tumour growth was increased by co-culture with control fibroblasts isolated from tumour-bearing lungs, but not when fibroblasts with stable Mmp2 knockdown were used. This result prompted us to assess whether MMP2 was responsible for a tumour-proliferative, activated fibroblast phenotype. To test this, we evaluated: (a) fibroblasts from wild-type tumour-bearing lungs, with or without shRNA-mediated MMP2 knockdown; and (b) normal, quiescent fibroblasts isolated from either WT or Mmp2(-/-) mice. Quantitative PCR revealed that Mmp2 knockdown attenuated expression of two markers of activation (α-smooth muscle actin and vimentin), but there was minimal expression in quiescent WT or Mmp2(-/-) fibroblasts, as expected. Placing quiescent fibroblasts under activating conditions led to increases in activation-associated transcripts in WT but not Mmp2(-/-) fibroblasts. Additionally, Mmp2 knockdown fibroblasts showed significantly decreased expression of the matrix transcripts collagen I, collagen IV and fibronectin. Addition of active TGFβ was sufficient to rescue the MMP2-dependent collagen I and IV expression, while MMP2-induced collagen expression was blocked by the addition of TGFβ1-neutralizing antibody. Gene expression data in stromal cells of human breast cancers reveal that MMP2 expression is also positively correlated with activation and matrix transcripts. Thus, we present a model whereby MMP2 production in tumour fibroblasts is important for TGFβ1 activity and subsequent activation of fibroblasts to a matrix-producing, proliferation-supportive phenotype. Overall, our results reveal a previously undefined role for MMP2 in metastatic outgrowth mediated by fibroblasts, and extend the mechanisms by which MMPs contribute to tumour progression.
Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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20 MeSH Terms
Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer.
Li C, Ma H, Wang Y, Cao Z, Graves-Deal R, Powell AE, Starchenko A, Ayers GD, Washington MK, Kamath V, Desai K, Gerdes MJ, Solnica-Krezel L, Coffey RJ
(2014) J Clin Invest 124: 2172-87
MeSH Terms: Animals, Antigens, CD, Cadherins, Cell Line, Tumor, Colonic Neoplasms, Dual Specificity Phosphatase 6, Epithelial-Mesenchymal Transition, HEK293 Cells, Humans, Intestinal Mucosa, Mice, Mitogen-Activated Protein Kinase 1, Neoplasm Invasiveness, Neoplasm Proteins, Proteins, Vimentin, Zebrafish, Zebrafish Proteins
Show Abstract · Added May 27, 2014
The epithelial-to-mesenchymal transition (EMT) transcriptional program is characterized by repression of E-cadherin (CDH1) and induction of N-cadherin (CDH2), and mesenchymal genes like vimentin (VIM). Placenta-specific 8 (PLAC8) has been implicated in colon cancer; however, how PLAC8 contributes to disease is unknown, and endogenous PLAC8 protein has not been studied. We analyzed zebrafish and human tissues and found that endogenous PLAC8 localizes to the apical domain of differentiated intestinal epithelium. Colon cancer cells with elevated PLAC8 levels exhibited EMT features, including increased expression of VIM and zinc finger E-box binding homeobox 1 (ZEB1), aberrant cell motility, and increased invasiveness. In contrast to classical EMT, PLAC8 overexpression reduced cell surface CDH1 and upregulated P-cadherin (CDH3) without affecting CDH2 expression. PLAC8-induced EMT was linked to increased phosphorylated ERK2 (p-ERK2), and ERK2 knockdown restored cell surface CDH1 and suppressed CDH3, VIM, and ZEB1 upregulation. In vitro, PLAC8 directly bound and inactivated the ERK2 phosphatase DUSP6, thereby increasing p-ERK2. In a murine xenograft model, knockdown of endogenous PLAC8 in colon cancer cells resulted in smaller tumors, reduced local invasion, and decreased p-ERK2. Using MultiOmyx, a multiplex immunofluorescence-based methodology, we observed coexpression of cytosolic PLAC8, CDH3, and VIM at the leading edge of a human colorectal tumor, supporting a role for PLAC8 in cancer invasion in vivo.
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18 MeSH Terms
Differential vimentin expression in ovarian and uterine corpus endometrioid adenocarcinomas: diagnostic utility in distinguishing double primaries from metastatic tumors.
