bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1247: Transcriptional regulation of VEGF by WT1 and AR in prostate cancer
Authors: Eisermann Kurtis , Reese Jennifer L. , Broderick Carly J. , Fraizer Gail C. 
Published: February 2011

Abstract
Identifying molecular mechanisms that influence prostate cancer progression is central to understanding how this disease develops. Angiogenesis is key for cancer development and growth as tumors require new blood vessels for nutrients and oxygen. Vascular endothelial growth factor (VEGF) is the most important signaling protein involved in angiogenesis and is up-regulated by oncogene expression among other things. Previous studies have shown that the zinc finger transcription factor WT1 (Wilms tumor 1) transcriptionally regulated VEGF in multiple cell lines. Additionally, WT1 activation of VEGF required an intact zinc finger domain and was mediated by DNA binding. Potential WT1 binding sites were identified in the VEGF promoter using in silico approaches and shown to bind WT1 protein using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. Luciferase reporter assays showed increased activation of the VEGF promoter by over-expression of WT1. Additional factors known to induce VEGF expression are growth factors, hypoxia and hormones. How androgen regulates VEGF transcription is unknown, but we have identified two potential androgen receptor (AR) binding sites within 2kb of the transcriptional start site and demonstrated reporter activation by R1881 treatment of transfected LNCaP cells. This study examined the effect of mutating selected WT1 and AR binding sites in the VEGF promoter to determine whether they were responsible for activation of VEGF transcription. Mutating these binding sites by site-directed mutagenesis significantly decreased activation of the VEGF promoter by WT1 and the androgen analog R1881 in LNCaP cells. As predicted, treatment with the anti-androgen casodex similarly eliminated hormone response of the VEGF promoter, suggesting that androgens are functioning via androgen signaling. This was confirmed in vivo by both western blot analysis of VEGF protein and quantitative real-time PCR measurement of VEGF mRNA in cells treated with casodex. This is important because androgen signaling is vital to normal prostate development and malignant prostate growth. Overall these results show that both WT1 and AR transcriptionally regulate VEGF expression in prostate cancer cells and these factors directly bind and activate the promoter in vivo. Understanding how angiogenesis is regulated will lead to improved therapy and prevention of prostate cancer progression.
This work was supported by NIHR15CA11360 (GF), Sigma Xi GIAR220034 (KE), and GSSKSU (KE)
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 1247.
Abstract 125: The DNp73 isoform provides novel insights into the regulation of p53 by BRCA1 to favor cell survival over cell death
Authors: Scata Kimberly A. , El-Deiry Wafik S. 
Published: February 2011

Abstract
BRCA1, the first breast cancer susceptibility gene to be identified, remains an enigma. Many roles have been ascribed to BRCA1 including DNA repair, cell cycle checkpoint activation, transcriptional regulation and chromatin remodeling. We have previously established that BRCA1 overexpression induces the stabilization of p53 without activating pro-apoptotic targets of p53, and that BRCA1 can protect cells from DNA damage-induced p53-dependent cell death. This seems to be specific to pro-apoptotic targets because p53 is still able to activate target genes involved in cell cycle arrest or DNA repair. In our efforts to understand this phenomenon, we have found that BRCA1 induces many of the same post-translational modifications that DNA damage induces including key phosphorylations and the acetylation of lysine 120 of p53, known to be important for apoptosis. Moreover, BRCA1-stabilized p53 localizes to the promoter regions of pro-apoptotic target genes whose expression is not upregulated. We hypothesized that p53 family members p63 and/or p73 may regulate the selectivity of p53 action in response to BRCA1. Unexpectedly, we found that BRCA1 upregulates DNp73 expression, an isoform of the p53 family member p73 lacking the transactivation domain, that has been previously implicated in cell survival. This observation has important implications for understanding the selectivity of p53-dependent transcription as well as the tumor suppressive action of BRCA1 that favors DNA repair over cell death. Our ongoing studies are evaluating the effects of the BRCA1-induced DNp73 isoform on interactions between p53 and p53 family members that regulate the genes involved in cell fate. These findings unravel a novel mechanism by which the selectivity of p53-dependent gene expression is regulated BRCA1 and further unravels the complex nature of these p53 and BRCA1 tumor suppressor pathways.
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 125.
Abstract 1255: Protein kinase C epsilon (PKCε) as a target for lung cancer treatment: Essential role of PKCε in tumor growth and metastatic dissemination of non-small cell lung cancer (NSCLC) cells
Authors: Caino M. Cecilia , Haber Cynthia C. Lopez , Kim Jeewon , Kazanietz Marcelo G. 
Published: February 2011

