bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1225: Regulation of ARE-mediated mRNA decay during colorectal tumorigenesis
Authors: Blanco Fernando F. , Sanduja Sandhya , Young Lisa , Dixon Dan 
Published: February 2011

Abstract
Colon cancer is mediated through various genetic alterations that promote the initiation and progression of tumorigenesis. As a consequence of these defects, overexpression of many oncogenic factors promoting enhanced cell growth and inflammation are observed. In the normal intestinal epithelium, oncogenic factor gene expression is controlled through AU-rich mRNA elements (AREs) that target mRNA for rapid decay. However, ARE-mRNA turnover is compromised during colon tumorigenesis resulting in a 3- to 4-fold enrichment in ARE-containing genes. To better understand how loss of ARE-mRNA decay contributes to colon tumorigenesis, the role of the mRNA decay factor tristetraprolin (TTP) in normal and tumor cells was examined. The RNA-binding protein TTP binds ARE motifs and promotes rapid mRNA decay by sequestering the mRNA to cytoplasmic sites known as processing bodies (P-bodies). Here, we demonstrate that treatment of non-transformed intestinal epithelial cells with TGF-B inhibited ARE-mRNA expression. This effect of TGF-B occurred through a Smad-dependent induction of TTP expression and this led to a 2-fold increase in cytoplasmic P-body assembly. These findings indicate that induction of post-transcriptional regulation is a novel growth-inhibitory feature of TGF-B in normal cells. Colon cancer progression is frequently characterized by the presence of activating mutations in the RAS proto-oncogene, and, in this context, the tumor-promoting effects of TGF-B signaling are observed. Using an intestinal epithelial cell model stably transfected with an inducible oncogenic Ras cDNA, we determined the impact of oncogenic cellular transformation on TTP expression. In cells expressing oncogenic Ras, the expression of TTP was decreased and these cells were rendered refractory to TGF-B-mediated TTP induction. The functional significance of this loss of TTP expression in transformed cells is observed with a 2-fold decrease in P-body formation. Consistent with this, colon cancer cells and tumor tissue show decreased TTP expression compared to normal tissue and a respective loss of P-body formation. Taken together, these results demonstrate that loss of the mRNA decay factor TTP occurs during colon tumorigenesis, thereby compromising ARE-mRNA decay and resulting in stabilization of various cancer-associated mRNAs. Through its ability to modulate expression of a majority of oncogenic factors, these findings define a role for TTP in tumor-suppressor capacity in the context of colon cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1225.
Abstract 1227: Inhibition of the RSK2-ATF1 signaling axis by eriodictyol suppresses neoplastic cell transformation
Authors: Liu Kangdong , Cho Yong-Yeon , Yao Ke , Pugliese Angelo , Zheng Duo , Zhang Jishai , He Zhiwei , Malakhova Margarita , Ma Wei-Ya , Bode Ann , Dong Ziming , Dong Zigang 
Published: February 2011

