bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3941: Altered helical structures: Repair and induction of genomic instability
Authors: Rogers Faye A. 
Published: February 2011

Abstract
Naturally occurring DNA sequences capable of forming H-DNA (triplexes) are found in the human genome as frequently as 1 in every 50,000 base pairs. These sequences, typically located in promoters and exons have been found to be intrinsically mutagenic and are believed to be involved in the regulation of expression of several cancer-linked genes. To counteract the potentially devastating effects of altered helical structures on genomic integrity, an intricate balance between DNA repair and apoptosis is critical. In the present work, we have investigated the potential for non-canonical structures to trigger pro-apoptotic pathways. In conjunction with the use of a fibroblast line containing multiple chromosomal target sites, sequence-specific triplex-forming oligonucleotides (TFOs) were used to synthetically create altered helical structures. Our studies demonstrate that DNA damage induced by these structures can trigger the switch from DNA repair to apoptosis. Additional studies were initiated to determine whether key proteins that contributed to cellular survival by participating in the repair of helical distortions also played a role in triggering the cell to activate a pro-apoptotic pathway. The TFIIH factor, XPD has been implicated in our studies to occupy a central role in triggering apoptosis in response to excessive H-DNA induced damage. Knock-down of XPD resulted in a significant decrease in H-DNA induced apoptosis, thus suggesting that key proteins that contribute to cellular survival by acting in DNA repair become executioners in the face of excess DNA damage. The maintenance of this mechanism may be of central importance for avoiding progression to cancer, because the default mechanism of apoptosis prevents expansion of cells in which unrepaired damage would lead to mutation and 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 3941.
Abstract 3942: Novel mechanism for inactivation of the DNA damage response during apoptosis
Authors: Solier Stéphanie , Pommier Yves 
Published: February 2011

Abstract
Apoptosis, programmed cell death, is required in multicellular organisms for various physiological processes. Disruption of the equilibrium between cell death and proliferation is one of the mechanisms of tumor formation. Therefore, one of the challenges and one of the ongoing approaches for cancer therapy is to develop pro-apoptotic agents. One such agent is TRAIL (Tumor necrosis factor-Related Apoptosis-Inducing Ligand), a promising therapy in development because it induces apoptosis preferentially in cancer cells compared to normal cells. We recently identified the “apoptotic ring”, a previously unnoticed process of cellular apoptosis by the nuclear peripheral staining of phosphorylated DNA damage response (DDR) proteins including γ-H2AX, ATM, DNA-PK and Chk2. The γ-H2AX apoptotic ring forms in the early phase of the apoptotic response to a broad range of stimuli including TRAIL in different cell types. It differs from the focal pattern response (DDR nuclear foci) to DNA damaging agents. Because γ-H2AX is a fundamental chromatin modification in response to DNA double-strand breaks and serves as a molecular platform for the docking of DDR protein complexes and for amplifying the DDR, we were particularly interested to determine whether the apoptotic γ-H2AX response led to the full recruitment of the DDR factors. Here we looked at MDC1 (mediator of DNA damage checkpoint 1) which normally binds to γ-H2AX in response to DNA damage and amplifies the DDR. We will report that during TRAIL-induced apoptosis, MDC1 does not exhibit an apoptotic ring. Lately a new phosphorylation of histone H2AX on tyrosine 142 (P-Y142-H2AX) has been described, thereby preventing the binding of MDC1 to γ-H2AX. However, we find that Y142 phosphorylation is reduced in response to TRAIL and uncovered a novel mechanism to explain the inactivation of MDC1-mediated transduction of the DDR during apoptosis. Indeed, we demonstrate for the first time that MDC1 is cleaved by caspase-3 during apoptosis, separating the FHA (forkhead-associated) and the BRCT (breast cancer C-terminal) domains, and consequently disrupting the linkage to γ-H2AX and other DNA damage responsive proteins.
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 3942.
Abstract 3947: PARP-1 as a therapeutic target in gliomas
Authors: Seoane Marcos , Iglesias Pablo , Castro Lydia , Arce Victror M. , Costoya Jose A. 
Published: February 2011

