bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1595: Phosphomimetic mutation of hnRNP A1 inhibits AKT-dependent IRES function and results in mTOR inhibitor sensitivity
Authors: Martin Jheralyn , Masri Janine , Cloninger Cheri , Holmes Brent , Lichtenstein Alan , Gera Joseph F. 
Published: February 2011

Abstract
The relative activity of the Akt kinase has been demonstrated to be a major determinant of sensitivity of tumor cells to mTOR inhibitors. Our previous studies have shown that the multifunctional RNA-binding protein hnRNP A1 regulates a salvage pathway which facilitates IRES-dependent mRNA translation of critical cellular determinants in an Akt-dependent manner following mTOR inhibitor exposure. This salvage pathway functions by stimulating IRES-dependent translation in cells with relatively quiescent Akt resulting in resistance to rapamycin. However, the pathway is repressed in cells with elevated Akt activity rendering cells sensitive to rapamycin induced G1 arrest as a result of the inhibition of global eIF-4E-mediated translation. Akt phosphorylation of hnRNP A1 at serine 199 has been demonstrated to inhibit IRES-mediated translation initiation. Here we describe a phosphomimetic mutant of hnRNP A1 (S199E) which binds both the cyclin D1 and c-MYC IRES RNAs in vitro and results in inhibition of IRES function in dicistronic mRNA reporter assays. Utilizing cells in which Akt is conditionally active, we demonstrate that overexpression of this mutant renders quiescent Akt-containing cells sensitive to rapamycin in vitro and in xenografts. We also demonstrate that activated Akt is strongly correlated with elevated phospho- ser199-hnRNP A1 levels in a panel of 22 glioblastomas. These data demonstrate that the phosphorylation status of hnRNP A1 ser199 regulates the Akt-dependent sensitivity of cells to rapamycin and may have utility as a surrogate biomarker to stratify those tumors which may be most sensitive to mTOR inhibitor therapy.
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 1595.
Abstract 1597: Expression of caPCNA and antineoplastic action of caPeptides in pancreatic cancer cells
Authors: Shen Fei , Hickey Robert , Kamran Jasmine , Phipps Elizabeth A. , Malkas Linda H. 
Published: February 2011

Abstract
Our laboratory previously reported the identification of an acidic isoform of proliferating cell nuclear antigen (caPCNA) in various cancer cells, which appears to be associated, at least in part, with malignant transformation of cells. The current studies show the expression of caPCNA in BXPC-3, Paca-2 and Capan-1 pancreatic cancer cells. Since Proliferating Cell Nuclear Antigen (PCNA) is involved in DNA replication and repair in prokaryote and eukaryote cells, we hypothesize that caPCNA is likely to perform similar functions specifically in cancer cells. Antibodies developed against caPCNA showed growth inhibition activity in cancer cells suggesting caPCNA is related to the proliferation of malignant cells. In order to begin to understand the function of caPCNA in cellular malignant transformation, we have investigated the interaction of caPCNA with its binding partners including flap structure-specific endonuclease 1(Fen-1) and xeroderma pimentosum complementation group G (XPG). We have identified an amino acid domain sequence that confers the cancer cell specificity of caPCNA. In the course of our studies we synthesized small caPCNA related peptides (caPeptides) derived from this sequence that promote cancer cell cytotoxicity. caPeptides have the potential ability to compete with several cellular proteins that participate in DNA replication, repair, cell cycle control, transcription, and chromosomal recombination for their naturally occurring binding site on caPCNA and block binding of full length caPCNA to these proteins. The disruption of the interaction between caPCNA and its binding proteins prevents cancer cellular functions (vital cellular machinery) that recruit caPCNA and therefore may lead caPCNA-derived peptides to be cytotoxic by themselves or in combination with cancer chemotherapeutic drugs. These peptides, either alone or in combination with other anticancer agents are potentially useful cancer chemotherapeutics or augmentors of the pharmacodynamic effect of specific anti-cancer chemotherapeutics. Our results show that these peptides demonstrate promising growth inhibition and cytotoxicity in pancreatic cancer cells. Considering that pancreatic cancer is well known for its high mortality rate due to its chemotherapy ineffectiveness our studies render further investigations on the action of caPCNA and the anti-neoplastic mechanism of the peptides in pancreatic 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 1597.
Abstract 1599: Expression of therapeutics targets in osteosarcoma : Effects of chemotherapy and evolution of disease
Authors: Versleijen-Jonkers Yvonne M.H. , van de Luijtgaarden Addy C.M. , Leus Manon A. , Roeffen Melissa H.S. , Flucke Uta E. , van der Geest Ingrid C.M. , van der Graaf Winette T.A. 
Published: February 2011

