bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4730: Inhibition of the p53-HDMX interaction sensitizes melanoma to chemotherapy
Authors: Russell Elisabeth A. , Gembarska Agnieszka , Marine Jean-Christophe , Bernal Federico 
Published: August 2012

Abstract
Melanoma is the leading cause of death from skin disease worldwide. It is an aggressive cancer that is often resistant to conventional chemotherapy and radiation-based therapy. The combination of a low survival rate in metastatic disease and lack of successful treatment options underscores the need to elucidate novel methods to target melanoma. More than 95% of human melanomas retain wild type p53, the protein responsible for maintaining genomic integrity; and HDMX, a negative regulator of p53 that neutralizes p53, has recently been found to be overexpressed in 65% of human cutaneous melanoma. These features suggest that targeting the p53-HDMX interaction in melanoma could not only restore the tumor suppressor function of p53, but also sensitize melanoma cells to treatment with conventional chemotherapeutic agents which rely on an intact p53 response. We have previously demonstrated that a hydrocarbon-stapled α-helix based on the transactivation domain of p53 (SAH-p53-8) efficiently disrupts p53-HDM2 and p53-HDMX complexes allowing for p53 to induce apoptotic cell death. Here, we show that SAH-p53-8 treatment is cytotoxic to metastatic melanoma cells by a p53-dependent mechanism. Additionally, SAH-p53-8 sensitizes melanoma to treatment with either cisplatin or the HDM2-specific inhibitor Nutlin-3. Importantly, the inhibition of the p53-HDMX complex arrests the growth of human metastatic melanoma in vivo. The restoration of functional p53 activity provides a basis for a previously unrecognized targeted therapy for metastatic melanoma.
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 4730. doi:1538-7445.AM2012-4730
Abstract 4733: Function of cytoplasmic histone deacetylase 5 is required for HIF-1α stability
Authors: Chen Shuyang , Ying Chengqian , Liang Dongming , Jethava Niti , Sang Nianli 
Published: August 2012

Abstract
Hypoxia is frequently associated with solid tumors and ischemic disorders, which are the top two leading causes of mortality in the world. Hypoxia-inducible factor 1 is a major regulator of angiogenesis and cellular adaptation to hypoxia. Accordingly HIF function has been considered a therapeutic target for multiple diseases. Histone deacetylase (HDAC) activity has been involved in regulating HIF function and HDAC inhibitors (HDACIs) have been documented to repress HIF function. However, histone deacetylases encompass multiple members, each has different cellular functions. HDACIs in clinical application or under development generally inhibit more than one HDAC. It is unclear which specific member of the HDAC family is involved in the regulation of HIF function. We present data here to show that histone deacetylase 5 (HDAC5) is required for HIF-1α protein stability. Knock-down of HDAC5 impaired hypoxic accumulation of HIF-1α and its function. In contrast, knock-down of HDAC1, HDAC3 or HDAC6 showed little or no effect. On the other hand, overexpression of HDAC5 enhanced HIF-1α stability. Specifically, cytosol localized HDAC5 mutant shows stronger effects on stabilizing HIF-1α compared to wild-type HDAC5. Mutation demolishing the deacetylase activity abolished the ability of HDAC5 to stabilize HIF-1α. Taken together, our data suggest that a cytosolic deacetylase activity of HDAC5 is required to stabilize HIF-1α. These findings also suggest that HDAC5 could be biological target for therapies based on modulating HIF function. This work is supported in part by grant R01-CA129494 (N.S.) from NCI, NIH.
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 4733. doi:1538-7445.AM2012-4733
Abstract 4734: Genes cooperatively downregulated by combined mTOR/histone deactylase (HDAC) inhibition are overexpressed in myeloma patients with lower survival
Authors: Michalowski Aleksandra M. , Simmons John K. , Patel Jyoti , Kuehl W Michael , Zhang Shuling , Landgren Ola , Mock Beverly A. 
Published: August 2012

