bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4715: Activation of lytic cycle of Epstein-Barr virus by suberoylanilide hydroxamic acid affects apoptosis and tumor growth suppression of nasopharyngeal carcinoma
Authors: Chiang Alan KS , Hui Kwai Fung 
Published: August 2012

Abstract
Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV). We examined the in vitro and in vivo effects of suberoylanilide hydroxamic acid (SAHA), a FDA-approved histone deacetylase inhibitor, on EBV lytic cycle induction in NPC and investigated the cellular consequences. Micromolar concentrations of SAHA potently induced EBV lytic cycle with replication of EBV DNA, expression of immediate early (Zta and Rta), early (BMRF1) and late (gp350) lytic proteins and production of infectious viral particles in culture supernatants in three of four EBV-positive NPC cell lines. One NPC cell line had abortive EBV lytic cycle (no EBV DNA replication or late lytic protein expression) induction. Same concentrations of SAHA effected enhanced killing of EBV-positive NPC cells in comparison with EBV-negative counterparts, as measured by MTT assay. Increased percentages of annexin V-positive and TUNEL-positive cells and proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), caspase-3, -7 and -9 in EBV-positive versus EBV-negative NPC were also observed. Immunofluorescence staining and flow cytometry showed that the majority of NPC cells (&gt;85%) expressing Zta, BMRF1 or gp350 lytic protein co-expressed cleaved caspase-3. Tracking of expression of EBV lytic protein and cleaved caspase-3 showed that proportion of NPC cells co-expressing EBV lytic protein and cleaved caspase-3 increased over time. Furthermore, knockdown of Zta expression by short-hairpin RNA significantly decreased proteolytic cleavage of caspase-3 in SAHA-treated EBV-positive NPC cells whilst overexpression of Zta induced apoptosis of EBV-positive NPC cells, confirming that lytic cycle induction programmed NPC cells to apoptosis. Interestingly, inhibition of EBV DNA replication and late lytic protein expression by phosphonoformic acid did not impact on SAHA's induced cell death in NPC, suggesting that early rather than late phase of EBV lytic cycle contributed to the apoptotic effect. In vivo effects of SAHA on EBV lytic cycle induction and tumor growth suppression were observed in NPC xenografts established in nude mice. Taken together, our data indicated that activation of lytic cycle from latent cycle of EBV by SAHA effects apoptosis and tumor growth suppression of NPC thereby providing experimental evidence for virus-targeted therapy against EBV-positive cancer. This project is funded by NPC Area of Excellence (AoE/M 06/08 Center for Nasopharyngeal Carcinoma Research) and Epstein-Barr virus research (# 20004525) grants of AKSC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4715. doi:1538-7445.AM2012-4715
Abstract 4717: The anti-leukemic efficacy of the histone deacetylase inhibitor phenylbutyrate (PB): Reversal of epigenetic inactivation of WNT signalling pathway by PB
Authors: Miller Alexandra C. , Cohen Stuart , Rivas Rafael , Miller Karvelisse , Lison Paul 
Published: August 2012

Abstract
The histone deacetylase inhibitor (HDAC), phenylbutyrate (PB), is a novel antitumor agent. PB has shown anti-cancer efficacy in clinical trials and in in vitro and in vivo models. The anti-neoplastic effects have been linked to protein farnesylation inhibition and pro-apoptotic action in radiation-induced acute myeloid leukemia (AML) mice and malignant cells. Histone deacetylase (HDAC) is involved in epigenetic control of gene expression. The objective of the current study was to evaluate additional mechanisms i.e., epigenetic activity, of PB. A radiation late effects model was used to study PB epigenetic mechanisms. Mice were sub-lethally irradiated (3.5 Gy, 60Co) to induce leukemia. To test the anti-leukemia efficacy of PB and epigenetic mechanisms, mice were irradiated and then injected with PB (25 ug/kg) or saline daily 3 x weekly (2 weeks) for a total of 6 doses. Secreted Frizzled-related protein genes (SFRPs), which function in the Wnt signaling pathway, have been found to be down-regulated by promoter hypomethylation in human acute myeloid leukemia. Therefore, the methylation status of SFRP genes was analyzed in 20 samples obtained from radiation-induced AML mice. Aberrant CpG island methylation was observed in all four SFRP genes tested by methylation-specific PCR in AML mice. The frequencies of aberrant methylation among the irradiated mice samples were 55% for SFRP1, 30% for SFRP2, 15% for SFRP4, and 32% for SFRP5. In contrast, mice irradiated and treated with PB demonstrated aberration frequencies of 12% for SFRP1, 6% for SFRP2, 0% for SFRP4, and 4% for SFRP5 at 120 days post-radiation. At day 120 post-radiation, 50% of irradiated mice had developed leukemia while only 20% of mice treated with PB showed leukemia. The results demonstrate 1) that PB is an effective countermeasure against radiation-induced leukemia, 2) that epigenetic alterations are associated with radiation-induced leukemia and 3) that PB's efficacy may be associated with prevention of epigenetic disturbances involved in leukemogenesis. These studies do not reflect the opinion of the U.S. Government or the U.S. Department of Defense and are the scientific opinions of the author. This work was supported by DTRA Grant G1B2BJ, G2B2EM, AFRRI/USUHS RAB5AH, EU05-0089, and EU07-102.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4717. doi:1538-7445.AM2012-4717
Abstract 472: Nek3 kinase in breast cancer pathogenesis: The role of paxillin phosphorylation
Authors: Harrington Katherine , Clevenger Charles 
Published: August 2012

