bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1970: SOCS-1,-3 gene delivery in gastric cancer cells induces a potent anti-proliferative effect via the suppression of JAK/STAT and P38 MAPK signaling pathways
Authors: Urase Maiko , Serada Satoshi , Souma Yoshihito , Iwahori Kouta , Shimada Kazuki , Nishida Toshirou , Fujimoto Minoru , Naka Tetsuji 
Published: August 2014

Abstract
BACKGROUND:Enhanced activation of inflammatory cytokines signaling transductions have been suggested as a driving force in the development of gastric tumors. The suppressor of cytokine signaling (SOCS) family proteins are important negative regulator of proinflammatory cytokine signals and have been reported to be frequently silenced by DNA methylation of CpG islands in gastric cancer (GC). The aim of this in vitro assessment was to evaluate the role of SOCS-1 and SOCS-3 in the proliferation of GC cell through regulating cytokine signaling pathways. MATERIAL AND METHODS:Six GC cell lines (NUGC3, AGS, MKN45, NUGC4, MKN7, and MKN74) were used in this study. Methylation status of SOCS-1/-3 was assessed by methylation specific PCR. The concentrations of IL-6 in the cell culture supernatant was measured by ELISA. Adenovirus vectors encoding either SOCS-1 or SOCS-3 were constructed for gene delivery to GC cells. The status of activated kinases and downstream proteins were determined by Western blot analysis. Anti-proliferative effects in GC cells were assessed by WST-8 assay.
RESULTS: In six GC cell lines used in our study, SOCS-1 and SOCS-3 genes were methylated except one cell line, and two cell lines (NUGC3, AGS) showed elevated endogenous IL-6 production with constitutively phosphorylated STAT3. Unexpectedly, anti-IL-6R antibody did not affect both of the cell proliferation and the status of phosphorylated STAT3 in these two cell lines. In contrast, adenovirus-mediated SOCS-1 /-3 gene delivery markedly reduced cell proliferation of these cells. The anti-proliferative effect of SOCS-1/-3 correlated with decreased levels of the activation of STAT3 and p38 MAPK. Cell proliferation assay confirmed that the blockade of JAK/STAT and p38 MAPK signaling pathways also reduced cell proliferation of these cell lines. CONCLUSIONS: Our results indicated that the DNA methylation of SOCS-1/-3 may be associated with GC proliferation, and highlighted an anti-proliferative potential of SOCS-1/-3 through the inhibition of JAK/STAT and p38 MAPK signaling pathways independently IL-6 signaling. Thus, DNA methylation of SOCS-1/-3 can be a molecular marker of GC progression, and their forced expression may represent a novel therapeutic application as a multi-growth signal inhibitor for GC treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1970. doi:10.1158/1538-7445.AM2011-1970
Abstract 1972: Nicotine regulates DNA-binding protein inhibitor (Id1) through a Src-dependent pathway promoting tumorigenic properties and chemoresistance in pancreatic adenocarcinoma
Authors: Treviño José G. , Pillai Smitha R. , Kunigal Sateesh S. , Chellappan Srikumar P. 
Published: August 2014

Abstract
Nicotine, an addicting component of an established risk factor (tobacco) for pancreatic cancer is identified as a tumor promoter potentially acting through activation of oncogenes such as Src, a non-receptor protein tyrosine kinase. Recent studies from our laboratory have shown that the Id1 transcription factor (inhibitor of DNA binding/Differentiation) is induced by nicotine in NSCLC cells. Id1 has been shown to play a role in tumor progression by promoting angiogenesis, invasion, and chemoresistance. Further, Src and its family of non-receptor protein tyrosine kinases (SFKs) play a role in angiogenesis, tumor progression, and chemoresistance. Based on our observations on NSCLC cells, we hypothesize nicotine-induces Id1 expression in a Src-dependent fashion and promotes tumorigenesis and chemoresistance. Protein analysis, mRNA expression, and further experiments were determined in a panel of pancreatic cancer cells, PANC-1, Mia-Paca-2, L3.6pl, and L3.6plGemRes by western blot analysis and RT-PCR respectively. Our results demonstrate that stimulation with nicotine (1 µM), and activation of nAChR, resulted in phosphorylation of Src, indicative of activation, and its family of kinases. Nicotine also induced Id1 expression at similar concentrations. Inhibition of SFK activity with Dasatinib (500nM) did not allow serum or nicotine-induced SFK activity and subsequent Id1 expression. Specific inhibition of c-Src expression with short-interfering RNA (siRNA) decreased constitutive and nicotine-induced Id1 expression and depletion of Id1 expression by siRNA or short-hairpin RNA (shRNA) significantly reduced the proliferative (80%) and invasive property (75%) of pancreatic cancer cells, a property often mediated by Src. Additionally, inhibition of Src and Id1 expression in innate or established gemcitabine resistant cancer cells resulted in gemcitabine sensitization at IC50, 250 ng/ml. To determine if nicotine contributes to gemcitabine chemoresistance potentially through a Src-dependent Id1 signaling axis, we exposed gemcitabine-sensitive cells to nicotine with subsequent exposure to gemcitabine. Nicotine promoted a 2-fold increase in cell proliferation and a 4.5-fold reduction in apoptosis. Further, nicotine induced phosphorylation of key Src-dependent signaling enzymes involved in proliferation and apoptosis, Erk1/2 and Akt respectively. We demonstrate that Id1, by a nicotine promoting Src-dependent pathway, contributes to signaling pathways involved in tumor progression and establishment of a chemoresistant phenotype in pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1972. doi:10.1158/1538-7445.AM2011-1972
Abstract 1973: Caveolin-1 promotes cell proliferation, EGFR activation and tumor growth in kidney cancer
Authors: Xu Chao Ying (Sarah) , Wang Yi , Roche Olga , Moriyama Eduardo , Ohh Michael 
Published: August 2014