Abstract
Protein Kinase C epsilon (PKCε), a member of the PKC family of phorbol ester/diacylglycerol receptors, has been recently shown to be highly overexpressed in non-small cell lung carcinomas (NSCLCs) compared to normal lung epithelium. The fact that several of the most common genetic alterations in lung cancer, such as EGFR, K-Ras, or PI3K mutations, could signal through PKCs, led us to hypothesize that PKCε may contribute to lung tumorigenesis. We found that the expression of PKCε was markedly up-regulated in NSCLC cell lines (H358, H441, H322, H1299, and A459) relative to immortalized non-tumorigenic cells (HBEC-3). Stable knockdown of PKCε in NSCLC cells using shRNA lentiviruses impaired cell survival in response to serum starvation, as well as it increased the sensitivity to senescence induction by phorbol esters. Moreover, anchorage-dependent and -independent growth were markedly reduced in PKCε-depleted NSCLC cells. Notably, silencing of PKCε-expression in NSCLC impaired motility in response to PMA, FBS or TGFα. Treatment of NSCLC cells with PMA led to a significant enhancement in cell motility as well as it promoted ruffle formation. Both ruffle formation and migration were mediated by PKCε. Moreover, PMA caused a marked enhancement in Rac1-GTP levels in NSCLC cells, but this effect was lost when PKCε was knocked down using RNAi. To address the relevance of our findings in an in vivo setting, we examined the requirement of PKCε in tumorigenesis and metastasis. Remarkably, PKCε-depleted H358 cells have impaired tumorigenic potential when inoculated into nude mice. At early time points during tumor formation (6-15 days) we observed a significant increase in apoptotic cells in PKCε-depleted H358 xenografts compared to controls, as determined by TUNEL. These in vivo results were validated pharmacologically by means of a specific inhibitor of PKCε translocation/activation. Indeed, delivery of the specific PKCε inhibitor
εV1-2 by osmotic minipumps greatly reduced the rate of tumor growth in nude mice. Finally, we sought to study whether PKCε is implicated in tumor dissemination. Using a tail vein injection assay, we found that stable depletion of PKCε essentially impaired the appearance of lung metastatic foci in nude mice. In summary, our results established PKCε as a key mediator of lung tumorigenesis and provided strong evidence that elevated PKCε levels in NSCLC cells play a key role in metastatic dissemination. We speculate that PKCε is an attractive pharmacological target for lung cancer treatment.
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 1255.
Abstract 1264: Extracellular galectin-3 induces tumor-specific apoptosis through the interaction with highly glycosylated cell surface β1 integrin
Authors: Lee Sok-Hyong , Zerrouqi Abussamad , Devi Saroja , Van Meir Erwin G. 
Published: February 2011