Abstract
Gliomas are the most common primary tumors in the brain. We use this tumor type as a paradigm of oncogenic transformation. Deregulation of signal transduction pathways are commonly found both in low- and high-grade gliomas. Moreover, all WHO grade III and IV (GBM) show a disruption of cell cycle due to alterations in at least one out of three families of proteins involved in G1/S transition, such as: CDKs, INK4a-ARF or Rb.
Oncogenic HRas (HRasV12) expression recapitulates gain-of-function mutations in several growth factor receptors in glial cells, resulting in the activation of different downstream effectors such as Raf/MEK/ERK and PI3K/AKT signaling pathways. The hyperactivation of growth signaling pathways, phenocopied by HRasV12, increases cell proliferation rate in the absence of senescence, facilitating their transformation into tumoral cells. Furthermore, our data indicate that HRasV12 is able to cooperate with Rb loss in the tumor malignization.
Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of DNA damage. Despite its important role in the cellular response to genotoxic stress, PARP-1 is not required for survival and Parp-1−/− mice are viable and fertile. These mice do not develop early onset tumors and tumor latency is increased in PARP-1 knockout mice that are deficient for p53. Accordingly, here we observed that Parp-1−/− astrocytes display a marked proliferative decrease when compared with Parp-1+/+ astrocytes which express HRasV12, either in a Rb+/+ or in a Rb−/− context.
Given that loss of PARP-1 are less susceptible to HRasV12 induced transformation, the inactivation of PARP-1 with chemical inhibitors is a potential therapeutic approach to restrain the tumor progression. Interestingly, in our model of gliomagenesis PARP-1 chemical inhibition (PJ34) leads to a significant fall in the proliferative rate in HRasV12 astrocytes comparable to Parp-1−/− astrocytes, and is also able to reduce tumor progression even when HRasV12 cooperates with Rb loss. These results indicate that treatment with PARP-1 inhibitors might be a potential therapy for this type of tumors.
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 3947.
Abstract 395: Rapid engraftment of human primary acute leukemic cells in NOD/SCID mice by intrasplenic inoculation: a robust human primary leukemia (Hukemia) model for preclinical evaluation of new therapies
Authors: Liang Huang , Zhang Amy , Wang Na , Ma Shuyan , Liu Jingping , Qi Xiaoxu , Song Xiaoming , Chen Taiping , Xia Michelle , Wery Jean-Pierre , Chen Xingjun , Chen Yiyou , Zhou Jianfeng , Zhou Pengfei 
Published: February 2011

Abstract
The ability to engraft human leukemia cells directly from patient samples into immunodeficient rodents such as NOD/SCID mice would be uniquely valuable in preclinical prioritization of novel therapies for future clinical trial. The aim of this study was to develop an animal model for human acute leukemia in which the kinetics, characteristics and chemosensitivity of leukemia can be sequentially monitored in individual immunodeficient mouse model. Continuous xenografts from 28 acute myeloid leukemia (AML) patients and 18 acute lymphoblastic leukemia (ALL) patients with AML-ETO, CBFβ/MYH11, TAL/SIL1, MLL/AF4 fusion genes were established in NOD/SCID mice by intrasplenic inoculation of human leukemic cells from born marrow. Progression of leukemia was monitored throughout the development of disease by determination of immunophenotyping and karyotyping of the engraftment tumor cells. Chemosensitivity and in vivo efficacy to standard of care therapies were screened in xenografts from both AML and ALL patients. Genetic lesions and special surface markers in different passages of cells in recipient mice were also examined by gene array and FACS analysis. Intrasplenic inoculation of leukemia cells significantly enhanced the engraftment rate and expedited disease development when compared with I.V. route. Relative to engrafted human primary cells, negligible changes in growth rates, chromosomal aberrations and immunophenotype were observed at second, third and fourth passages. The in vivo sensitivity of xenografts to standard of care correlated significantly with clinical course and patient outcome. We have also uncovered key molecular events and serum immunoassay biomarkers which correlate with the efficacy and potency of the drugs for AML and ALL models. The biologic and genetic characteristics and patterns of chemosensitivity of xenografts from acute leukemia patients accurately reflect the clinical disease. The efficient engraftment and rapid expansion of the leukemia within NOD/SCID mice affords a robust model for the preclinical evaluation of new therapies.
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 395.
Abstract 3954: A role for the cholecystokinin 2 receptor (CCK-2R) in promoting cancer progression
Authors: Mayne Cerys M. , Grabowska Anna M. , Watson Susan A. 
Published: February 2011

