bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5356: Inactivation of Foxo3a and increased expression of Id1 by the Epstein-Barr Virus-encoded LMP1 facilitates resistance to TGF-β-mediated growth inhibition in nasopharyngeal epithelial cells
Authors: Lo Angela KF , Dawson Christopher W. , Young Lawrence S. 
Published: February 2011

Abstract
The universal association of Nasopharyngeal carcinoma (NPC) with EBV underscores the importance of EBV infection to the development of this disease. The EBV-encoded Latent Membrane Protein-1 (LMP1) is believed to be a key factor in NPC development due to its ability to induce cellular transformation in various cell types. As a viral mimic of CD40, LMP1 functions as a constitutively active TNF receptor, altering multiple signal cascades and activating a plethora of downstream targets. LMP1 has been shown to inactivate the transcriptional activity of Foxo3a, a tumor suppressor that can inhibit the proliferation of tumor cells. LMP1 has also been found to increase expression of Id1, a transcriptional repressor that can inhibit the expression of differentiation-linked genes. Here, we report that inactivation of Foxo3a by LMP1 facilitates Id1 induction. Using a panel of LMP1 mutants, we identified the CTAR1 domain of LMP1 as being responsible for Foxo3a inactivation and Id1 upregulation.
Through the use of dominant negative proteins, shRNA silencing or selective pharmacological inhibitors, we demonstrate that Foxo3a inactivation by LMP1 is mediated through the LMP1 CTAR1 domain and requires activation of the Akt and Erk-MAPK signaling pathways. Whilst engagement of the Akt, Erk-MAPK and NIK-dependent noncanonical NF-κB pathways by LMP1 are involved in Id1 upregulation, we found that LMP1 CTAR2 domain-mediated IKKβ-dependent canonical NF-κB signaling negatively regulates Id1 expression, suggesting that CTAR2 may antagonize CTAR1-mediated regulation of Id1. LMP1 has been shown to inhibit TGFβ-mediated growth inhibition by disrupting various facets of TGFβ signaling. Here we show that stable “knock-down” of Id1 in LMP1 expressing NP69 cells after stable expression of Id1-specific shRNA, reduced the growth inhibitory effect of TGFβ. The interplay between LMP1, Foxo3a and Id1 is likely to contribute to the characteristic resistance of LMP1 to TGFβ-mediated signaling and cell growth arrest. The data presented in this study may offer a novel therapeutic approach for EBV associated epithelial cancers.
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 5356.
Abstract 5358: Epstein-Barr Virus-encoded BARF1 gene stimulates gastric epithelial cell MMP-1 secretion through ERK activation
Authors: Jeong Jin-Yong , Byun Hyun-Jeong , Woo Jun Hee , Kim Chul Woo , Kim Woo Ho , Chang Mee Soo 
Published: February 2011

Abstract
The Epstein-Barr virus (EBV), originally isolated from Burkitt's lymphoma tissue, has now been associated with various epithelioid diseases and many other malignancies, including gastric adenocarcinoma. Our interest has been focused on the BARF1 early gene from EBV, which has ability to induce oncogenic transformation in rodent fibroblasts and to immortalize monkey kidney primary epitherial cells. The aim of this study was to investigate the effect of BARF1 expression in gastric cancer cells. First, a pEGFP vector containing the full length BARF1 gene was constructed and transfected into EBV negative gastric cancer cell lines (AGS and SNU601). Microarray analysis was then performed and gene expression profiles were analyzed and compared between the cell containing full length BARF1 gene and the vector control. We found that matrix metalloproteinase-1 (MMP-1) was significantly up-regulated in the cell containing BARF1 gene. The MMP-1 mRNA and protein expression levels are confirmed by RT-PCR and Western blotting. Additionally, the mobility of BARF1 transfectants was increased in scrape-wound migration assay compared with the vector control cells. Because MMP-1 secretion in other cell types is extracellular signal regulated kinase (ERK)-dependent, we examined mitogen-activated protein kinase (MAPK) ERK activation in response to BARF1. BARF1 also induced activation of ERK. To determine whether BARF1-induced MMP-1 secretion was ERK-dependent, we used PD98059 and UO126, the specific inhibitors of MEK, the proximal activator of ERK. UO126 and PD98059 inhibited ERK activation and MMP-1 secretion, indicating that MMP-1 secretion in response to BARF1 was MEK- and ERK-dependent. Because p38 activity mediates MMP-1 secretion in dermal fibroblasts and several other cell types, but inhibits MMP-1 secretion in cytokine-stimulated AGS cells, we also examined the effects of p38 inhibition on MMP-1 secretion in response to BARF1. p38 inhibition with the specific p38 inhibitors, SB203580 and SB202190, enhanced MMP-1 secretion, as well as ERK activation. These results indicate that EBV-encoded BARF1 gene stimulates gastric epithelial cell MMP-1 secretion via ERK activation. This is the first report that a viral protein, BARF1, is capable of regulating MMP-1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5358.