Abstract
Galectins are a family of animal lectins, which bind beta-galactose moieties. Gal3 is the only chimeric family member of Gals and consists of a collagen-like N-terminal region and a C-terminal carbohydrate recognition domain (CRD), which has binding affinity for galactose and N-acetyl-lactosamine. Gal3 is known to be secreted through Golgi apparatus-independent alternative pathway. Previously, we found that stimuli-induced p53 activation induced bystander killing effect against adjacent cells. This p53 bystander effect is mediated through the secretion of Gal3 with the requirement of p53-dependent induction of tumor suppressor activated pathway-6 (TSAP6). We found the apoptotic activity of extracellular Gal3: a variety of tumor cell types (malignant glioma, breast, colon, prostate, lung) are sensitive to Gal3-mediated killing, while normal cells (fibroblast, endothelial) are not affected. We demonstrated that conditional sGal3 induction (tet-on system) in glioma xenografts strongly inhibits tumor growth without overt toxicity in mice. We found that Gal3-mediated tumor cell killing was neutralized with lactose, a Gal3-CRD binding ligand, and Gal3-mediated apoptosis was inhibited by treatment with a caspase 9 inhibitor (LEHD) but not by a caspase 8 inhibitor (IETD). Gal3 interacts with several glycosylated cell surface proteins. We identified that Gal3-induced tumor specific apoptosis is mediated through Gal3-beta1 integrin binding through GST-Gal3 pulldown assay, cell membrane-specific Gal3-beta1 integrin co-immunoprecipitation, and beta1 integrin siRNA neutralization. Further, the treatment of N-glycosylation inhibitor (tunicamycin) interfered with Gal3-beta1 integrin interaction whereas, O-glycosylation inhibitor (benzyl-O-N-acetyl-D-galactosamine) increased N-glycosylation of beta1 integrin as well as consequent Gal3-beta1 integrin interaction and Gal3-mediated apoptosis. In summary, our data demonstrate that extracellular Gal3 interacts with tumor cells through highly-glycosylated cell surface beta1 integrin through its CRD binding and consequently induces apoptosis. These findings are important for our understanding of tumor-specific killing of Gal3 and suggest that Gal3 can be exploited as a therapeutic agent for cancer.
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 1264.
Abstract 1281: Endothelial cells promote the cancer stem cell phenotype of human colorectal cancer cells
Authors: Lu Jia , Bose Debashish , Zhou Yunfei , Gaur Puja , Samuel Shaija , Fan Fan , Xia Ling , Ye Xiang-Cang , Sceusi Eric , Tozzi Federico , Mani Sendurai A. , Ellis Lee M. 
Published: February 2011

Abstract
Background: Cancer stem cells (CSC), which possess the properties of self-renewal, multi-potential differentiation and tumor initiation, can arise either from normal stem cells or due to the influence of the tumor micro-environment. This study was done to determine the potential role of endothelial cell (EC) derived paracrine factors on promoting the CSC phenotype in human colorectal cancer (CRC) cells.
Methods: RFP-labeled human CRC cells HCT116 were co-cultured with RF24 ECs (immortalized HUVECs) under low serum conditions. After FAC-sorting for the CRC cells, the CSC population was analyzed by 1) the Aldefluor assay, 2) sphere forming ability, and 3) Western blot analysis for the CSC markers CD133 and CD44. In addition, low serum condition media obtained from either ECs or parental CRC cells (control), was added to CRC cells to determine its effect on the CSC phenotype. In order to characterize the apoptotic effect of EC derived factors on CRC cells, we performed Annexin V staining by FACS, PARP cleavage, Caspase 3 cleavage, and Bcl2 levels by Western blotting. Using MTT assay, we determined the effect of EC derived factors on chemo-sensitivity of CRC cells exposed to 5-FU.
Results: Co-culturing of CRC cells with ECs markedly increased the ALDH-positive population from 5% to 18%, and the sphere forming ability by more than 4-fold in CRC cells. In addition, CRC cells also displayed increased CD133 (6-fold) and CD44 (4-fold) protein levels. Furthermore, this effect could be mimicked simply by co-culturing CRC cells with conditioned media obtained from ECs. Similarly, treatment of CRC cells with conditioned medium from ECs significantly increased the ALDH-positive population from 4% to 8%, sphere forming ability &gt;3-fold, and the expression of CD133 (7-fold) and CD44 (6-fold). Conditioned medium from ECs, concomitantly decreased spontaneous apoptosis in CRC cells as demonstrated by a 3-fold decrease in Annexin V-positive population (21% to 7%), down-regulation of cleaved PARP and Caspase 3, and up-regulation of Bcl2. CRC cells exposed to EC conditioned medium also displayed decreased sensitivity to 5-FU [&gt;10-fold increase of the IC50 from 2.0 μg/ml to 22.3 μg/ml (p&lt;0.05)].
Conclusions: Exposure of CRCs to ECs increased CSC properties, and decreased spontaneous apoptosis. Since, this effect can also be mimicked by the conditioned media, additional experiments to identify and validate the soluble factors that mediate this effect are in progress.
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 1281.
Abstract 1307: Downregulation of vascular endothelial cell growth inhibitor (VEGI; TNFSF15) expression in endothelial cells by interferon-γ
Authors: Lu Yi , Chen Li , Li Lu-Yuan 
Published: February 2011