Abstract
Breast cancer progression to metastatic disease is responsible for the majority of breast cancer related deaths. The acquisition of a motile and invasive phenotype is a critical step in the metastatic process. The hormone prolactin (PRL) is increasingly recognized as contributing to the development and progression of human breast cancer. In particular, data from our laboratory has shown that PRL serves as a chemoattractant for breast cancer cells and can stimulate the formation of the focal-adhesion complex that is necessary for cell motility. PRL mediates its biological effects through binding to the PRL receptor (PRLr) and initiates several downstream signaling cascades, including activation of the serine/threonine kinase, Nek3. Nek3 regulates breast cancer cell survival, motility and invasion and has been shown to interact with the focal-adhesion adaptor protein, paxillin, in a PRL-dependent manner. Interestingly, we have determined that knockdown of Nek3 by siRNA significantly decreases the phosphorylation of paxillin, which suggests that paxillin may represent a novel substrate of Nek3. Given these findings, we sought to further elucidate the role of Nek3 in the regulation of paxillin phosphorylation and function in breast cancer. Co-immunoprecipitation analysis using mutant truncated proteins demonstrated that Nek3 interacts with the C-terminal region of paxillin, which contains 4 tandem LIM domains. Additionally, to determine the specific site(s) of phosphorylation an in vitro kinase assay was performed and it was determined that Nek3 directly phosphorylates paxillin at T401 located in the LIM2 domain. It is known that LIM2 and LIM3 comprise the focal adhesion targeting motif of paxillin and phosphorylation in this region plays an important role in modulating its activity. Ongoing studies will determine the biological effects of Nek3-mediated phosphorylation at paxillin T401 by examining the effect on breast cancer cell motility and invasion as well as the effect on paxillin localization and function in the focal adhesion complex. These studies will provide novel mechanistic insight into how Nek3-mediated phosphorylation of paxillin contributes to the pathogenesis of breast cancer. We propose that Nek3 is a potential novel therapeutic target for the treatment of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 472. doi:1538-7445.AM2012-472
Abstract 4723: HO-3867, a STAT3 inhibitor induces G2/M arrest and apoptosis in BRCA1-mutated ovarian cancer cells
Authors: Tierney Brent J. , McCann Georgia , Cohn David E. , Sudhakar Meryl , O'Malley David , Karuppaiyah Selvendiran 
Published: August 2012