Abstract
The ribosomal S6 kinase 2 (RSK2), a member of the p90RSK (RSK) family of proteins, is a widely expressed serine/threonine kinase and its activation enhances cell proliferation. Here we report that activating transcription factor 1(ATF1) is a novel substrate of RSK2 and the RSK2-ATF1 signaling axis plays an important role in neoplastic cell transformation. RSK2 phosphorylates ATF1 at Ser63 and enhances the transactivation and transcriptional activities of ATF1. Computational modeling, high-through put screening and in vitro pull down assays demonstrated that eriodictiol, a flavanone found in fruits, binds with the N-terminal kinase domain and linker region of RSK2 and inhibits RSK2 N-terminal kinase activity. In a cell culture system, eriodictyol treatment suppressed phosphorylation of ATF1, but did not affect phosphorylation of RSK, MEK1/2, ERK1/2, p38 or JNKs, indicating that eriodictyol specifically inhibits RSK2 signaling. Furthermore, eriodictyol inhibited RSK2-mediated ATF1 transactivation activity and cell transformation induced by tumor promoters in JB6 Cl41 mouse skin epidermal cells. In a foci formation assay, knockdown of RSK2 or ATF1 suppressed foci formation compared with RasG12V, RasG12V/RSK2, RasG12V/ATF1 and RasG12V/RSK2/ATF1 expressing cells. In addition, eriodictyol treatment showed the same effect as RSK2 knockdown in foci formation. Taken together, these results indicated that the RSK2-ATF1 signaling axis plays an important role in neoplastic cell transformation and eriodictyol is a new natural compound for selectively inhibiting RSK2 kinase activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1227.
Abstract 1232: Aberrant JAK/STAT signaling confers epigenetic silencing of STAT3 targets in gastric cancer by integrated microarray and bioinformatic analysis
Authors: Chang Alex L.Y. , Dittner Claudia , Chou Jian-Liang , Cheng Alfred S.L. , Lin Jiayuh , Yeh Kun-Tu , Chan Michael W.Y. 
Published: February 2011

Abstract
Gastric cancer is the 2nd leading cause of cancer worldwide. One of the major risk factors of gastric cancer is infection of H. pylori. Patients infected with CagA-positive H. pylori would have increased risk of gastric cancer. Previous studies including ours have demonstrated that infection of CagA-positive H. pylori induced activation of JAK/STAT3 signaling pathway. However, the role of aberrant activation of this signaling pathway in gastric cancer is not clear understood. We hypothesized that aberrant activation of JAK/STAT signaling may lead to epigenetic silencing of STAT3 target genes in gastric cancer. In this study, we transfected a constitutively activated mouse STAT3 mutant (STAT3c) into MKN28 gastric cancer cell line in which the JAK/STAT signaling pathway is not active. STAT3c stable transfectant MKN28/STATc-16 showing hyper-phosphorylation of STAT3 demonstrated increased cell proliferation as compared to vector control MKN28/C-9. In order to identify STAT3 target genes that are epigenetically down-regulated in MKN28/STATc-16 cells, expression microarray using Agilent 44K oligonucleotide microarray coupled bioinformatic analysis were performed. Our result showed that there are 2945 genes showing at least 1.5 fold down-regulation in MKN28/STATc-16 cells as compared with vector control. By whole genome bioinformatic analysis, 397 genes with STAT3 binding sites within 5kb of a CpG island were discovered. Integrated analysis revealed that there are 18 downregulated genes with a STAT3 binding site around the promoter CpG island. Further characterization of two STAT3 target, NR4A3 and LOXL4 demonstrated that promoter hypermethylation of these 2 genes were observed in MKN28/STATc-16 cells but not the vector control. Demethylation treatment using 5azaDC also restored expression of these 2 genes in MKN28/STATc-16 cells. These phenomena may be partially related to the up-regulation of DNMT1 in MKN28/STATc-16 cells. In conclusion, our result demonstrated that aberrant JAK/STAT3 signaling may lead to epigenetic silencing of its target gene in gastric cancer. The role of STAT3 in mediating epigenetic silencing of NR4A3 and LOXL4 and its clinical significance in gastric cancer patients is currently under investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1232.
Abstract 1256: Protein kinase G type Iα activity in human ovarian cancer cells contributes to enhanced Src activation and DNA synthesis/cell proliferation
Authors: Wong Janica C. , Leung Elaine L. , Johlfs Mary G. , Tsang Benjamin K. , Fiscus Ronald R. 
Published: February 2011