Abstract
Introduction
The receptor activator of nuclear factor kb/-ligand/osteoprotegerin (RANK/RANKL/OPG) triad and insulin-like growth factor 1 receptor (IGF1R) system are potential therapeutic targets in osteosarcoma. We studied the consistency of expression of specific targets over time and across lesions within subjects. This aids to select biomarkers for future therapies and to determine an optimal sequence of targeted and cytotoxic therapy.
Materials and methods
Immunohistochemical staining was performed on paraffin-embedded therapy-naïve biopsies, post-neoadjuvant chemotherapy resection specimens, and metastatic lesions for RANK, OPG, IGF1R, IGF1, phosphorylated protein kinase B (pAKT), mammalian target of rapamycin (pMTOR) and extracellular-regulated kinase (pERK). Staining intensity was scored as absent (0), weak (1) or strong (2). Change of expression between lesions within subjects was interrogated by Wilcoxon signed rank tests.
Results
49 tumor samples of 28 patients were available (staining results presented in table 1). No change in RANK or OPG expression was observed. After chemotherapy pERK (p=0.008) and pMTOR expression (p=0.015) decreased; pERK and IGF1R expression (both p=0.046) were lower in metastases than in primary tumors. Expression of IGF1 and pAKT remained unchanged.
Discussion
The choice for a therapeutic regimen is increasingly guided by presence of specific molecular alterations in tumor tissue. Variation of target expression over time and across lesions within subjects is a known phenomenon in common cancers. In osteosarcomas, we found a rather consistent expression signature with the exception of pERK, pMTOR and IGF1R, which were downregulated after exposure to chemotherapy or in metastatic lesions.
Conclusion
Screening for biomarkers for specific targeted drugs in osteosarcoma should not be limited to a single tumor sample. It is likely from our data that an optimal sequence of targeted therapies and cytotoxic drugs exists.Table 1:Staining results (%) Biopsy (n=28)Resection (n=13)Metastasis (n=8)Intensity012012012RANK014860158513088OPG4544383954255025IGF140960217900100IGF1R778681577145729pmTOR252946691515431443pAKT11503931393129710pERK001005404650050
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 1599.
Abstract 1603: The VEGF, PDGF and STAT3 pathways are the potential therapeutic targets to treat endometrial cancer
Authors: Korovkina Victoria P. 
Published: February 2011

Abstract
Progesterone inhibits growth of endometrial cancer through its receptors A (PRA) and B (PRB) although the molecular mechanisms of inhibition have yet to be fully characterized. A global analysis of gene regulation in human endometrial cancer cells that express heterologous progesterone receptors was performed to identify the candidate genes that mediate inhibitory effects of progesterone in endometrium. Data indicate that progesterone down-regulates the expression of vascular endothelial growth factor A (VEGFA), platelet derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3). Down-regulation of VGFA is mediated by the PRA whereas both PRA and PRB are required to attenuate expression of PDGFA and STAT3 genes. These results suggest that progesterone exerts the growth-limiting effects in endometrium via inhibition of angiogenesis and proliferation. VGFA, PDGFA and STAT3 pathways may be central to the inhibitory effects of progesterone in endometrial cancer and may constitute the important targets for therapeutic interventions.
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 1603.
Abstract 1604: HFE is a new target molecule for cancer treatment
Authors: Lee Sang Y. , Slagle-Webb Becky , Sheehan Jonas M. , Connor James R. 
Published: February 2011