Abstract
Background and aims: The gastrointestinal (GI) hormone, gastrin, promotes cancer progression and its down-regulation has been linked to reduced cancer stem cell numbers. Gastrin acts through the cholecystokinin 2 receptor (CCK-2R) and its biological effects are blocked by CCK-2R inhibitors. We investigated a potential role for CCK-2R in promoting survival of cancer stem cells using RNAi combined with a sensitive method to detect CCK-2R mRNA.
Materials and methods: A panel of cancer cell-lines was used, including GI, glioblastoma and small cell lung cancer (SCLC), with CCK-2R-transfected cells as a positive control. Linear-after-the-Exponential (LATE)-PCR was used to quantify CCK-2R gene expression and its sensitivity compared with a Taqman-based assay. Flow cytometry was used to investigate receptor protein expression. The activity of CCK-2R promoter reporters constructed in pGL4, using between 250 and 2000bp of DNA upstream of the CCK-2R start codon, was quantified using luciferase assays.
Results: LATE-PCR for CCK-2R gene expression is 1000-fold more sensitive than the Taqman-based assay. Cell-lines from the panel, including HCT116 (colorectal) and H209 (SCLC), in which CCK-2R mRNA was not detectable by the Taqman assay, were positive using the LATE-PCR. CCK-2R siRNAs resulted in up to 86% knockdown of the receptor in CCK-2R-transfected AGS cells, confirming the specificity of the LATE-PCR. FACS analysis for the CCK-2R protein suggests the presence of a small population of cells within HCT116 (colorectal) and AGS (gastric) cell-lines that express CCK-2R very highly. CCK-2R expression was enriched when cells were grown as colospheres and RNAi demonstrated a role for the CCK2R in promoting cell survival. The CCK-2R promoter constructs were active in cancer cell-lines, indicating that the 250bp proximal to the CCK-2R start codon are most crucial for transcription. However, transcriptional activity did not always correlate with gene expression.
Conclusions: LATE-PCR provides a highly sensitive method for detection of genes such as CCK-2R which have important biological functions but low expression. An element just upstream of the CCK-2R transcriptional start site appears to be controlling transcription in cell-lines showing low levels of endogenous expression of the CCK-2R genes, but lack of correlation between the RNA levels and transcriptional activity suggests possible post-transcriptional regulation of this gene. CCK-2R protein expression is elevated in a subset of cells, and may play a role in promoting survival of cancer stem 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 3954.
Abstract 3957: Identification of activated receptor tyrosine kinases in gastric cancer cells
Authors: Yoon Sang Hyun , Lee Myung Eun , Jeung Hei-Cheul , Jung Jae-Joon , Kim Tae Soo , Chung Hyun Cheol , Shin Sang Joon , Rha Sun Young 
Published: February 2011

