bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2922: NDC-1308 inhibits growth of lung and pancreatic tumors in vivo by blocking chromosome replication of cancer cells
Authors: Yarger James G. , Weitman Steven , Weitman Steven , Meibohm Bernd , Gately Stephen , Nye Steven 
Published: February 2011

Abstract
Identification of the cellular mechanisms that alter normal cell growth may be exploited for creating new drugs that treat cancers with unmet needs. For example, recent evidence by our group, and others, suggests that proliferation of lung and pancreatic cancer cells may be controlled by the estrogen receptors alpha (ER-alpha) and beta (ER-beta). If accurate, designing drugs that enhance the proposed inhibitory function of ER-beta versus the stimulatory function of ER-alpha, should lead to cessation of cell division and potentially to cell death. We previously demonstrated that an estradiol-like compound, NDC-1308, is cytotoxic to 14 different tumor cell lines in vitro with an EC50 of 10-20 uM. As predicted, receptor binding studies confirmed that NDC-1308 binds preferentially to ER-beta compared to ER-alpha. A more detailed in vitro analysis showed that NDC-1308 causes a substantial reduction in the transcription of 27 genes involved in chromosomal replication, likely disrupting the cell cycle of the cancer cells. To determine the efficacy of NDC-1308 to kill tumor cells in vivo, xenograft studies were carried out using SCID mice injected with A549 (lung) and BxPC3 (pancreas) tumor cell lines. Mice (N=15 per treatment group) were administered either 8, 16 or 24 mg/kg of NDC-1308 via tail vein injection. Depending on the schedule, the mice were dosed every other day or every third day and the tumor weights followed for two additional weeks after ending treatment. The results show that tumor size was substantially smaller (2 to 3-fold) in NDC-1308 treated animals versus untreated controls. We conclude that intravenous administration of NDC-1308 can cause a cessation of tumor growth in a mouse model of lung and pancreatic cancer. Consistent with the proposed mechanism of action and recent rat pharmacokinetic data (t1/2=120min), increasing the dose or decreasing the time between doses enhanced the effect of NDC-1308 on tumor growth in the xenograft model. Future studies will include large animal safety and toxicity studies leading to IND submission and Phase I clinical trials.
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 2922.
Abstract 2923: Estrogen signaling modulates cisplatin resistance in the treatment of human non-small cell lung cancer
Authors: Márquez-Garbán Diana C. , Patel Amitkumar D. , Chen Hsiao-Wang , Goodglick Lee , Fishbein Michael C. , Garon Edward B. , Garbán Hermes J. , Pietras Richard J. 
Published: February 2011

Abstract
Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancers. Standard initial chemotherapy for patients with advanced NSCLC is a platinum-based regimen, with data showing that these therapies elicit a modest improvement in patient survival. However, a major limitation to cisplatin therapy is development of drug resistance, leading to cancer progression and reduced patient survival. Cisplatin acts by interacting with DNA to form adducts that, in turn, activate signaling pathways for cell death (apoptosis). DNA damage-mediated apoptotic signals, however, can be blocked, and the resistance that ensues is a major drawback of cisplatin therapy. Resistance mechanisms, such as increased DNA adduct repair, may be modulated by interactions with other signaling pathways for cell survival, and emerging data suggest that estrogens may play a role in this process. To understand how estrogens modulate cisplatin resistance in vitro, we used two models of human NSCLC, A549 and H23 cells, that proliferate in response to estradiol-17β (E2) and express estrogen receptors and aromatase (enzyme that produces estrogens locally). Cisplatin markedly reduces tumor cell growth and enhances apoptosis in both models. However, the antitumor action of cisplatin is significantly blocked when cells are treated with estrogen in vitro. Using qRT-PCR and Western immunoblot analysis of excision repair cross-complementing-1 (ERCC1) protein (repairs cisplatin-induced DNA damage), we find that ERCC1 mRNA and protein levels are significantly increased in the presence of estrogen, thereby suggesting a potential mechanism for estrogen-induced cisplatin resistance. Analyses of the 5’-regulatory region of the human ERCC1 gene revealed putative half-estrogen responsive elements in close proximity with sp1 and AP1 sites. Chromatin immunoprecipitation assays showed binding of estrogen receptors to these promoter sites. Furthermore, treatment of human NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. A new strategy to block NSCLC progression may be use of cisplatin with simultaneous suppression of estrogen signaling (such as use of aromatase inhibitors). [Supported by NIH Lung Cancer SPORE, National Lung Cancer Partnership and Stiles Program funds].
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 2923.
Abstract 293: Regulation of inhibitor of differentiation 1 (Id1) by PKC signaling in the intestinal epithelium
Authors: Hao Fang , Pysz Marybeth A. , Haas Kristin N. , Curry Kathryn J. , Vollmer Thomas R. , Black Adrian R. , Black Jennifer D. 
Published: February 2011