Abstract 536: Mesenchymal stromal cells promote tumor growth both in vitro and in vivo
Authors: Suzuki Kazuhiro , Origuchi Makoto , Kanehira Masahiko , Sun Ruowen , Takahata Takenori , Itoh Jugoh , Fukuda Shinsaku , Umezawa Akihiro , Saijo Yasuo 
Published: February 2011

Abstract
[Background] Mesenchymal stromal cells (MSCs), also referred as mesenchymal stem cells are pluripotent progenitor cells that differentiate into chondrocytes, adipocytes, osteoblasts and other types of cell. Although MSCs are resident mainly in bone marrow, MSCs are found in adipose tissue, lung, and many other organs where MSCs maintain and regenerate the connective tissues of organs. Recent report proposed that MSCs also migrate and function as stromal cells in the tumor tissues. Effects of MSCs on tumor growth in vitro and in vivo are still unclear. In this study, we verified tumor promotion by MSCs and analyzed mechanisms. [Method] B16-LacZ, a melanoma cell line expressing β-galactosidase protein, was tested for their growth rate by X-gal colorizing assay in the presence or absence of mouse bone marrow MSCs in vitro. Growth of B16-LacZ was also examined in the detached condition using cell disk or conditioned medium from MSCs. Next, B16-LacZ and Lewis Lung Carcinoma (LLC) cells were mixed with MSCs at 1/1 and 1/5 ratios and subcutaneously inoculated into mice. Tumor sizes were measured and immunostaining of CD31 was performed to evaluate angiogenesis. We also determine the secretion of soluble factors associated with angiogenesis in cultured medium from B16-LacZ alone, MSCs alone, or B16-LacZ and MSCs ELISA. [Result] Proliferation of B16-LacZ co-cultured with MSCs exhibited 5.8 times greater than that of B16-LacZ alone in vitro (P&lt;0.01). In detached condition, using cell disk or conditioned medium from MSCs, the growth rate was only 1.6 times (P&lt;0.01) in cell disk, and 1.4 times (P&lt;0.05) in conditioned medium at 60-hour incubation. Mixed group of B16-LacZ and MSCs at 1/1 and 1/5 ratios developed 2.3 times (P&lt;0.05) and 4.3 times (P&lt;0.01) grater tumor compared to B16-LacZ alone in vivo. MSCs alone did not develop a tumor. Results of LLC experiments were similar to B16-LacZ experiments. Tumor vessel area of mixture of B16-LacZ and MSCs was 2.4 times (P&lt;0.05) at 1/1 and 4.2 times (P&lt;0.01) at 1/5 ratio lager than B16-LacZ alone. The amount of the secretion of LIF, M-CSF, MIP-2 and VEGF factors from MSCs were significantly larger compared with B16-LacZ. The amount of the secretion from co-culture of B16-LacZ and MSCs was almost the same as the MSCs alone group. [Conclusion] MSCs promoted tumor growth both in vitro and in vivo, and promotion of tumor growth by MSCs can be at least in part attributed to the tumor angiogenesis.