Abstract
Tumor hypoxia is associated with disease progression, drug resistance and poor prognosis. It has been shown previously that hypoxia prolongs the activation of epidermal growth factor receptor (EGFR) by delaying clathrin-dependent endocytosis-mediated deactivation of receptors. Recently, caveolin (CAV) mediated signaling and trafficking have been reported to be involved in the oncogenesis of many tumours, including clear cell renal cell carcinoma (CCRCC). However, the role of CAV-1 in the tumor progression is unclear. Here, we show that the loss of von Hippel-Lindau (VHL) protein – the principal negative regulator of hypoxia-inducible factor (HIF) – increases the auto-phosphorylation of epidermal growth factor receptor (EGFR), thus attributing to an enhanced ligand-independent cell signaling pathway, majorly Ras-Raf-MEK-ERK pathway, and leading to cell proliferation. The auto-phosphorylation of EGFR is due to the HIF-dependent overexpression of caveolin-1 (CAV-1) at the level of transcription, which enhances the association between EGFR and CAV-1 and the auto-dimerization of EGFR. Primary CCRCC tumors and numerous hypoxia treated tumor cell lines exhibit significantly higher expression of CAV-1 protein. Using a dorsal skin-fold window chamber on SCID mice, shCAV-1 knockdown 786-O tumor cell line exhibits lower growth than that of shscramble counterpart in xenografts. These findings support a model in which tumour hypoxia or oncogenic activation of HIF prolongs ligand-independent RTK signaling through the over-expression of CAV-1. Given the oncogenic role of CAV-1, it should be considered as a future therapeutic target in cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1973. doi:10.1158/1538-7445.AM2011-1973
Abstract 1977: N-glycosylation level of the type II TGF-β receptor is important for the stability and cell surface localization and affects TGF-β resistance in cancer cells
Authors: Kim Young-Woong , Park Jinah , Lee Hyun-Ju , Kim Seong-Jin 
Published: August 2014

Abstract
N-linked glycosylation is a critical determinant of protein structure and function, regulating processes such as protein folding, stability, localization, ligand-receptor binding and intracellular signaling. The type II TGF-β receptor (TβRII) plays a crucial role in the TGF-β signaling pathway. Although N-linked glycosylation of TβRII was first demonstrated over a decade ago, it is unclear how this modification affects TβRII biology. By generating deficient N-linked glycosylation (dNG) mutants, in which each asparagine was converted to glutamine, we show here that N-linked glycosylation occurs on two conserved asparagine residues in the extracellular domain of TβRII. dNG mutant TbRII lines indeed exhibited defective N-linked glycosylation. Notably, non-glycosylated TβRII was more sensitive to proteasome-mediated degradation than fully N-glycosylated TβRII, suggesting that the N-linked glycosylation protects TβRII from proteasome-mediated degradation. Defective N-linked glycosylation also induced TβRII to accumulate in the endoplasmic reticulum (ER), resulting in decreased expression on the cell surface compared to N-glycosylated TβRII. Ultimately, upon TGF-β stimulation, cells expressing dNG mutant TβRII lines were not efficiently able to activate downstream signaling due to the decreased number of cell surface-expressed receptor molecules. These findings demonstrate that N-linked glycosylation is essentially required for the stability and cell surface localization of TβRII. Moreover, by comparing the N-linked glycosylation levels of TβRII in various cancer cell lines, we suggest that the degree of N-linked glycosylation of TβRII might be one of molecular mechanisms involved in the different cellular responses of cancer cell lines upon TGF-β treatment, shedding light on the N-linked glycosylation that fosters TGF-β resistance in many cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1977. doi:10.1158/1538-7445.AM2011-1977
Abstract 1979: Role of Akt1 on the viability, migration and cytoskeleton organization of murine mammary tumor cells reexpresing glypican-3 (GPC3)
Authors: Romero Silvina A. , Lago Huvelle María A. , Peluffo Guillermo , de Kier Joffé Elisa Bal , Peters María Giselle 
Published: August 2014