Abstract
We have previously shown that basal activity of the nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG) signaling pathway protects human ovarian cancer cells against spontaneous apoptosis and confers resistance to cisplatin-induced apoptosis. The present study determines whether basal PKG activity up-regulates Src and induces cell proliferation in human ovarian cancer cells. PKG-Iα was identified as the predominant isoform of PKG expressed in both cisplatin-sensitive OV2008 and cisplatin-resistant A2780cp human ovarian cancer cells. In both cell lines, both ODQ, an inhibitor of endogenous-NO-induced cGMP biosynthesis, and DT-2, highly-specific inhibitor of PKG-Iα activity, as well as PKG siRNA caused concentration-dependent inhibition of DNA synthesis (assessed by BrdU incorporation) under normal (plus-serum) growing conditions, indicating an important role of basal cGMP/PKG-Iα activity in promoting cell proliferation. DNA synthesis in OV2008 cells was dependent on Src activation, determined using selective Src inhibitor, 4-(4′-phenoxyanilino)-6,7-dimethoxyquinazoline (SKI-1). In vitro co-incubation of human recombinant Src and PKG-Iα resulted in Src-mediated tyrosine-phosphorylation of PKG-Iα and enhanced Src autophosphorylation at tyrosine-416, suggesting that Src directly tyrosine-phosphorylates PKG-Iα and the interaction between PKG-Iα and Src also leads to enhanced Src activation. The result was further confirmed by using immunoprecipitation of PKG, showing a concentration-dependent decrease in PKG tyrosine-phosphorylation by SKI in both ovarian cancer cell lines. In intact OV2008 cells, inhibition of basal PKG-Iα activity with DT-2 dramatically reduced endogenous Src activation and completely blocked the elevation of DNA synthesis stimulated by EGF. The data suggest that Src activation and DNA synthesis/cell proliferation in human ovarian cancer cells are dependent on endogenous basal PKG-Iα activity. The NO/cGMP/PKG-Iα signaling pathway may provide a novel therapeutic target for disrupting the proliferation of ovarian cancer cells.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1256.
Abstract 1263: Induction of nonsteroidal anti-inflammatory drug-activated gene-1 (Nag-1) by NSAIDs: role of p75NTR
Authors: Wynne Shehla , Djakiew Daniel 
Published: February 2011

Abstract
Epidemiologic studies have shown that patients with long term consumption of certain nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit a reduced incidence of prostate cancer. Treatment of prostrate cancer cell lines with NSAIDs leads to caspase mediated apoptosis. Previously, our laboratory has demonstrated that R-flurbiprofen and Ibuprofen induce the expression of the pro-apoptotic protein p75NTR in PC-3, DU-145 and LNCaP prostate cancer cell lines, with a subsequent decrease in cell survival. The p75NTR is a member of the Tumor Necrosis Factor Receptor superfamily of death receptors. It acts as a tumor suppressor in the normal prostate. The expression of p75NTR is lost as prostate cancer progresses and is minimal in established metastatic prostate cancer cell lines such as PC-3, DU-145, and LNCaP. The observed increase in p75NTR protein due to R-flurbiprofen and Ibuprofen treatment occurs as a result of activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Here we show that the upregulation of p75NTR following treatment with NSAIDs corresponds to a concomitant upregulation of the NSAID activated gene-1 (Nag-1) protein, a pro-apoptotic member of the TGF beta family, in PC-3 cells. Nag-1 has been linked to decreased cell proliferation in many studies, and has been shown to play a pro-apoptotic role in breast, colorectal, gastric and prostate cancer cells. Nag-1 is also known by the names GDF −15, MIC-1, PDF, PLAB and PTGFB. This study also shows that Nag-1 protein induction following NSAID treatment is mediated by the p38 MAPK pathway, and is downstream of the p75NTR induction. This is the first report of a relationship between p75NTR and Nag-1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1263.
Abstract 1270: Elevated levels of poly(ADP-ribose) lead to novel apoptotic signaling and the induction of caspase-independent cell death
Authors: Feng Xiaoxing , Zhou Yiran , Koh David W. 
Published: February 2011