Abstract
To improve gastric cancer treatment, relevant molecular targets need to be identified. Receptor tyrosine kinases (RTKs) are multifunctional transmembrane proteins and important mediators of the signaling cascade, determining key roles in diverse biological processes like proliferation, growth, differentiation, and apoptosis of cancer cells. To determine if any of these RTKs are activated in gastric cancer, we performed phospho-receptor tyrosine kinase array with 25 gastric cancer cell lines using Human Phospho-RTK Antibody Proteome Profiler Array (R&D Systems) which includes 42 different tyrosine kinases. Relative levels of tyrosine phosphorylation of RTKs among these cell lines were determined as a ratio relative to four positive phosphorylated tyrosine kinase control's intensity in each membrane.
We found that various growth factor receptor tyrosine kinases were differentially activated and 15 of 42 RTKs were highly activated with mean intensity &gt;5 among 25 gastric cancer cell lines. The highly activated RTKs were: EGFR (93.2), ErbB2 (33.0), HGFR (27.6), ErbB3 (26.2), IGF-IR (17.2), InsulinR (13.9), Mer (12.9), FGFR2α (11.4), Dtk (10.1), EphA7 (9.5), Tie-2 (8.9), MSPR (6.5), c-Ret (6.4), FGFR3 (5.4), and ErbB4 (5.1). These receptors basically belong to the EGF, HGF, FGF, Insulin, Tie, and Ephrin growth factor gene families_all of which are involved in cell proliferation, differentiation or signal transduction. We confirmed that increased RTKs phosphorylation observed by RTK array analysis was correlated with the expression level of each protein by immunoblotting. Additionally, we showed that Met gene amplification by quantitative real-time PCR is associated with Met activation in gastric cancer cell lines. In conclusion, these activated RTKs may work as potential therapeutic targets in gastric cancer and helpful to understand the molecular mechanisms underlying tumor development.
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 3957.
Abstract 3958: IL-6 stimulates cell motility in squamous cell carcinoma of head and neck (SCCHN) cells through CK2 phosphorylation and stabilization of TWIST
Authors: Su Yingwen , Xie Tongxin , Fredrick Mitchell J. , Daisuke Sano , Myers Jeffrey N. 
Published: February 2011

Abstract
Squamous cell carcinoma of head and neck (SCCHN) is the tenth most common cancer in the world. Unfortunately, the survival of patients with SCCHN has not improved in the last 40 years. Therefore new targets for therapy are needed, and to this end we are studying signaling pathways activated by IL-6 which we have found stimulates cell migration and soft agar growth in SCCHN. Our data show that IL-6 increases TWIST expression in a transcription-independent mechanism in many SCCHN cell lines. Further investigation reveals TWIST can be phosphorylated upon IL-6 treatment. By computation prediction (http://hits.isb-sib.ch/cgi-bin/PFSCAN), we found that TWIST has a putative phosphorylation site for casein kinase 2 (CK2) suggesting that this kinase could serve as a link between IL-6 stimulation and Twist stability. To test this hypothesis, we used a CK2 inhibitor and shRNA to CK2 and found that these interventions inhibited IL-6 stimulation of TWIST stability. In addtion, mutation of the putative CK2 phosphorylation site (S18/S20) in TWIST decreased the amount of phospho- ATP incorporated by TWIST in an in vitro kinase assay and altered TWIST stability. In soft agar colony forming assays, the CK2 inhibitor, DMAT, was found to decrease the number of IL-6 stimulated colonies formed by SCCHN cells. To our knowledge, this is the first report to identify the importance of IL-6 stimulated CK2 phosphorylation of TWIST in SCCHN and supports the previous findings from other researchers. As CK2 inhibitors are currently under phase I clinical trials, our findings indicate that CK2 may be a viable therapeutic target in SCCHN. Therefore, further pre-clinical studies of this inhibitor are underway.
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 3958.
Abstract 3962: Wnt signaling modulates the Hedgehog pathway by stabilizing GLI1 mRNA
Authors: Noubissi Felicite , Goswami Srikanta , Sanek Nicholas A. , Kawakami Kazuyuki , Minamoto Toshinari , Moser Amy , Grinblat Yevgenya , Spiegelman Vladimir S. 
Published: February 2011

Abstract
Wnt and Hedgehog signaling pathways play central roles in embryogenesis, stem cell maintenance, and tumorigenesis. These two pathways being fundamental in the coordination of developmental transitions, have been postulated to interact, or cross-regulate at multiple levels yet the mechanisms of these interactions are not well-understood.
Here, we show that Wnt signaling pathway stimulates the transcriptional output of Hedgehog signaling. We demonstrate that Wnt/β-catenin signaling induces the expression of an RNA-binding protein, CRD-BP, which, in turn, binds and stabilizes GLI1 mRNA, causing an elevation of GLI1 expression and transcriptional activity.
The newly described mode of regulation of GLI1 appears to be important to several functions of Wnt, including survival and proliferation of colorectal 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 3962.
Abstract 3964: Transforming growth factor-beta dependent regulation in breast cancer progression
Authors: Kim Hye Ok , Song Junkyu , Cho Chang Hoon , Yoon Kyung-sik ,   Department of Biochemistry and Molecular Biology (BK21 project), MRC for Bioreaction to ROS and Bi
Published: February 2011