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 536.
Abstract 5363: HER-2 over-expression in a subset of soley estrogen-induced breast tumors in intact female ACI rat
Authors: Li Sara Antonia , Hong Yan , Li Jonathan J. 
Published: February 2011

Abstract
Breast cancer comprises about 30% of all cancers occurring in USA women. Gene profiling expression data of human breast cancer have characterized luminal A and B subtypes, comprising 73% of all breast cancers in women, as exhibiting both estrogen receptor alpha (ERα) and progesterone receptor (PR) positivity, as well as over-expression of FOX-A1 and GATA-3 transcription factors, and primarily p53wt. It is well established that 25-30% of these human breast cancers exhibit amplification of the gene or over-expression of the protein product of human epidermal growth factor receptor-2 [HER-2/neu, also known as epidermal growth factor receptor 2 (ErbB-2)], a tyrosine kinase transmembrane receptor involved in signal transduction pathways leading to cell growth and differentiation, and playing a crucial role in the acceleration and evolution of cancer. In breast cancer, its over-expression is associated with poor prognosis and increased metastatic potential. We have shown that the intact female ACI rat breast tumor model induced by estrogen remarkably recapitulates the aforementioned luminal A/B subtypes of human breast cancer, both in its histopathological progression and molecular alterations. In addition, this estrogen-induced mammary tumor is characterized by c-myc amplification, cyclin E1, MDM2, and Aurora A/B mitotic kinase over-expression, centrosome over-duplication, chromosomal instability, and aneuploidy; the defining feature of human breast cancer. Employing western blot analyses, we now report that 29% of 17β-estradiol-induced primary ACI rat breast tumors exhibited pronounced levels of HER-2/neu expression. Immunohistochemical analyses revealed that the HER-2/neu over-expression was confined to pre-invasive lesions, cribiform and comedo ductal carcinomas in-situ (DCIS), and primary invasive tumors, suggesting that estrogen is in some manner involved in initiating its over-expression in a subset of these breast tumors. However, the large majority of estrogen-elicited mammary tumors in ACI rats were essentially devoid of HER-2/neu expression. [Supported by the Susan G. Komen for the Cure Grants BCTR42906 and BCTR0600996].
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 5363.
Abstract 5369: AN019 in combination with ionizing radiation retards intracranial tumor growth and inhibits angiogenic induction in vitro and in vivo
Authors: Gondi Christopher S. , Gorantla Bharathi , Rao A.K.S. Bhujanga , Amala K. , Naidu M.U.R. , Jogi K.V. , Ramana G.V. , Chowdary M. Praveen , Rao Jasti S. 
Published: February 2011

Abstract
Successful treatment of malignant glioma is hampered by the development of resistance to alkylating agents such as Temozolomide (TMZ). The addition of radiation to a TMZ treatment regime has shown promising results with reported survivability of up to 5 years. One of the side effects of Temozolomide is the increased activation of angiogenic factors which may work contrary to the desired result. In this report we demonstrate the development of a novel compound AN019, showing specific VEGF suppression accompanied with anti-angiogenic and anti-proliferative properties in gliomas. We used U87, a glioma cell line, and EGFRvIII over-expressing glioma xenograft 4910 cells for this study. Deduced IC50 values indicated that AN019 had greater anti-proliferative effect than Temozolomide (U87: AN019=103µM, TMZ=768µM; 4910: AN019=169µM, TMZ=582µM). Matrigel invasion assay indicated that AN019 retarded the invasive potential of both U87 and 4910 glioma cells over TMZ treated cells which was enhanced after radiation treatment. In-vitro angiogenic and migration assays showed an almost complete inhibition of angiogenic induction and migration in U87 and 4910 cells after AN019 treatment when compared to TMZ. Cell cycle analysis revealed that 100µg/ml concentration of AN019 was sufficient to achieve &gt;70% apoptosis in both U87 and 4910 cells, whereas 150µg/ml of TMZ was required to achieve the same response. Western blot and ELISA for the expression of VEGF levels indicated that lower concentrations of AN019 (U87=86±3µg/ml and 12±1µg/ml with radiation; 4910=100±1µg/ml and 6µg/ml with radiation) were required for 50% inhibition of VEGF expression. TMZ treatment required a higher concentration to achieve similar 50% inhibition of VEGF expression (U87=80±10µg/ml and 12±3µg/ml with radiation; 4910=100±3µg/ml and 27±3µg/ml with radiation). Animal studies showed that oral doses of AN019 (20mg/kg) regressed tumors in all animals and 70% of the animals showed complete absence of intracranial tumors, whereas TMZ (100mg/kg) treated animals also showed regression of tumors with a 30% cure rate. Overall, our results demonstrate that AN019 has anti-angiogenic, anti-proliferative and anti-tumorogenic properties which may have clinical implications.