Abstract
The metabolism of poly(ADP-ribose) (PAR) is activated by DNA damage, where PAR polymerase-1 (PARP-1) transfers ADP-ribose onto nuclear proteins to form PAR and PAR glycohydrolase (PARG) catalyzes its degradation. Previous findings show that high levels of PAR lead to its presence in the cytoplasm, where it signals the release of the proapoptotic protein, apoptosis inducing factor (AIF). Our studies suggest that inhibiting PAR glycohydrolase (PARG), and thus promoting increased levels of PAR, will increase the efficacy of anti-cancer agents by promoting this alternative cell death pathway mediated by AIF. The objective of this study is to elucidate the pathway of cytoplasm PAR cell death signaling in cancer cells. We utilized MDA-MB-231 breast cancer cells to reveal the ability of AIF to induce cancer cell death following caspase inhibition. In addition, PARG null embryonic trophoblast stem cells were utilized to determine the cytoplasmic PAR signaling pattern and to purify the PAR-modified nuclear proteins released in the cytoplasm. FACS analysis demonstrated equivalent levels of cell death with or without caspases and Western blot revealed a robust release of AIF from the mitochondria following DNA damage. Following low-dose DNA-damaging agent treatment in PARG null cells, cytoplasmic PAR was detected concurrently with AIF translocation to the nucleus, as shown by Western blot and confocal immunofluorescence. In PARG null cells in the absence of stress, cytoplasmic PAR levels were maximal after 3 days as shown by cell fractionations and Western blot. The cytoplasmic fraction containing PAR was then purified using dihydroxyboronyl Bio-Rex affinity chromatography. The purified PAR-modified proteins were treated with phosphodiesterase to remove all PAR and SDS-PAGE analysis demonstrated several proteins ranging from 20-50 kDa, which together serve as the cytoplasmic signal that causes AIF release from the mitochondria. These proteins potentially reveal novel nuclear-to-mitochondrial cell signaling ligands that are necessary for the induction of the AIF pathway of caspase-independent cell death. Taken together, the results demonstrate the importance of AIF in cancer cell death and novel insight into the cell death signaling by PAR that produces AIF-mediated cell death. Therefore, ability to increase PAR levels by inhibiting PARG is potentially a unique method to induce the death of cancer cells by an alternative cell death pathway.
This research was supported by funding from the American Cancer Society and the Pharmaceutical Research Manufacturers of America.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1270.
Abstract 128: Role of ΔNp63α and its effect in cisplatin-mediated chemoresistance
Authors: Sen Tanusree , Chatterjee Aditi , Sen Nilkantha , Hoque Mohammad Obaidul , Sidransky David 
Published: February 2011

Abstract
ΔNp63α, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative ΔNp63. Increasing evidence show that ΔNp63α is upregulated in various cancers, and plays a central role in both development and tumorigenesis by promoting cell survival. The aim of our current study is to provide insight into the molecular mechanisms accounting for the role of ΔNp63α in tumorogenesis and its involvement in chemoresistance induced by cisplitin. We have investigated the downstream mechanisms by which ΔNp63α elicits tumorigenesis via AKT pathway. Both overexpression and RNAi experiments with ΔNp63α revealed that it can regulate the expression of AKT. These results demonstrate a link between ΔNp63α and the anti-apoptotic pathway. Of clinical relevance is the fact that ΔNp63α protein level is increased in chemoresistant cell line and that inhibitition of ΔNp63α leads to chemosensitivity. Thus, beyond its importance in development and differentiation, we describe the mechanism by which ΔNp63α exerts cell survival and the induction of tumorogenesis and chemoresistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 128.
Abstract 1286: Endothelin-1-induced angiogenesis is regulated by PHD2 in a HIF-1α-dependent manner
Authors: Spinella Francesca , Rosanò Laura , Caprara Valentina , DiCastro Valeriana , Nicotra Maria Rita , Natali Pier Giorgio , Bagnato Anna 
Published: February 2011