Abstract
Transforming growth factor-ß (TGF-ß) has a wide range of biologic functions such as the regulation of cell growth, differentiation, and immunologic response in various types of cells. The involvement of TGF-ß in the pathogenesis of breast cancer has been proposed based on its capacity to stimulate the production of extracellular matrix (ECM) proteins and to regulate their metabolism. Induction of plasminogen activator inhibitor-1 (PAI-1) by TGF-ß may contribute to the degradation of extracellular matrix during cancer invasion by decreasing the adhesive strength of cells. Thus, it is important to clarify the mechanism of TGF-ß-induced PAI-1 production. Several polymorphisms have been described in the PAI-1 gene. We examined the influence of the G/A (−844) and 4G/5G (−675) polymorphisms in the promoter region on TGFß-induced PAI-1 expression by breast cancer cells (MDA-MB231, MCF7). The genotype of breast cancer cells was identified by sequencing. TGF-ß-induced PAI-1 mRNA expression was determined by real time polymerase chain reaction (PCR). Activation of MAPKs and Smad proteins was evaluated by an immunoblot analysis. The activities of PAI-1 promoter were measured by a luciferase reporter assay. TGF-ß increased PAI-1 expression in a genotype-dependent manner, higher values observed for MDA-MB231 (4G/4G, A/A) compared with MCF7 (5G/5G, G/G). These results suggest that regulation by TGF-ß influences the PAI-1 polymorphism-dependent expression in breast cancer cells. Analysis of PAI-1 genotype may help identifying subgroups of breast cancer risk.
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 3964.
Abstract 3967: Dihydrotestosterone downregulates expression of smad3 in prostate epithelial cells through a transcriptional mechanism, promoting androgenic protection against TGF-beta-induced apoptosis
Authors: Song Kyung , Wang Hui , Krebs Tracy L. , Wang Bingcheng , Kelley Thomas J. , Danielpour David 
Published: February 2011

Abstract
Androgens suppress TGF-beta responses in the prostate through mechanisms that are not fully explored. We have recently reported that 5a-dihydrotestosterone (DHT) suppresses the ability of TGF-beta to inhibit proliferation and to induce apoptosis of prostatic epithelial cells, and provided evidence that such suppression was fueled by the transcriptional downregulation of TGF-beta receptor II (TbRII). We now show that AR activated by DHT suppresses the TGF-beta-induced phosphorylation of Smad3 in LNCaP cells overexpressing TbRII under the control of a CMV promoter, suggesting that transcriptional repression of TbRII alone does not fully account for the impact of DHT on TGF-beta responses. Instead, we demonstrate that such suppression occurs through loss of total Smad3, resulting from transcriptional suppression of Smad3. Consistent with this mechanism, we report that loss of Smad3 mRNA inversely correlates with elevated AR mRNA in a cohort of human prostate tissues (p &lt; 0.0001). We provide evidence that DHT downregulates the promoter activity of Smad3 in various prostate cancer cell lines, including NRP-154+AR, DU145+AR, LNCaP, and VCaP, at least partly through androgen-dependent inactivation of Sp1. Moreover, we show that overexpression of Smad3 reverses the ability of DHT to protect against TGF-beta-induced apoptosis in NRP-154, supporting our model that loss of Smad3 by DHT is involved in the protection against TGF-beta-induced apoptosis. Together, these findings suggest that deregulated/enhanced expression and activation of AR in prostate carcinomas may intercept the tumor suppressor function of TGF-beta through transcriptional suppression of Smad3, thereby providing new mechanistic insight on the development of castration-resistant prostate 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 3967.