Abstract
The molecular pathogenesis of many cancer types, including multiple myeloma (MM) and mantle cell lymphoma (MCL), involves alterations in the PI3K/Akt/mTOR and cyclin/CDK/CDKI/Rb (Rb) pathways. Previously, we showed that the combination of an HDAC inhibitor (HDACi) with rapamycin synergistically inhibited proliferation in 88% of human MM cell lines tested, and effectively controlled tumor growth in preclinical studies. To gain an initial understanding of the molecular mechanism of the synergistic action of the drug combination, we used an unbiased systems-level approach to analyze our gene expression profile (GEP) data with weighted gene co-expression network analysis (WGCNA). This analysis delineated the contribution of HDACi and rapamycin, singly and in combination, to the overall gene expression change of the combination by considering not only measures of fold-change and significance testing, but also the degree of gene expression inter-connectedness. WGCNA identified five gene modules, each representing a particular gene expression effect of the combination. Each gene module was individually tested for functional and clinical enrichment using gene set enrichment analysis (GSEA) and survival analyses with Cox regression. Of particular interest, the module containing genes cooperatively affected by both compounds was highly enriched (p&lt;0.001) for genes involved in cell cycle (especially mitotic processes), immune recognition, and DNA damage/repair, which we investigated further. Genes down-regulated by the drug combination were most significantly correlated with genes over-expressed in MM patients. Furthermore, analysis of the cooperative drug signature in publicly available patient GEP datasets with survival annotation found it predictive of increased survival (p&lt;0.01), thus linking the drug combination-induced transcriptional changes to predictions for enhanced survival.
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 4734. doi:1538-7445.AM2012-4734
Abstract 4758: Self-assembled superparamagnetic iron oxide nanoparticles for targeted cancer therapy
Authors: Sailaja G. S. , Gondi Christopher S. , Bhoopathi Praveen , Gorantla Bharathi , Rao Jasti S. 
Published: August 2012

Abstract
Surface engineered iron oxide nanoparticles offer greater potential for targeted gene therapy as compared to many of the current treatment modalities for cancer. The intrinsic superparamagnetism of iron oxide nanoparticles along with a bio-inspired coating to circumvent the physiological and cellular barriers suggests their usefulness as an efficient non-invasive therapeutic option to invoke the desired response at the tumor site. In the present study, a novel functionalized iron oxide nanoparticle based polyplex system that explores the greater potentials of self-assembly together with magnetic targeting is employed for “smart targeting” and to improve therapeutic index. Poly (L-glutamic acid) functionalized iron oxide nanoparticles (Feg) were synthesized and complexed with plasmid DNA containing the gene of interest in the presence of carboxymethyl chitosan (CMCS). The preliminary characterization of the nanoparticles was performed by X-ray diffraction and FT-IR analysis. The formation and the internalization of Feg-CMCS-DNA polyplex occurred irrespective of the type of DNA as illustrated by gel retardation assay and Prussian blue staining, respectively. The Feg-CMCS nanoparticles, when conjugated with secreted protein acidic and rich in cysteine (SPARC)-overexpressing plasmid, showed excellent cytocompatibility (evident from MTT assay, morphology and organization of cytoskeleton) with comparable in vitro biofunctionality (illustrated by western blot analysis) as that of a commonly used transfection agent. The supramolecular assembly of the (Feg-CMCS-SPARC) polyplex system was manifested by scanning and transmission electron micrographs. The mechanism of internalization of the polyplex system and the role of magnetic field in enhancing the internalization were observed by transmission electron microscopy. Further, Feg-CMCS-SPARC polyplex transfection resulted in significant inhibition of in vitro tumor angiogenesis. This study highlights the superior efficacy of Feg-CMCS-SPARC self-assembled polyplex system for use as a localized therapeutic drug in vivo at the tumor site.
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 4758. doi:1538-7445.AM2012-4758
Abstract 476: The effects of the synthetic triterpenoid acetylenic tricyclic bis-(cyano enone) on cell migration and epithelial-to-mesenchymal transition
Authors: Chan Eddie , Guglielmo John Di 
Published: August 2012