Abstract
Background: BRCA1 plays an important role in DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. BRCA-mutated ovarian cancer often presents at an advanced stage, however, patients have shown improved responses with platinum-based chemotherapy versus sporadic cases. In spite of this, most patients will develop a recurrence and eventually succumb to the disease. Preclinical studies are currently investigating natural compounds and their analogs for tumor-directed targets in ovarian cancer cell models. The aim of this study is to investigate whether the STAT3 inhibitor HO-3867, a novel curcumin analog, has a therapeutic effect on BRCA1-mutated ovarian cancer. Methods: Expression of STAT family proteins, cell cycle, apoptotic and DNA repair proteins were evaluated via western blot on BRCA- mutated and non-mutated ovarian cancer cell lines. Cell viability and proliferation were analyzed with MTT and clonogenic assays. Cell cycle analysis and apoptosis assays were performed using flow cytometry and Annexin V staining. Reactive oxygen species (ROS) staining was performed using immunofluoresence. Finally, STAT3 overexpression or suppression experiments were performed using transfected wild-type STAT3 cDNA and STAT3 siRNA, respectively. Results: Our novel agent, HO-3867, and a commercial STAT3 inhibitor, STATIC, significantly inhibited BRCA-mutated cancer cells in vitro, in a dose-dependent manner. HO-3867 induced G2/M arrest with increased expression of p53 and p21 and with decreased cdk5 and cyclin D1 expression. BRCA-mutated cells treated with HO-3867 exhibited an increased induction of apoptosis with elevated levels of cleaved caspase-3, caspase-7, and PARP. Tyrosine-phosphorylated STAT3 (pTyr705) exhibited higher expression levels in BRCA-mutated cancer cells compared with other STAT proteins. Furthermore, treatment of these cells with HO-3867 resulted in decreased expression of pTyr705 and other DNA repair proteins. In addition, HO-3867 treatment induced more ROS in BRCA-mutated cells compared with wild-type cells, with no increased induction in benign ovarian surface epithelial cells. Furthermore, we confirmed that the over-expression of STAT3 cDNA provides resistance to HO-3867 induction of apoptosis. Conclusion: Our results show that HO-3867, a potential STAT3 inhibitor, may be effective in the treatment of BRCA-mutated ovarian cancer, although continued studies are needed to elucidate the exact mechanism of action.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4723. doi:1538-7445.AM2012-4723
Abstract 4725: Inhibition of the Hedgehog signaling pathway - a new target in treatment for children with neuroblastoma
Authors: Wickstrom Malin , Dyberg Cecilia , Shimokawa Takashi , Baryawno Ninib , Milosevic Jelena , Fuskevag Ole M. , Larsson Rolf , Zaphiropoulos Peter G. , Kogner Per , Johnsen John I. 
Published: August 2012

Abstract
Background: Neuroblastoma originates from neural crest cells and is one of the most common and deadly tumors of childhood. The majority of tumors develop therapy resistance with fatal clinical outcome despite intensive multimodal therapy. The Hedgehog (HH) signaling pathway is fundamental in embryonic development, controlling cell fate and proliferation. Activation of HH signaling is involved in several cancers, among them pediatric cancers. Studies have revealed that human neuroblastoma cells express high levels of proteins involved in HH signaling. GANT61 was recently identified as an inhibitor of GLI1 and GLI2, important transcription factors in the HH signaling pathway. The aim of this study was to investigate the impact of antagonists of HH signaling in neuroblastoma through characterization of the effects of small molecule inhibitors of the HH pathway, in vitro and in vivo. Methods: Cytotoxic activity of HH inhibitors was studied in cell viability and clonogenic assays. The molecular mechanisms were characterized using cell- and molecular biology techniques. Xenograft studies in mice were performed to validate the therapeutic effects and toxicity in vivo. Results: The cytotoxicity of different HH inhibitors (cyclopamine, SANT1 and GANT61) was evaluated in a panel of human neuroblastoma cell lines. GANT61 was the most potent drug tested with IC50 values in the range of 5.8 - 13 µM after 72h incubation. Expression of GLI1 significantly correlated to the log IC50 for GANT61 (R2=0.88), the higher the expression of GLI1 the lower the amount of GANT61 was required to inhibit cellular growth. We also saw an inverse correlation with MYCN (R2=−0.88). When measured with a GLI-dependent luciferase reporter plasmid, the GLI activity was decreased with 36% to 80% after GANT61 treatment (10 µM, 48h) depending on cell line. Investigation of cell cycle regulation and cell death demonstrated that GANT61 inhibited proliferation and induced apoptosis. siRNA experiments revealed that knockdown of GLI1 reduced proliferation more potently than GLI2, GLI3 and SMO inhibition. GANT61 significantly inhibited tumor growth in neuroblastoma xenografts in nude NMRI nu/nu mice without causing any sign of toxicity. Conclusions: These results suggest that inhibitors of the HH signaling pathway such as GANT61 may constitute a novel option for treatment to patient with high-risk neuroblastoma without MYCN-amplification.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4725. doi:1538-7445.AM2012-4725
Abstract 4731: Cytotoxic versus cytostatic effects in tumor models by spiro-oxindole-based modulators of the MDM2-p53 interaction
Authors: Meaux Isabelle , Barrière Cédric , McEachern Donna , Guerif Stéphane , Besret Laurent , Dos-Santos Odette , D'Agostino Stéphane , Sanchez Isabelle , Gorge-Bernat Dimitri , Pannier Pascal , Ratet Nathalie , Watters James , Miao Harry , Sager Jason , Lengauer Christoph , Garcia-Echeverria Carlos , Wang Shaomeng , Leopold Lance , Debussche Laurent 
Published: August 2012