Desouki MM, Kallas SJ, Khabele D, Crispens MA, Hameed O, Fadare O
(2014) Int J Gynecol Pathol 33: 274-81
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Carcinoma, Endometrioid, Diagnosis, Differential, Female, Humans, Immunohistochemistry, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Neoplasms, Multiple Primary, Ovarian Neoplasms, Predictive Value of Tests, Sensitivity and Specificity, Uterine Neoplasms, Vimentin
Show Abstract · Added May 19, 2014
This study aimed to assess the diagnostic value of vimentin expression in differentiating endometrioid adenocarcinoma of primary uterine corpus and ovarian origin. Immunohistochemical analyses for the expression of vimentin in tumoral epithelial cells were performed on 149 endometrioid adenocarcinomas wherein the primary sites were not in question, including whole tissue sections of 27 carcinomas of uterine corpus origin (and no synchronous ovarian tumor), 7 carcinomas of ovarian origin (and no synchronous uterine corpus tumor) and a tissue microarray (TMA) containing 91 primary uterine corpus and 24 primary ovarian carcinomas. We also assessed 15 cases that synchronously involved the uterine corpus and ovary, 15 cases of metastasis to organs/tissues other than uterine corpus or ovary as well as 7 lymph node metastases. Vimentin was negative in 97% (30/31) of primary ovarian carcinomas. In contrast, 82% (97/118) of primary uterine corpus carcinomas were vimentin-positive. Vimentin expression was discordant in 53% of synchronous tumors. The sensitivity and specificity of negative vimentin staining in predicting an ovarian primary were 97% and 82%, respectively, whereas parallel values for positive vimentin staining in predicting a primary uterine tumor were 82% and 97%, respectively. The pattern of vimentin expression in all cases was maintained in their respective regional lymph nodes and distant metastases. In conclusion, ovarian and uterine corpus endometrioid adenocarcinomas have different patterns of vimentin expression. If validated in larger and/or different data sets, these findings may have diagnostic value in distinguishing metastatic lesions from double primary tumors involving both sites.
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19 MeSH Terms
Murine colitis is mediated by vimentin.
Mor-Vaknin N, Legendre M, Yu Y, Serezani CH, Garg SK, Jatzek A, Swanson MD, Gonzalez-Hernandez MJ, Teitz-Tennenbaum S, Punturieri A, Engleberg NC, Banerjee R, Peters-Golden M, Kao JY, Markovitz DM
(2013) Sci Rep 3: 1045
MeSH Terms: Animals, Colitis, Dextran Sulfate, Escherichia coli, Macrophages, Mice, Mice, Knockout, NADPH Oxidases, Nitric Oxide, Phagocytosis, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Vimentin
Show Abstract · Added May 4, 2017
Vimentin, an abundant intermediate filament protein, presumably has an important role in stabilizing intracellular architecture, but its function is otherwise poorly understood. In a vimentin knockout (Vim KO) mouse model, we note that Vim KO mice challenged with intraperitoneal Escherichia coli control bacterial infection better than do wild-type (WT) mice. In vitro, Vim KO phagocytes show significantly increased capacity to mediate bacterial killing by abundant production of reactive oxygen species (ROS) and nitric oxides, likely due to interactions with the p47phox active subunit of NADPH oxidase. In acute colitis induced by dextran sodium sulfate (DSS), Vim KO mice develop significantly less gut inflammation than do WT mice. Further, Vim KO mice have markedly decreased bacterial extravasation in the setting of DSS-induced acute colitis, consistent with decreased intestinal disease. Our results suggest that vimentin impedes bacterial killing and production of ROS, thereby contributing to the pathogenesis of acute colitis.
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Upregulated expression of integrin α1 in mesangial cells and integrin α3 and vimentin in podocytes of Col4a3-null (Alport) mice.
Steenhard BM, Vanacore R, Friedman D, Zelenchuk A, Stroganova L, Isom K, St John PL, Hudson BG, Abrahamson DR
(2012) PLoS One 7: e50745
MeSH Terms: Animals, Autoantigens, Collagen Type IV, Disease Models, Animal, Glomerular Basement Membrane, Integrin alpha1, Integrin alpha3, Mesangial Cells, Mice, Mice, Knockout, Nephritis, Hereditary, Podocytes, Up-Regulation, Vimentin
Show Abstract · Added August 21, 2013
Alport disease in humans, which usually results in proteinuria and kidney failure, is caused by mutations to the COL4A3, COL4A4, or COL4A5 genes, and absence of collagen α3α4α5(IV) networks found in mature kidney glomerular basement membrane (GBM). The Alport mouse harbors a deletion of the Col4a3 gene, which also results in the lack of GBM collagen α3α4α5(IV). This animal model shares many features with human Alport patients, including the retention of collagen α1α2α1(IV) in GBMs, effacement of podocyte foot processes, gradual loss of glomerular barrier properties, and progression to renal failure. To learn more about the pathogenesis of Alport disease, we undertook a discovery proteomics approach to identify proteins that were differentially expressed in glomeruli purified from Alport and wild-type mouse kidneys. Pairs of cy3- and cy5-labeled extracts from 5-week old Alport and wild-type glomeruli, respectively, underwent 2-dimensional difference gel electrophoresis. Differentially expressed proteins were digested with trypsin and prepared for mass spectrometry, peptide ion mapping/fingerprinting, and protein identification through database searching. The intermediate filament protein, vimentin, was upregulated ∼2.5 fold in Alport glomeruli compared to wild-type. Upregulation was confirmed by quantitative real time RT-PCR of isolated Alport glomeruli (5.4 fold over wild-type), and quantitative confocal immunofluorescence microscopy localized over-expressed vimentin specifically to Alport podocytes. We next hypothesized that increases in vimentin abundance might affect the basement membrane protein receptors, integrins, and screened Alport and wild-type glomeruli for expression of integrins likely to be the main receptors for GBM type IV collagen and laminin. Quantitative immunofluorescence showed an increase in integrin α1 expression in Alport mesangial cells and an increase in integrin α3 in Alport podocytes. We conclude that overexpression of mesangial integrin α1 and podocyte vimentin and integrin α3 may be important features of glomerular Alport disease, possibly affecting cell-signaling, cell shape and cellular adhesion to the GBM.