Abstract
The endothelin B receptor (ETBR) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1α is essential for melanomagenesis and progression. In melanoma cells cultured in normoxic conditions, ET-1, ET-2, and ET-3 through ETBR enhance HIF-1α and HIF-2α expression, and activity and both transcriptional factors regulate the expression of target genes, such as vascular endothelial growth factor (VEGF) and ET-1 in response to ETs or hypoxia. In turn, ETs control HIF-1α stability by inhibiting its degradation. In particular, ETs through ETBR markedly decrease prolyl hydroxylase domain (PHD)2 mRNA and protein levels and promoter activity. In addition, we found that activation of phosphatidylinositol 3-kinase (PI3K)-dependent integrin linked kinase (ILK)-AKT-mammalian target of rapamycin (mTOR) pathway is required for ETBR-mediated PHD2 inhibition, HIF-1α, HIF-2α, and VEGF expression. At functional level, PHD2 knockdown does not further increase ETs-induced angiogenesis and melanoma cell invasiveness demonstrating that these processes are regulated in a PHD2-dependent manner. In human primary and metastatic melanomas, that express high level of HIF-1α, ETBR expression is associated with low PHD2 levels. In melanoma xenografts, ETBR blockade by ETBR antagonist results in a concomitant reduction of angiogenesis, HIF-1α, HIF-2α and VEGF expression, and an increase in PHD2 levels. In conclusion, we identified the underlying mechanism by which ET-1 controls HIF-1α stability and thereby regulates angiogenesis and tumor invasion through the regulation of PHD2. These results further indicate that targeting ETBR may represent a potential therapeutic treatment of melanoma by impairing HIF-1α stability. Supported by AIRC.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1286.
Abstract 1287: Anastellin, the fibronectin-derived angiogenesis inhibitor, activates a proangiogenic signature in stromal fibroblasts
Authors: You Ran , Zheng Mingzhe , McKeown-Longo Paula J. 
Published: February 2011

Abstract
Fibronectin is an extracellular matrix protein that is important in the regulation of angiogenesis, tumor progression and tumor metastasis. Anastellin, a peptide fragment derived from the first Type III repeat in Fibronectin (III1c), has been shown to prevent tumor angiogenesis in mouse models of human cancer and to inhibit serum-dependent growth of endothelial microvessel cells. To determine whether anastellin might have additional roles in the tumor microenvironment, we evaluated the effect of anastellin on gene expression in human dermal fibroblasts. Microarray analysis (Human Cancer PathwayFinder RT2 Profiler PCR Array) indicated that addition of anastellin to fibroblasts induced the expression of several genes including the proangiogenic inflammatory mediators, IL-8 and TNF-α. PCR analysis confirmed that expression of both TNF-α and IL-8 were markedly increased within 2 hrs suggesting a direct effect of anastellin on fibroblast gene expression. ELISA assay of the conditioned medium of anastellin treated cells indicated that the increased gene expression was accompanied by the secretion of IL-8 and TNF-α protein, which was detected between 2-4 hrs of anastellin treatment. Changes in gene expression were preceded by increased phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK as well as the nuclear translocation of NF-κB. PCR and ELISA analysis showed that the NF-κB inhibitor (BAY 11-7082) completely inhibited the induction of IL-8 and TNF-α. The inhibitor of p38 MAPK activity (SB 203580) and the inhibitor of JNK (SP600125) each partially attenuated the induction of IL-8 and TNFα while the combination of inhibitors completely blocked gene expression and the nuclear translocation of NF-κB in response to anastellin. Taken together, these data indicate that treatment of dermal fibroblasts with anastellin causes activation of the p38 and JNK MAPK pathways which converge downstream to promote the NF-κB dependent expression of IL-8 and TNF-α. These data suggest that fibronectin matrix remodeling induces the expression of proangiogenic cytokines by stromal cells present in the tumor microenvironment. This mechanism may represent a novel pathway of tumor resistance to angiogenesis blockade. This work is supported by NIH grant CA69612.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1287.