Abstract
Two spiro-oxindole-based modulators -compounds A and B - of the MDM2-p53 protein-protein interaction display suitable pharmacological properties and are currently under advanced preclinical development (1). In vitro, these compounds induce massive cell death in a subset of relevant tumor models such as MDM2-amplified SJSA-1, while they can significantly block cell proliferation without detectable cytotoxic effect in other human cell lines (e.g. HCT116). To better characterize in vivo the different tumor cell sensitivity of these novel MDM2 antagonists, quantitative and longitudinal pharmacodynamic effects have been determined in several preclinical settings: i) anti-tumor efficacy, ii) activation of p53-dependent molecular biomarkers such as p53 itself, p21, MDM2, PUMA, Noxa, Bax and MIC-1 and iii) downstream biological effects monitored by immuno-assays as well as by in vivo fluorescence tomography and PET imaging. The results obtained from these studies have revealed striking differences in the biological read-outs associated with the observed cytotoxic versus cytostatic effects and provide guidance for the use of certain biomarkers in the clinical development of this new generation of anti-cancer agents. 1. Wang S. et al., AACR, Orlando FL, 2011, Abstract LB-204
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4731. doi:1538-7445.AM2012-4731
Abstract 4736: N-myc downstream regulated gene 1: A novel mediator of hypoxia-driven chemoresistance in glioblastoma
Authors: Blaes Jonas , Weiler Markus , Sahm Felix , Pfenning Philipp-Niclas , Pusch Stefan , Jugold Manfred , Kempf Tore , Warnken Uwe , Weller Michael , Schnölzer Martina , Hartmann Christian , von Deimling Andreas , Wick Wolfgang 
Published: August 2012

Abstract
Like other solid tumors, glioblastomas (GB) feature vast hypoxic areas that are thought to promote tumor growth, angiogenesis and even drug resistance and hence facilitate an aggressive growth and recurrence after treatment. Elucidation of hypoxia-signalling and identification of the major regulators of hypoxia-dependent chemoprotection seems logical for the optimization of current treatment regimens. Using comparative 2D gel electrophoresis and mass spectrometry analysis, we here identify N-myc downstream regulated gene 1 (NDRG1) as upregulated by chronic sublethal hypoxia in GB cell lines. Immunohistochemical analysis of human astrocytoma specimens shows a marked increase in expression from WHO °II to °IV and a preferential perinecrotic localization of NDRG1 in GB. In vitro, besides the hypoxia-driven induction of NDRG1, which is mediated by Hif1α and Hif2α, NDRG1 is also induced by irradiation. NDRG1 limits glioma cell invasiveness in vitro and reduces proliferation in vitro and in vivo. Furthermore NDRG1 acts antiangiogenic with reduced endothelial cell migration and sprouting, and interferes with the expression of multiple angiogenesis-related signalling molecules. Most interestingly NDRG1 protects from temozolomide (TMZ)-induced G2/M-arrest and subsequent reduction of tumor cell proliferation. Analyzing pairs of GB tissue samples of relapsed glioblastoma patients reveals a dramatic increase of NDRG1-positive cells suggesting a treatment-related selection for NDRG1 expressing populations and a potential role for NDRG1 in the recurrence of GB. In line with these findings, quantifying the NDRG1 status in tissue specimens of the UKT05 GB trial, which looked at a dose-intensified TMZ therapy plus standard radiotherapy, reveals a negative correlation between NDRG1 status and overall survival. In the present work we identify hypoxia-driven NDRG1 as a modulator of tumor growth, invasion, angiogenesis and as a novel mediator of chemoresistance towards TMZ in GB. Our findings shed light on the role of hypoxia in adaption to chemotherapeutic treatment and introduce NDRG1 as a promising candidate for targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4736. doi:1538-7445.AM2012-4736
Abstract 4738: The early response protein EGR-1 mediates vitamin E γ-tocotrienol-induced apoptosis in pancreatic cancer cells
Authors: Wang Chen , Pimiento Jose M. , Husain Kazim , Zhang Anying , Tong Zhongsheng , Malafa Mokenge P. 
Published: August 2012