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 5369.
Abstract 5372: Mechanisms of synergy of histone deacetylase inhibitors, belinostat and depsipeptide, with DNA damaging agents, etoposide and cisplatin in small cell lung cancer cell lines
Authors: Luchenko Victoria , Salcido Crystal D. , Zhang Yongwei W. , Mumau Melanie D. , Agama Kelli , Giaccone Giuseppe , Pommier Yves , Bates Susan E. , Varticovski Lyuba 
Published: February 2011

Abstract
Small cell lung cancer (SCLC) is the most aggressive type of lung carcinoma. SCLC has a high response rate to chemotherapy, but rapid onset of drug resistance. Chemotherapeutic treatment using combinations of drugs that target different signaling pathways improves overall survival of patients with SCLC. Histone deacetylase (HDAC) inhibitors regulate epigenetic changes and play a role in regulating cell cycle progression and have been suggested as potential therapeutic agents for SCLC. HDAC inhibition is thought to relax DNA, thereby allowing increased access of transcription factors to certain promoters. Likewise, they could increase accessibility of DNA to cytotoxic agents. We examined whether two distinct HDAC inhibitors, belinostat and depsipeptide, have an effect on SCLC cell lines and whether they could be combined with conventional agents used for SCLC, VP16 (etoposide) and cisplatin. We used simultaneous and schedule-dependent treatment protocols of SCLC cells with single drugs and drug combinations. Computational analysis of cell survival using combination index (CI) showed that HDAC inhibitors synergized with DNA damaging agents when administered simultaneously, but this effect was only additive if cells were pre-treated with HDAC inhibitors for 24 hours prior to DNA damaging agents. In addition, using DNA damaging agents 24 hours prior to HDAC inhibitors was clearly antagonistic with CI &gt;1 for all drugs and cell lines tested. Because of a potential use of belinostat and depsipeptide for therapy of SCLC in combination with conventional chemotherapies, we examined the mechanisms of synergy and protection between these agents. We found that PARP degradation was complete when drugs were used simultaneously, but was decreased if HDAC inhibitors were used prior to cisplatin or etoposide. Similar effects were observed by analysis of cell cycle and γH2AX phosphorylation. Thus, schedule of drug administration will be critical for development of clinical protocols for therapy of SCLC using these agents.
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 5372.