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14 MeSH Terms
Transforming growth factor β suppresses osteoblast differentiation via the vimentin activating transcription factor 4 (ATF4) axis.
Lian N, Lin T, Liu W, Wang W, Li L, Sun S, Nyman JS, Yang X
(2012) J Biol Chem 287: 35975-84
MeSH Terms: Activating Transcription Factor 4, Animals, COS Cells, Cell Differentiation, Cell Line, Tumor, Chlorocebus aethiops, Mice, Mice, Knockout, Osteoblasts, Osteocalcin, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Rats, Signal Transduction, Smad Proteins, TOR Serine-Threonine Kinases, Transcription, Genetic, Transforming Growth Factor beta, Up-Regulation, Vimentin
Show Abstract · Added October 31, 2013
ATF4 is an osteoblast-enriched transcription factor of the leucine zipper family. We recently identified that vimentin, a leucine zipper-containing intermediate filament protein, suppresses ATF4-dependent osteocalcin (Ocn) transcription and osteoblast differentiation. Here we show that TGFβ inhibits ATF4-dependent activation of Ocn by up-regulation of vimentin expression. Osteoblasts lacking Atf4 (Atf4(-/-)) were less sensitive than wild-type (WT) cells to the inhibition by TGFβ on alkaline phosphatase activity, Ocn transcription and mineralization. Importantly, the anabolic effect of a monoclonal antibody neutralizing active TGFβ ligands on bone in WT mice was blunted in Atf4(-/-) mice. These data establish that ATF4 is required for TGFβ-related suppression of Ocn transcription and osteoblast differentiation in vitro and in vivo. Interestingly, TGFβ did not directly regulate the expression of ATF4; instead, it enhanced the expression of vimentin, a negative regulator of ATF4, at the post-transcriptional level. Accordingly, knockdown of endogenous vimentin in 2T3 osteoblasts abolished the inhibition of Ocn transcription by TGFβ, confirming an indirect mechanism by which TGFβ acts through vimentin to suppress ATF4-dependent Ocn activation. Furthermore, inhibition of PI3K/Akt/mTOR signaling, but not canonical Smad signaling, downstream of TGFβ, blocked TGFβ-induced synthesis of vimentin, and inhibited ATF4-dependent Ocn transcription in osteoblasts. Thus, our study identifies that TGFβ stimulates vimentin production via PI3K-Akt-mTOR signaling, which leads to suppression of ATF4-dependent Ocn transcription and osteoblast differentiation.
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20 MeSH Terms
Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease.
López-Guisa JM, Rassa AC, Cai X, Collins SJ, Eddy AA
(2011) Am J Physiol Renal Physiol 300: F1244-54
MeSH Terms: Animals, Chronic Disease, Disease Models, Animal, Fibrosis, Genotype, Integrin alphaVbeta3, Kidney, Kidney Diseases, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Myofibroblasts, Phenotype, Plasminogen Activator Inhibitor 1, Plasminogen Activators, RNA, Messenger, Receptors, Urokinase Plasminogen Activator, Time Factors, Up-Regulation, Ureteral Obstruction, Vimentin
Show Abstract · Added February 3, 2012
Vitronectin (Vtn) is a glycoprotein found in normal serum and pathological extracellular matrix. Given its known interactions with plasminogen activator inhibitor-1 (PAI-1) and Vtn cellular receptors, especially αvβ3 integrin and the urokinase receptor (uPAR), this study was designed to investigate its role in renal fibrogenesis in the mouse model of unilateral ureteral obstruction (UUO). Kidney Vtn mRNA levels were increased ×1.8-5.1 and Vtn protein levels ×1.9-3 on days 7, 14, and 21 after UUO compared with sham kidney levels. Groups of age-matched C57BL/6 wild-type (Vtn+/+) and Vtn-/- mice (n = 10-11/group) were killed 7, 14, or 21 days after UUO. Absence of Vtn resulted in the following significant differences, but only on day 14: fewer αSMA+ interstitial myofibroblasts (×0.53), lower procollagen III mRNA levels (×0.41), lower PAI-1 protein (×0.23), higher uPA activity (×1.1), and lower αv protein (×0.32). The number of CD68+ macrophages did not differ between the genotypes. Despite these transient differences on day 14, the absence of Vtn had no effect on fibrosis severity based on both picrosirius red-positive interstitial area and total kidney collagen measured by the hydroxyproline assay. These findings suggest that despite significant interstitial Vtn deposition in the UUO model of chronic kidney disease, its fibrogenic role is either nonessential or redundant. These data are remarkable given Vtn's strong affinity for the potent fibrogenic molecule PAI-1.
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22 MeSH Terms