Abstract
Increasing evidence supports a role for protein kinase C (PKC) signaling in regulation of intestinal epithelial self-renewal, and alterations in PKC isozyme expression/activity have been broadly linked to intestinal carcinogenesis. PKCα, which exhibits growth inhibitory and tumor suppressor properties in the intestine, is lost early during intestinal tumor development. To gain further insight into the tumor suppressive effects of PKCα signaling, we explored the consequences of restoration of PKCα expression in DLD-1 human colon cancer cells by microarray analysis. The most downregulated known gene in PKCα-expressing DLD-1 cells was inhibitor of differentiation 1 (Id1), a member of the Id family of dominant negative antagonists of bHLH transcription factors that has cell cycle stimulatory functions and has been associated with tumorigenesis in a number of systems. Suppression of Id1 protein by PKCα in colon cancer cells was confirmed by Western blot analysis in a panel of cell lines including DLD-1, HCT116, FET, FET/DNR, and GEO. Notably, activation of PKC/PKCα in non-transformed IEC-18 intestinal crypt cells also resulted in rapid and profound downregulation of Id1 mRNA and protein, pointing to a role for PKCα in Id1 regulation in the normal intestinal epithelium. PKC-induced suppression of Id1 was found to occur via an ERK/MAPK-dependent, PI3K-independent mechanism. Manipulation of Id1 levels in normal and transformed intestinal cells demonstrated its ability to affect two key cell cycle targets of PKCα, the potent mitogen cyclin D1 and the cdk inhibitor p21Waf1/Cip1. Knockdown of Id1 consistently decreased steady-state levels of cyclin D1, while overexpression of the factor resulted in reduced levels of p21Waf1/Cip1. Thus, Id1 appears to control the expression of important cell cycle regulators in intestinal cells. Immunohistochemical analysis of normal intestinal mucosa further demonstrated that PKCα activation, which occurs precisely at the point of growth arrest in the mid/upper crypt, coincides with marked downregulation of Id1 in vivo. Conversely, loss of PKCα in intestinal tumors is associated with Id1 overexpression. Ongoing studies are focused on delineating the link between the tumor suppressor functions of PKCα and its inhibitory effects on Id1 expression in intestinal cells. Supported by NIH grants DK54909, DK60632, CA16506, and CA113048.
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 293.
Abstract 2941: Rapid changes in chromatin structure in response to extracellular signals
Authors: Fernandez Alfonso G. , Di Lijun , Byun Jung , Fufa Temesgen , Gardner Kevin 
Published: February 2011

Abstract
Immediate early genes (IEGs) are well known to be rapidly and transiently induced at high levels of expression in response to various extracellular signals such as growth factors. These rapid changes in the transcriptional state of this class of genes raised questions regarding the role of higher order chromatin structure in this transient event of inducible gene expression. In these studies, we compared the degree of chromatin condensation in Jurkat cells before and after mitogen stimulation of c-fos, a well-known IEG. Soluble chromatin obtained from unstimulated and stimulated cells were collected for a sucrose gradient sedimentation assay in order to separate chromatin fibers by means of size and more importantly by the extent of structural condensation of the chromatin. Real time-PCR analysis of c-fos was then used as a tool to quantify the distribution of open and closed chromatin fibers across the collected fractions obtained from the sucrose gradients. The results suggested a major decondensation of the chromatin fiber at the c-fos gene upon stimulation. The unfolding of the chromatin structure upon stimulation is paired with a dramatic increase in histone acetylation as detected by chromatin immunoprecipiation (ChIP) at the promoter region. Histone hyperacetylation is known to cause destabilization of the higher order chromatin structure leading to an increase in chromatin accessibility as clearly shown in our DNase hypersensitivity studies. Taken together, we have detected a rapid decondensation of the chromatin fiber, which is believed to facilitate the rapid transcriptional response to extracellular signals. Our current interest lies in obtaining further information regarding the molecular events that are more directly related to destabilization of the higher order chromatin structure upon mitogen stimulation. Testing of various molecular candidates involved in chromatin destabilizing events include phosphorylation of linker histone H1, recruitment of histone variants and dramatic histone modications such as ADP-polyribosylation at the c-fos promoter region. A more detailed understanding on the rapid decondensation of the chromatin fiber would provide valuable information regarding the cascade of events that must take place in response to stress or extracellular signals.
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 2941.
Abstract 2943: Aurora kinase A induces miR-17-92 cluster through regulation of E2F1 transcription factor
Authors: He Shun , Yang Shangbin , Deng Guohua , Zhu Hongxia , Liu Mei , Zhang Wei , Quan Lanping , Bai Jinfeng , Xu Ningzhi 
Published: February 2011