Abstract
Previously, we have demonstrated that the restatement of GPC3 in the murine mammary adenocarcinoma LM3 cell line induces the inhibition of its metastatic ability in vivo, event associated with a partial reversion of the epithelial-mesenchymal transition. We also found that LM3-GPC3 cells present a constitutive lower activity of the Akt pathway.
The Akt kinases 1, 2 and 3 have a critical role in regulating survival, metabolism and other cellular activities. Their role on migration and metastasis is less clear. The aim of this study was to analyze the function of Akt1 on the viability, migration and cytoskeleton organization of LM3-GPC3 cells. Experiments were done employing two clones reexpressing GPC3 (LM3-GPC3) and two control clones transfected with the empty vector (LM3-vector).
By means of WB we determined that all the clones express similar levels of total Akt (1, 2 and 3). However, while LM3-vector cells presented a higher proportion of Akt2 (Akt1/Akt2=0.75), GPC3 reexpression reversed this relationship (Akt1/Akt2=1.45).
To study the role of Akt1, we introduced by viral infection a constitutively active variant of this isoform (CA Akt1) into LM3-GPC3 cells. We corroborated previous findings that GPC3 reexpression increases LM3 cell line susceptibility to death under serum deprivation (ANOVA-Bonferroni p&lt;0.001). However, CA Akt1 did not affect the viability of LM3-GPC3 cells (ANOVA, ns). While no changes were detected in the actin cytoskeleton organization, we found by wound healing assays that LM3-GPC3 cells expressing CA Akt1 were more motile than their controls (Wound coverage: LM3-GPC3 control=45% vs LM3-GPC3 CA Akt1=90%, ANOVA-Bonferroni p&lt;0.001).
These results suggest that the Akt family would have isoform-specific mechanisms to regulate the studied cellular parameters. Since the migration of LM3-GPC3 cells expressing CA Akt1 reached similar levels to those of LM3-vector clones, we conclude that GPC3 reduces the migratory ability of LM3 cells by inhibiting Akt1. On the other hand, CA Akt1 did not affect either viability or the organization of the actin cytoskeleton of LM3-GPC3 cells. Thus, we deduce that other isoforms of Akt and/or other signaling pathways are involved in the modulation of these cellular properties.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1979. doi:10.1158/1538-7445.AM2011-1979
Abstract 1980: The SIAH2-SMAD2/3/4 antagonism downstream of the K-RAS and TGFβ signaling pathways during tumor initiation, progression and metastasis of human cancer
Authors: Liao Yang , Edens Maryanne , Janknecht Ralf G. , Leof Edward B. , Tang Amy H. 
Published: August 2014

Abstract
The pivotal roles of the K-RAS and TGFβ signaling pathways have been well characterized in a number of normal and pathological conditions including human cancer. Hyperactivation of the ERBB/KRAS pathway is known to drive neoplastic transformation, tumorigenesis and metastasis in a large percentage of human cancers while the growth inhibitory actions of TGFβ are critical in preventing cancer. A better understanding of the antagonistic interaction and cross-talk between the K-RAS and TGFβ signaling pathways that control tumorigenesis and metastasis may give rise to novel therapeutic interventions. Our previous work has highlight the importance of SIAH2 in K-RAS-dependent tumorigenesis and metastasis in human cancer. In this study, we showed that SMAD2/3/4 – the essential downstream mediators of TGFβ signaling, are new SIAH2 substrates. SIAH2 physically interacts with, ubiquitinates and degrades SMAD2/3/4 (but not SMAD1 – the downstream mediator of the BMP signaling pathway). The identification of the SIAH2-mediated SMAD2/3/4 modulation/degradation may provide an additional mechanism to explain the well documented, but less understood ERBB/K-RAS and TGFβ antagonism described in normal development, tumorigenesis and metastasis. We propose that the tumor promoting activity of RAS/SIAH2 may be mediated through the degradation of SMAD2/3/4 proteins and thus the relief of TGFβ-dependent growth inhibition in response to ERBB/K-RAS activation. The discovery of the SIAH2-SMAD2/3/4 antagonism downstream of K-RAS and TGFβ signaling pathways may provide a novel mode of antagonistic cross-talk between these two important signaling pathways to explain the growth inhibitory action of the TGFβ pathway and the growth-promoting activity of the K-RAS pathway in the genesis, progression and metastasis of human cancer. Since the substrate specificity of ubiquitin-mediated proteolysis is primarily determined by the E3 ligase, our results provide new insights into the role of altered proteolysis in mediating the context-dependent ERBB/RAS-TGFβ antagonism and cross-talk in human cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1980. doi:10.1158/1538-7445.AM2011-1980
Abstract 1981: Tumor suppressor functions of the Src-like adaptor protein (SLAP) in colorectal cancer cells
Authors: Naudin Cécile , Leroy Cédric , Sirvent Audrey , Simon Valérie , Bourgaux Jean-François , Robert Bruno , Pannequin Julie , Hollande Frédéric , Roche Serge 
Published: August 2014