Abstract
Vascular endothelial growth inhibitor (VEGI) is a member of the tumor necrosis factor superfamily (TNFSF15) produced largely by endothelial cells. It functions as an endogenous inhibitor of neovascularization. We showed previously that VEGI inhibits angiogenesis by enforcing a growth arrest on quiescent endothelial cells while inducing apoptosis in proliferating endothelial cells. We also found that VEGI gene expression is down-regulated in growing endothelial cells in vitro as well as in tumor vasculatures. Here we show that, among a variety of inflammation-modulating cytokines we evaluated, interferon-γ (IFNγ) can down-regulate VEGI expression in human umbilical vein endothelial cells in a dose- and time-dependent manner. Neutralizing antibodies of IFNγ receptor 1 restores VEGI expression. IFNγ modulation of VEGI gene expression is mediated by unphosphorylated STAT1 rather than phosphorylated STAT1. These findings are consistent with the view that down-regulation of VEGI gene expression in endothelial cells by IFNγ is a prerequisite for the initiation and continuation of angiogenesis during inflammation.
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 1307.
Abstract 131: Mechanisms by which 2,3’, 4,5’ tetramethoxystilbene (TMS), a resveratrol derivative, induces death in breast cancer cells
Authors: Aiyar Sarah E. , Santen Richard J. , Park Hoyong , Aldo Paula B. , Mor Gil 
Published: February 2011

Abstract
We have examined a non-toxic pro-apoptotic agent, TMS (2, 3’,4, 5’ tetramethoxystilbene), which belongs to the Resveratrol family of stilbenes. To learn about the mechanism by which TMS achieved its effects we carried out microarray analysis and found that TMS treatment increased tubulin genes as well as stress response and pro-apoptotic genes. Fractionation studies uncovered that TMS treatment causes cleavage of Bax from the p21 form to a truncated p18 form. Co-localization analysis of immunofluorescent studies showed that Bax moved from the cytosol to the mitochondria. In addition, the pro-apoptotic proteins Noxa and Bim (EL, L, and S) were increased upon TMS treatment. Breast cancer cell lines reduced for Bax, Bim and Noxa are compromised for TMS-mediated cell death. Transmission electron microscopy revealed evidence of nuclear condensation, formation of apoptotic bodies and DAPI staining showed evidence of DNA fragmentation. TMS treatment was able to induce both caspase-independent and caspase-dependent death via the intrinsic death pathway.
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 131.
Abstract 1314: Real-time imaging of individual cancer cell nuclear-cytoplasmic dynamics of UV-induced apoptosis of cancer cells in the brain
Authors: Momiyama Masashi , Endo Itaru , Hoffman Robert M. 
Published: February 2011

Abstract
We have developed a novel in vivo mouse model to image cancer cell nuclear-cytoplasmic dynamics in the brain in real-time and to visualize UV-C light killing of these cells. We used dual-color fluorescent cancer cells that express green fluorescent protein (GFP) linked to histone H2B in the nucleus and retroviral red fluorescent protein (RFP) in the cytoplasm. In order to visualize metastatic single cancer cell nuclear-cytoplasmic dynamics in the brain, dual-color Lewis Lung carcinoma (LLC) cells were injected into the right internal carotid artery of nude mice. A craniectomy open window was made over the right parietal bone. Metastatic dual-color LLC cells were irradiated with a 3.6-watt hand held UV-C light source for 60 seconds. The cells were then observed over 24 hours at 3 hour intervals through the open craniectomy window. The cancer cells were observed in the brain with the Olympus OV100 Small Animal Imaging System under high magnification. Metastatic dual-color LLC cells were visualized at the subcellular level in the brain enabling apoptosis to be imaged by nuclear morphology. UV-C light induced apoptosis of the dual-color LLC cells in the brain. Aggregation of chromatin at the nuclear membrane and fragmented nuclei of the cancer cell were followed in real time in the brain. More than 90% of the cancer cells irradiated with UV-C light died and disappeared without overt toxicity of the host. The novel mouse model used here will enable a deeper understanding of cancer cell dynamics in the brain. UV-C light may be a powerful tool for treatment of cancer cells expressing fluorescent reporters which now can be effected in vivo (Proc. Natl. Acad. Sci. USA, 1-6, 14514-14517, 2009 and Molecular Cancer Therapeutics 8, 3001-3008, 2009).
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 1314.
Abstract 1315: Real-time imaging of nuclear-cytoplasmic dynamics in UV light killing of cancer cells expressing fluorescent proteins
Authors: Kimura Hiroaki , Tsuchiya Hiroyuki , Tomita Katsuro , Hoffman Robert M. 
Published: February 2011