Abstract
Aurora Kinase A (AURKA) encodes an evolutionally conserved serine/threonine kinase that plays a pivotal role in centrosome cycling during mitosis. Abnormal expression of AURKA has been observed in many malignancies, yet the exact role for AURKA in tumorigenesis still remains elusive. Here through a transcription factor array, we show that the transcription activity of E2F1 was increased by AURKA overexpression. Meanwhile, E2F1 protein level was found to be upregulated upon AURKA induction and the correlation between AURKA and E2F1 expression was also observed in breast cancer specimens. Further analysis revealed that AURKA increased E2F1 protein stability by inhibiting proteasome-dependent degradation of this protein. Additionally, a microRNA cluster, miR-17-92 was found to be upregulated upon AURKA overexpression, and this stimulation was largely repressed by small interfering RNA (siRNA) against E2F1. Chromatin immunoprecipitation further demonstrates that AURKA enhanced the in vivo occupancy of E2F1 to the promoter of the miR-17-92 cluster. These data reveal a novel link between AURKA and microRNAs via the regulation of E2F1, providing new clues for understanding the role of AURKA in tumorigenesis.
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 2943.
Abstract 2944: Genome-wide transcriptional modulation screening in non-smoking female lung cancer in Taiwan
Authors: Lu Tzu-Pin , Chen Pei-Chun , Lee Jang-Ming , Hsu Chung-Ping , Chen Shin-Kuang , Tsai Mong-Hsun , Hsiao Chuhsing K. , Chuang Eric Y. , Lai Liang-Chuan 
Published: February 2011

Abstract
Lung cancer has become the leading cause of cancer death in Taiwan and in most countries. Although smoking has been the major risk factor for lung cancer, less than 20% smokers develop lung cancer. In Taiwan, only about 50% of lung cancer cases were related to smoking, while more than 90% lung cancer females were non-smokers. In this study, we collected gene expression microarrays to investigate the pathogenesis process. One hundred and twenty lung tumor samples and their normal counterparts from non-smoking females were collected from National Taiwan University Hospital and Taichung Veterans General Hospital. RNAs from 60 paired samples were examined using Affymetrix Human U133 plus2.0 microarray. Paired t-tests were used to identify differentially expressed genes between tumor and normal tissues. The preliminary results showed there were 791 differentially expressed genes (p-value &lt; 10−14). Ingenuity Pathway Analysis (IPA) was utilized for further functional and pathway analyses on these genes, and the axon guidance signaling pathway was the most significantly enriched pathway. Among genes in the axon guidance signaling pathway, SEMA5A was chosen for further investigation because it was the most significant down-regulated gene in tumor tissue. Its down-regulation was validated by both real-time PCR and immunohistochemistry (IHC). Furthermore, Kaplan-Meier survival analysis showed that patients with low SEMA5A expression had poor overall survival as compared to those who had high SEMA5A expression. This significant association was also observed in two published studies. Therefore, these results indicated that the SEMA5A may play an important role in the carcinogenesis and can be a potential prognosis biomarker for non-smoking lung cancer females in Taiwan.
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 2944.
Abstract 2951: Nicotine induced EMT involves β-arrestin-1 mediated regulation of E2F1 target genes
Authors: Pillai Smitha R. , Damit Michael , Chellappan Srikumar 
Published: February 2011