Abstract
Background : The cytoplasmic tyrosine kinase Src is frequently deregulated in colorectal cancer (CRC) and this deregulation is implicated in tumour growth and in the induction of metastasis. How Src is activated in this cancer has not been clearly established. In contrast to Ras, Src activating mutations are rare events, suggesting the existence of alternative mechanisms for the induction of Src oncogenic activity. Here, we addressed whether Src deregulation involves inhibition of its negative regulators, including the Src-Like Adaptor Protein (SLAP).
Experimental procedures : SLAP expression was analyzed in colon cancer cells and in microdissected tissue samples of patients with CRC. The effect of SLAP was analyzed on the capacity of CRC cells to grow in soft agar and to induce tumours once engrafted in nude mice. The effect of SLAP on the invasive properties of CRC cells was investigated in vitro using Matrigel Boyden chamber assays, as well as in vivo following injection in the spleen of Balb-c mice.
Results : We found that SLAP is expressed in the healthy colon and that its expression is reduced in 60% of CRC biopsies tested. Moreover, we showed that SLAP overexpression dramatically reduced the capacity of CRC cells to induce primary tumours and liver metastases in vivo. Conversely, SLAP knock-down in early-stage CRC cells led to a remarkable induction of liver metastasis in mice. This novel function of SLAP required its myristoylation site as well as intact SH3 and SH2 domains. A proteomic approach is under way to identify SLAP partners involved in this tumor suppressor activity.
Conclusions: Our results suggest that, in addition to lymphocytes, SLAP also regulates transforming properties of CRC cells. We hypothesize that SLAP negatively regulates oncogenic signalling initiated by tyrosine kinases including Src.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1981. doi:10.1158/1538-7445.AM2011-1981
Abstract 1983: A cell-permeable Stat3 SH2 domain mimetic inhibitor of Stat3 activation inhibits growth of human breast tumor xenografts
Authors: Zhao Wei , Jaganathan Soumya , Zhang Xiaolei , Turkson James 
Published: August 2014

Abstract
Human tumors harbor multiple molecular aberrations that have become the driving force for uncontrolled cell proliferation and survival, and other tumor-associated processes. Constitutive activation of the Signal Transducer and Activator of Transcription (Stat) 3 protein is a frequent occurrence in many human cancers, including breast cancer. Given the role of aberrant Stat3 activity in human tumors, small-molecule Stat3 inhibitors would be useful novel therapeutics and tools for probing Stat3-mediated tumor processes. We herein report that a 28-mer peptide, SPI, composed of the amino acid residues 588-615 of the Stat3 SH2 domain, replicates Stat3 biochemical properties and functions as a Stat3 inhibitor. Studies show SPI and Stat3 (or Stat3 SH2 domain) both bind with similar affinities to known Stat3-binding phosphotyrosine (pY) peptide motifs, including the epidermal growth factor receptor (EGFR) peptides, pY1068EGFR and pY1086EGFR, and the high-affinity, interleukin-6 receptor (IL-6R)/gp130-derived peptide, GpYLPQTV-NH2. Consequently, SPI potently and selectively inhibits Stat3 SH2 domain:pY interactions and disrupts the binding of Stat3 to the IL-6R/gp130 peptide, GpYLPQTV-NH2. Fluorescence imaging studies show SPI is cell membrane-permeable. Treatment with SPI of malignant cells that harbor aberrant Stat3 activity resulted in the selective inhibition of constitutive Stat3 phosphorylation, and of Stat3 DNA-binding and transcriptional activities. By contrast, similar treatments have little or no effects on the induction of the Stat1, Stat5, and Erk1/2MAPK pathways in malignant cells or in EGF-stimulated fibroblasts. In contrast to normal cells, human breast, pancreatic, prostate, and non-small cell lung cancer cells harboring constitutively-active Stat3 are highly sensitive to SPI and undergo extensive morphology changes, concomitant with the loss of viability and apoptosis. Significantly, treatment with SPI or its inverse sequence version strongly inhibited the growth of human breast tumor xenografts in mice, which is associated with the down-regulation of the expression of the known Stat3-regulated genes, Cyclin D1, Bcl-xL and Survivin. Our study identifies SPI as a novel molecular probe for interrogating Stat3 signaling and that functions as a selective Stat3 inhibitor, which induces antitumor response in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1983. doi:10.1158/1538-7445.AM2011-1983