Abstract 5380: Disulfiram sensitised cytotoxicity of gemcitabine in human glioblastoma cell lines
Authors: Brown Sarah , Liu Peng , Goktug Tuge , Darling John , Wang Weiguang 
Published: February 2011

Abstract
The blood and brain barrier (BBB) and chemoresistance are the major obstacles for the success of glioblastoma multiforme (GBM) chemotherapy. It has been shown that high nuclear factor kappa B (NFκB) activity is highly related to chemoresistance. Gemcitabine (dFdC) can easily cross the BBB and gets into GBM tissues. Due to the chemoresistance of GBM cells to dFdC induced cytotoxicity, this drug is currently only used as a radiosensitiser for GBM treatment. Disulfiram (DS) is an anti-alcoholism medicine. Our previous study demonstrates that DS strongly inhibits NFκB activity and sensitises cancer cell lines to several anticancer drugs including dFdC. DS can freely pass through BBB. Therefore, we tested the chemosensitising effect of DS on dFdC in three GBM cell lines (U251MG, U87MG and U373MG). DS was cytotoxic to GBM cell lines. Copper (Cu) was essential for DS induced cytotoxicity in GBM cell lines. Cu or DS alone was not cytotoxic to GBM cell lines in vitro. Whereas high cytotoxicity (IC50 = 150 - 250 nM) was demonstrated when DS was dosed in combination with physiological concentration of Cu (1 µM). We also tested the chemosensitising effect of DS/Cu complex on dFdC in GBM cell lines. The GBM cell lines were highly resistant to dFdC induced cell death. DS significantly sensitised the cytotoxicity of dFdC in GBM cell lines (∼ 6 - 23-fold; Table 1). CI-isobologram analysis indicated that the combination effect between DS/Cu and dFdC was highly synergistic (Table 1). Flow cytometric data demonstrated that DS/Cu enhanced dFdC induced apoptosis. The molecular chemosensitising mechanisms of DS/Cu to dFdC in GBM cells are still not full elucidated. Our preliminary data indicated that DS/Cu simultaneously inhibited NFκB pathway and triggered reactive oxygen species (ROS)-JNK pathway.Cytotoxicity of dFdC alone or dFdC plus DS/Cu in GBM cell lines U251MGU87MGU373MGdFdC alone100.4 (22.3)&gt;40078.6 (5.6)dFdC + DS/Cu (1:10 ratio)17.5 (5.1)17.1 (3.0)6.8 (1.8)CI0.390.470.82
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 5380.
Abstract 5381: Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth
Authors: Maher Diane , Yallapu Murali M. , Sundram Vasudha , Bell Maria C. , Jaggi Meena , Chauhan Subhash C. 
Published: February 2011

Abstract
Background: Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, we demonstrate the chemo/radio-sensitizing potential of curcumin in a cisplatin resistant ovarian cancer cell line model. Additionally, due to suboptimal pharmacokinetics and low uptake of curcumin in tumors in vivo, we developed a curcumin nanoparticle formulation to improve its therapeutic efficacy.
Methods: Cisplatin resistant A2780CP ovarian cancer cells were pre-treated with curcumin followed by exposure to cisplatin or radiation and the effect on cell growth was determined by MTS and colony formation assays. The effect of curcumin pre-treatment on the expression of apoptosis related proteins and β-catenin was determined by Western blotting or Flow Cytometry. A luciferase reporter assay was used to determine the effect of curcumin on β-catenin transcription activity. The poly(lactic acid-co-glycolic acid) (PLGA) nanoparticle formulation of curcumin (Nano-CUR) was developed by a modified nano-precipitation method and physico-chemical characterization was performed by transmission electron microscopy and dynamic light scattering methods.
Results: Curcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. During the 6 hrs pre-treatment, curcumin down regulated the expression of Bcl-XL and Mcl-1 pro-survival proteins. Curcumin pre-treatment followed by exposure to low doses of cisplatin increased apoptosis as indicated by annexin V staining and cleavage of caspase 9 and Poly (ADP-ribose) polymerase (PARP). Additionally, curcumin pre-treatment lowered β-catenin expression and transcriptional activity. Physico-chemical characterization of Nano-CUR indicated an average particle size of ∼70 nm, steady release of curcumin over a period of 18 days and antibody conjugation characteristics. The Nano-CUR formulation also effectively inhibited the growth of ovarian cancer cells.
Conclusion: Curcumin pre-treatment enhances chemo/radio-sensitization in A2780CP ovarian cancer cells through multiple molecular mechanisms. Therefore, curcumin pre-treatment may effectively improve ovarian cancer therapeutics. A targeted PLGA nanoparticle formulation of curcumin is feasible and may improve the in vivo therapeutic efficacy of curcumin.
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 5381.