Abstract
During metastasis, epithelial tumor cells undergo epithelial to mesenchymal transition (EMT) allowing them to migrate to distant organs to establish secondary tumors. Cell migration is initiated by the asymmetrical localization of polarity proteins towards the leading edge. This stimulates the reorganization and polymerization of the microtubule and actin cytoskeletons, which form protrusions in the plasma membrane to drive the cell forwards. Metastasis accounts for over 90% of cancer related deaths, thus a reduction in cancer mortality will require therapies aimed at preventing or delaying the events of metastasis. Our lab has identified the synthetic triterpenoid, CDDO-Im, as a potent inhibitor of cell migration by inhibiting the polymerization of branched actin and disrupting the organization of the microtubule network (To et al., J Biol Chem. 2008, 2010). Recently, TBE-31 has been developed, which is a smaller 3-ring compound that contains the same active functional groups as CDDO-Im. Here we assessed the effects of TBE-31 on cell migration and EMT. TBE-31 was found to displace the polarity proteins from the leading edge of migrating cells and induce multiple cell protrusions. The microtubule network was also observed to be disorganized and the rate of polymerization for both tubulin and actin were lowered in the presence of TBE-31. These effects are believed to allow submicromolar concentrations TBE-31 to inhibit cell migration by as much as 60%. Finally, the reorganization of actin and formation of stress fibers normally associated with EMT was also inhibited by TBE-31 in A549 tumor cells. We are now confirming our results in a panel of lung tumor cell lines. In conclusion, TBE-31 disrupts the cytoskeleton and inhibits cell migration and preliminary data suggest TBE-31 may also hinder EMT. Further research will be needed to determine the overall impact these effects have on the progression of metastasis.
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 476. doi:1538-7445.AM2012-476
Abstract 4762: Effect of the phytochemical crinumaquine on prostate and prostate cancer cell lines
Authors: Liu Run-hui , Jin Huizi , Ke Xi-Song , Qu Yi , Hellem Margrete R. , Rostad Kari , Oyan Anne Margrete , Kalland Karl H. , Zhang Wei-Dong 
Published: August 2012

Abstract
We have published a new prostate cell culture model in which benign, immortalized prostate epithelial EP156T cells gave rise to progeny cells with a stepwise accumulation of defined malignant features. In a screen of a panel of phytochemicals using this cell culture model, the small molecular compound crinumaquine exerted differential effects on benign prostate cancer cells compared with progeny cells with accumulated malignant features. The differential effect included proliferation and induction of a striking phenotype of the more malignant cells. The induced phenotype comprised extensive membrane protrusions and cell contacts between neighbouring cells following crinumaquine treatment for 2 - 4 days. Conditioned medium from the changed cultures induced a similar phenotype within hours in non-treated cells. Genome-wide gene expression analysis using the Agilent 44k oligoarray platform revealed that crinumaquine treatment reduced expression of multiple genes involved in cell division and strongly induced several genes involved in apoptosis induction. Furthermore, crinumaquine treatment induced multiple genes of cell adhesion modules such as gap junctions, adherens junctions and desmosomes. These findings have motivated further examinations of the ability of crinumaquine to compromise epithelial to mesenchymal plasticity and its potential in the treatment of prostate 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 4762. doi:1538-7445.AM2012-4762
Abstract 477: Bcl-2 suppresses cell spreading, adhesion and migration in non-small cell lung cancer cells
Authors: Halim Hasseri , Chanvorachote Pithi 
Published: August 2012