Abstract
Our laboratory pioneered dual-color cancer cells, in which red fluorescent protein (RFP) is expressed in the cytoplasm and green fluorescent protein (GFP) in the nucleus (Cancer Research 64, 4251-4256, 2004; Nature Protocols 1, 928-935, 2006). Total cellular dynamics can be visualized in the living dual-color cells in real time. In this study, we investigated the cancer-cell-killing efficacy of UV light using the dual-color cancer cells. For UV irradiation experiments, a Benchtop 3UV transilluminator, which emits UVC with an emission peak at 254 nm; UVB with an emission peak at 302 nm; and UVA with an emission peak at 365 nm; was used. After exposure to various doses of UVA, UVB, or UVC, apoptotic, necrotic and viable cells were quantitated under fluorescence microscopy using dual-color 143B human osteosarcoma cells (143B). UV-induced cancer cell death was wave-length and dose dependent. After UVA exposure, most cells were viable even if the UV dose was increased up to 200 J/m2. In the UVB group, cell death began to appear when irradiated at 50 J/m2. For UVC, the rate of cell killing was proportional to increased UVC irradiation. 25 J/m2 UVC irradiation killed over 40% of the 143B dual-color cells. However, the rate of cell killing plateaued at 100 J/m2. We also tested 50J/m2 UVC and 100J/m2 of UVB on four types of dual-color cancer cell lines. UV-induced cancer cell death varied among the cell lines. Cell death began about 4 hours after irradiation and continued until 10 hours after irradiation. Real-time movies were made of cells undergoing UV-induced cell death. Most cells died via apoptosis and only a small portion of them died via necrosis. We will develop UV irradiation for treatment of fluorescent-protein-expressing minimal residual cancer remaining after resection.
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 1315.
Abstract 1317: The 2-phenylbenzimidazole-5-sulfonic acid sunscreen agent photosensitizes oxidized guanines following UVA or UVB exposure
Authors: Bastien Nathalie , Millau Jean-François , Rouabhia Mahmoud , Davies Jerry R. , Drouin Régen 
Published: February 2011

Abstract
The 2-phenylbenzimidazole-5-sulfonic acid (PBSA) is a sunscreen agent widely used in the cosmetic industry because it absorbs strongly at UVB wavelengths providing a good protection against the cyclobutane pyrimidine dimer (CPD) generation. Previous studies have shown that PBSA oxidize guanine bases in vitro (isolated DNA). Due to its potential phototoxic effect, it is of great interest to determine whether PBSA can play the role of a photosensitizer in cellulo. For this purpose, we investigated in vitro and in cellulo (in fibroblasts) the effect of 0 to 4 mM PBSA on DNA damage formation after UVA or UVB irradiation. In order to monitor oxidized bases and CPD formation, DNA was digested with either endonuclease III and FaPy-DNA glycosylase or T4 endonuclease V and photolyase, then analyzed by means of glyoxal gel electrophoresis and ligation-mediated polymerase chain reaction (LMPCR). We found that in cellulo and in vitro, PBSA provided a good protection against CPD formation, but induced oxidative damage and DNA-strand breaks. Moreover, with the LMPCR technology we were able to determine that oxidative damage were preferentially formed at guanine sites. Our results indicate that PBSA has the potential to act as a double-edged sword toward DNA, on one hand it blocks the formation of CPDs after UVB and on the other hand increase the formation of oxidized guanines upon UVA and UVB irradiation. This raises major concern regarding its suitability for sunscreen applications.
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 1317.