Abstract
Cigarette smoking is strongly correlated with the onset of non-small cell lung cancer. Nicotine, an active component of tobacco smoke has been found to induce proliferation, invasion and epithelial-mesenchymal transition in NSCLC cell lines. While nicotine by itself is not carcinogenic, it can induce cell proliferation utilizing a scaffolding protein, β-arrestin-1 which translocates to nucleus and associates with E2F1 transcription factor. In addition, nicotine induces changes in gene expression consistent with epithelial-mesenchymal transition characterized by increase in the levels of mesenchymal proteins like vimentin and fibronectin. In this study we demonstrate that mesenchymal markers such as vimentin and fibronectin are E2F1 regulated and β-arrestin-1 is involved in regulating their expression in response to nicotine stimulation. Analysis of vimentin and fibronectin promoters revealed the presence of potential E2F binding sites. Transient transfection experiments in A549 cells using vimentin and fibronectin promoter constructs showed that these promoters were induced significantly by E2F1 and repressed by Rb. Depletion of E2F1 using siRNAs resulted in down regulation of vimentin and fibronectin as seen by Real-Time PCR. Chromatin immunoprecipitation assays on quiescent as well as nicotine stimulated A549 cells showed a robust recruitment of E2F1 and β-arrestin-1 to vimentin and fibronectin promoters. In addition, depletion of β-arrestin-1 resulted in down regulation of vimentin and fibronectin expression as revealed by western blot and Real-Time PCR. Nicotine stimulation resulted in the induction of vimentin and fibronectin promoters when A549 cells were transfected with reporter constructs while β-arrestin-1 depleted cells did not show promoter induction with nicotine stimulation. Boyden chamber assays conducted on β-arrestin-1 knocked down cells showed that ablation of β-arrestin-1 resulted in the inhibition of nicotine induced migratory and invasive potential of cells. Taken together, these data suggest that β-arrestin-1 contributes to nicotine induced epithelial-mesenchymal transition by regulating E2F1 mediated vimentin and fibronectin expression.
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 2951.
Abstract 2952: Gene expression profiling in gastric adenomas and carcinomas
Authors: Kim Won Kyu , Koh Kwi Hye , Nam Suk Woo , Rhee Hwanseok , Kim Hoguen , Hyunki Kim 
Published: February 2011

Abstract
A subset of gastric carcinogenesis is a multistep process, which progresses from chronic gastritis, atrophy, intestinal metaplasia, adenoma and finally leads to gastric carcinoma. To explore the transcriptomic change during the gastric adenoma-carcinoma sequence, a total 26 snap-frozen samples (8 paired normal mucosa, adenoma and carcinoma cases and additional 2 carcinomas) were analyzed by oligonucleotide microarrays. We identified 60 gradually up and down regulated genes according to normal, adenoma and carcinoma sequence. Twenty one genes were gradually decreased from normal mucosa to adenoma to carcinoma and 39 genes were gradually increased. We validated the expression of hydroxyprostaglandin dehydrogenase 15 (HPDG15), follistatin-like 1 (FSTL1), trefoil factor 1 (TFF1) and trefoil factor 2 (TFF2) by real time RT-PCR. The identified gene sets according to adenoma-carcinoma sequence might play critical roles in gastric carcinogenesis.
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 2952.
Abstract 2955: LSm1 over expression contributes to an increase in alternative splicing in lung cancer cells
Authors: Watson Patricia M. , Boylan Alice , Watson Dennis K. 
Published: February 2011

Abstract
RNA splicing is a key molecular event that allows for substantial protein diversity. Through this process, a single gene magnifies its coding capacity by expressing several related proteins with diverse and often antagonistic functions leading to cell or tissue specific changes in mRNA through changes in splice site choice. Alternative splicing, which represents the suppression of constitutive splice sites and/or the use of suboptimal sites, is elevated in cancer and many other disease states. Pre-mRNA splicing is coordinated by the spliceosome, a macromolecular ribonuclear complex that assembles on the pre-mRNA as it is transcribed. Due to the number of proteins involved in splicing, the diversity of pre-mRNA substrates and the multi-step process of spliceosome assembly and catalysis, regulation of splicing can occur at any point in the pathway. The LSm proteins are a family of eight RNA binding proteins that form two seven membered ring structures and contribute to mRNA stability and splicing. LSm1 forms a complex with LSm2-7 that targets mRNA for degradation in P bodies. LSm8 also forms a complex with LSm2-7 that binds the U4 U5 U6 tri-SNRP, an integral part of the spliceosome. Previously, it was shown that LSm1 was elevated in many different types of cancer and contributed to the malignant phenotype. Recently, alternative splicing has been shown to contribute to the activation of oncogenes and the inactivation of tumor suppressor genes. To determine if the over expression of LSm1 could contribute to alternative splicing, a well differentiated lung cancer cell line was infected with adenovirus expressing the open reading frame of LSm1 or GFP. The RNA from these cells was analyzed for alternative splicing using Agilent SpliceArray™ microarray slides. Significant differences were seen between the cells treated with control virus and the LSm1 expressing virus in the splicing patterns of several genes that could contribute to the cancer phenotype, including hepatoma derived growth factor (HDGF), CD44 and c-myc. Thus, over expression of LSm1 leads to changes in alternative splicing that impacts the malignant phenotype of cancer cells.
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 2955.