Abstract
Bcl-2 is mainly thought to regulate cell apoptosis. However, little is known about its regulation associated with cell metastasis. Here, we demonstrate that Bcl-2 plays an important role in the cell spreading, adhesion and migration of non-small cell lung cancer cells. To study the role of Bcl-2, mutant cell lines exhibiting stably up-regulated and down-regulated Bcl-2 were generated using Bcl-2 plasmid and RNA interference. As compared to control H460 cells, Bcl-2 overexpressed cells exhibited significantly decreased cell spreading, adhesion and migration. Consistent with these results, the loss of Bcl-2 in Bcl-2 knockdown cells increased cell spreading, adhesion and migration. The morphology characteristics study has shown that Bcl-2 increased mesenchymal-epithelial transition phenotype whereas the loss of Bcl-2 increased epithelial-mesenchymal transition phenotype. The increase of fluorescent intensity of phalloidin staining in Bcl-2 overexpressed cells suggesting actin polymerization might be responsible in the supression of cell spreading, adhesion and migration. This result may explain why Bcl-2 has been suggested as a prognostic factor for survival in lung cancer patients.
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 477. doi:1538-7445.AM2012-477
Abstract 4773: Synergistic effects of chitosan and docosahexanoic acid on osteopontin expression and secretion in an ovarian cancer cell line, SKOV-3
Authors: Williams Ebonee , Otenyo Phane , Carr Domonique , Hicks Antoine , Macaulay Daniel , Peterson Deforest , Stone Julia , Carson Laura , Regisford Gloria C. 
Published: August 2012

Abstract
Current treatment for the deadliest gynecological disease, ovarian cancer, is surgical debulking followed by chemotherapy or radiotherapy, but reoccurrence is still significantly high. Hence, there is a need for alternative treatments, and more specifically a natural therapeutic product. Recent studies have shown that natural products, such as chitosan and omega-3 fatty acids, inhibit the proliferation of cancer cells. Osteopontin (OPN), a cell surface and secretory glycoprotein, has been implicated as an important biomarker for ovarian cancer. Therefore, the objective of this study was to determine the effect of chitosan and DHA on OPN secretion and expression levels in an ovarian cancer cell line, SKOV-3 cells. We hypothesized that chitosan and DHA will decrease OPN expression in a dose-dependent manner. To test our hypothesis, SKOV-3 cells were treated with (a) 0 ng/mL, (b) 1% acetic acid; (c) 250 ng/mL of chitosan, (d) 100 µM of DHA, (e) 250 ng/mL of chitosan + 100 µM of DHA for 24 and 48 hours. Western Blot analysis and immunocytochemistry were performed to observe the expression and localization of OPN, while an ELISA was used to determine OPN secretion. Quantitative RT-PCR was also performed to determine OPN mRNA expression in the treated cells. Osteopontin (OPN) protein was localized on the surface of SKOV-3 cells and its expression decreased in both chitosan and DHA-treated cells. Furthermore in cells treated with both chitosan and DHA, there was an even greater decrease in OPN expression. The synergistic effects of chitosan and DHA suggest that these natural products may serve as potential natural treatment for ovarian 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 4773. doi:1538-7445.AM2012-4773
Abstract 4776: From in-silico screening to anti-cancer activity: The discovery of a potent inhibitor targeting the JNK-JIP interaction
Authors: Kaoud Tamer S. , Yan Chunli , Tseng Chun-Chia , Jose Jiney , Devkota Ashwini K. , Taliaferro Juliana , Ren Pengyu , Dalby Kevin 
Published: August 2012