Abstract
Background: Vitamin E tocotrienols are bioactive components of cereal foods such as oats, barley, rice bran, and palm, that have demonstrated anticancer and chemopreventive activities in various types of cancer. Recently we have shown that γ-tocotrienol is the most bioactive tocotrienol against pancreatic cancer both in vitro as well as in vivo. However, the molecular mechanism of action of tocotrienols in pancreatic cancer has not been fully elucidated. In this work, we investigated the early genes associated with Vitamin E γ-tocotrienol induced apoptosis, and therefore identify novel pathways related with its anticancer effects. Methods: Human pancreatic cancer MiaPaca-2 cells were treated with γ-tocotrienol (50 µM) and vehicle (ethanol) for 3 h and were subjected to microarray analysis using costume Affymetrix for the identification of early regulatory genes. Early growth response protein-1 (EGR-1) was one of those early response genes induced by γ-tocotrienol. Then we evaluated the protein expression of EGR-1 by real-time PCR and western-blot in pancreatic cancer cell lines (MiaPaca-2 and Panc-1) after treatment with γ-tocotrienol. Mechanistic studies were conducted trough siRNA knockdown of EGR-1 and the rescue of Vitamin of γ-tocotrienol-induced apoptosis, anti-proliferative effects and signaling pathways. Results: We identified 8 genes that were induced and 8 genes that were suppressed early after treatment with γ-tocotrienol in MiaPaca-2 cells. Then we selected and focused on the EGR-1 for signaling pathway analysis. Induction of protein expression was noticed in both MiaPac-2 cells and Panc-1 (6 fold and 10 fold respectively;p&lt;0.05) after 24 h γ-tocotrienol treatment. γ-tocotrienol-induced apoptosis in MiaPac-2 cells and Panc-1 cells (PARP1 cleavage and Annexin V) was associated with induction of p-JNK, p-C-JUN, and EGR-1. Knockdown of EGR-1 in this two cell lines partially rescued γ-tocotrienol-induced apoptosis. Conclusion: Our data identifies EGR-1 as an early gene which is induced by Vitamin E γ-tocotrienol in pancreatic cancer cells. Activation of the EGR-1 pathway, may constitute a novel potential strategy for inhibiting pancreatic tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4738. doi:1538-7445.AM2012-4738
Abstract 4739: miR-627 and histone demethylase JMJD1A as new therapeutic targets in colon cancer
Authors: Padi Sathish , Guo Bin 
Published: August 2012

Abstract
Vitamin D has excellent antitumor activities against various types of cancers, but it cannot be used for cancer therapy due to its side effect of causing hypercalcemia. To understand its mechanism of action in tumor suppression, we investigated the effects of calcitriol (1α,25-dihydroxyvitamin D3, the active form of vitamin D) on microRNA expression in colon cancer cells. We identified miR-627 as the sole microRNA whose expression was stimulated by calcitriol. Furthermore, JMJD1A (jumonji domain containing 1A), the gene encoding a histone demethylase, was identified as the target of miR-627. By downregulating JMJD1A, miR-627 mediated the effects of calcitriol to increase histone H3K9 methylation and to suppress the expression of growth-promoting genes, such as GDF15. Calcitriol also induced miR-627 and downregulated JMJD1A in colon cancer xenografts in nude mice. Overexpression of miR-627 decreased JMJD1A and suppressed colon cancer growth both in vitro and in vivo in the nude mice. In addition, we found that miR-627 expression was decreased in human colon cancer specimens when compared to its levels in the normal colon tissues. Thus, miR-627 plays an important role in the epigenetic action of vitamin D in tumor suppression. miR-627 and JMJD1A may serve as potential targets to exploit the antitumor activity of vitamin D without eliciting its hypercalcemic side effect.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4739. doi:1538-7445.AM2012-4739