Abstract
The JNK signaling pathway is related to the pathogenesis of several diseases, including cancer (JNK2 selective inhibitors have been reported as potential suppressor of breast cancer cell migration). The JNK-JIP interaction represents an attractive target for the selective inhibition of JNK-mediated signaling. Herein, we applied a Hybrid Structure-Based Virtual-Screening (VS) workflow based on a combination of 3D shape and electrostatic similarity with GOLD (Genetic Optimization in Ligand Docking) and FRED (Fast Rigid Exhaustive Docking) docking screening techniques to discover novel scaffolds for small ATP-Independent JNK inhibitor targeting the JNK-JIP interaction. The starting point for the VS here was BI78-D3, which has been reported as the first inhibitor targeting JNK-JIP interaction. Out of 750 compounds representing the highest ranked by VS of NCI (National Cancer Institute) Diversity Set (∼250,000 compounds), 352 were tested by in-vitro cell-free kinase assay. The Ability of the used VS protocol to identify selective JNK inhibitors has been tested by screening those 352 compounds against five different kinases. The two tested atypical kinases (eEF2K and TrpM7) which has the least structure similarity with MAP kinases showed very limited inhibition if compared to JNK1 and JNK2, surprisingly, ERK2 and P38-alpha, the two structurally similar to JNK, showed similar results to the alpha kinases. This has been confirmed by an enrichment experiment that has been done using 350 compounds that randomly selected from the same library without employment of virtual screening, these compounds showed very similar inhibition pattern to both JNK and TrpM7 due to the loss of JNK selectivity that established by employment of VS. To validate the efficiency of the used VS protocol to identify inhibitors that bind the JIP-JNK binding site, we developed a displacement assay using FITC (Fluorescein-isothiocyanate) labeled-JIP peptide. Most of the compounds that inhibited JNK kinase activity more than 50% were able to decrease binding of the labeled JIP-peptide to JNK, suggesting the successful targeting of the substrate-binding site of JNK by the identified inhibitors. In summary, the used VS protocol identified novel scaffolds for JNK selective small ATP-Independent inhibitors targeting the JNK-JIP interaction. These compounds will be potential candidates as inhibitors of breast cancer cell migration.
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 4776. doi:1538-7445.AM2012-4776
Abstract 4789: Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics study of a thyroid hormone-regulated secretome in human hepatoma cells
Authors: Chen Cheng Yi , Chung I-Hsiao , Lin Kwang-Huei 
Published: August 2012

Abstract
The thyroid hormone, 3, 3′, 5-triiodo-L-thyronine (T3), regulates cell growth, development, differentiation, and metabolism via interactions with thyroid hormone receptors (TR). However, the secreted proteins that are regulated by T3 are yet to be characterized. In this study, we used the quantitative proteomic approach of stable isotope labeling with amino acids in cell culture (SILAC) coupled with nano-LC-MS/MS performed on a LTQ-Orbitrap instrument to identify and characterize the T3-regulated proteins secreted in human hepatocellular carcinoma cell lines overexpressing TRα1 (HepG2-TRα1). In total, 1742 and 1714 proteins were identified and quantified, respectively, in three independent experiments. Among these, 61 upregulated two-fold and 11 downregulated two-fold proteins were identified. Eight proteins displaying increased expression and one with decreased expression in conditioned media were validated using Western blotting. Real-time quantitative RT-PCR further disclosed induction of plasminogen activator inhibitor-1 (PAI-1), a T3 target, in a time-course and dose-dependent manner. Serial deletions of the PAI-1 promoter region and subsequent chromatin immunoprecipitation assays revealed that the thyroid hormone response element on the promoter is localized at positions –327/-312. PAI-1 overexpression enhanced tumor growth and migration in a manner similar to what was seen when T3 induced PAI-1 expression in J7-TRα1 cells, both in vitro and in vivo. An in vitro neutralizing assay further supported a crucial role of secreted PAI-1 in T3/TR-regulated cell migration. To our knowledge, these results demonstrate for the first time that proteins involved in the urokinase plasminogen activator system, including PAI-1, uPAR and BSSP4, are augmented in the extra- and intracellular space of T3-treated HepG2-TRα1 cells. The T3-regulated secretome generated in the current study may provide an opportunity to establish the mechanisms underlying T3-associated tumor progression and prognosis.
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 4789. doi:1538-7445.AM2012-4789