Abstract
Iron can enhance cell growth and metabolism. However insufficiently regulated iron can lead iron accumulation, enhancing oxidative stress and subsequent damage to DNA, and finally promote cancer. The HFE protein plays a key role in the regulation of body iron and is part of the innate immune system. HFE is the most commonly occurring polymorphism in Caucasians. The two most common HFE polymorphic alleles are C282Y and H63D. The variant forms of HFE have increased iron accumulation. To see the impact of HFE on the brain tumor development, at first, we determined the HFE expression. HFE strongly express in the brain tumors such as meningioma, glioblastoma, and astrocytoma at immunohistochemistry. Then, to assess the association between HFE variants and growth, we measured cell growth and tumor development. We found that human neuroblastoma cell lines that were stably transfected with the C282Y allelic HFE variant proliferated at a much higher rate than the same cell lines expressing the wild type or H63D gene variant at the cell proliferation assay and counting cell number. Furthermore, nude mice injected with glioma cells with the C282Y allele developed much faster and bigger tumor than the other type of HFE cell lines. Next, we transfected HFE siRNA into the cells to determine if the increased rate of proliferation was directly related to the protein associated with the C282Y allelic variant. HFE siRNA treatment significantly inhibited cell proliferation of C282Y transfected neuroblastoma cells. The effect was dose dependent. The cell growth was over 60 % decreased for cells cultured for 4 days after exposure to 15 nM of HFE siRNA. Meanwhile, cells transfected with non-specific siRNA (negative control) or the transfection reagent (mock) control siRNA showed no evidence of inhibited cell proliferation. HFE siRNA also inhibited cell proliferation of wild type and H63D allele cells. We also observed that HFE siRNA inhibited tumor development in the glioma cells injected nude mice. We are currently studying specific delivery system of HFE siRNA to the tumor cells. In summary, we found that HFE inhibition is enough to prevent cancer cell proliferation and 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 1604.
Abstract 1609: Functional analysis of SFRS10: A novel molecular target for anti-cancer drug
Authors: Wada Satoru , Eguchi Hidetaka , Tanimoto Keiji , Hiyama Keiko , Nishiyama Masahiko 
Published: February 2011

Abstract
[Background]
Development of novel molecular-target drugs is actively conducted: A large number of such drugs are under clinical trials. However, an ideal molecular-target drug with high-specificity and low-toxicity is yet to be developed. For epoch-making development of cancer drugs, it is necessary to further identify target candidates by unprecedented approach.
[Purpose]
Last year, we reported 13 candidate genes that contributed to an immortalization through comprehensive gene expression analysis of human mortal- and immortal-cells and tissues. Under the same procedure, we here added SFRS10 gene to the list. To evaluate its possibility as drug target, we attempted here a functional analysis of SFRS10.
[Materials and Methods]
Human colon cancer cell lines DLD-1 and HCC48 and pancreatic cancer cells MIAPaCa-2, KLM-1, and BxPC-3 were used in each experiment. Quantitative analyses of gene expression levels were conducted by real-time RT-PCR method using gene specific-primers and Universal Probe Library probes (Roche). Microarray analysis was conducted with 4×44K Whole Human Genome Microarray (Agilent). Pathway analysis was performed through the use of Ingenuity Pathways Analysis (IPA, Ingenuity® Systems, www.ingenuity.com). Knockdown experiments were performed using Stealth RNAi and RNAiMax reagent (Invitrogen). Cell proliferation was measured with MTT assay. Caspase activities were analyzed using ApoAlert Caspase Profiling Plate (Clontech). Cell cycle profile was obtained by measuring PI-stained cells with FACS “Calibur” (BD Biosciences).
[Results]
SFRS10 knockdown induced inhibition of cell proliferation of all the tested cells. Because knockdown efficiencies and cytostatic activities showed a good correlation in the experiment, we speculated that SFRS10 may have an important role for the cell proliferation. Treatment with SFRS10 siRNA induced cell cycle arrest in the S and G2/M phases and apoptosis in DLD-1 and KLM-1 cells. Moreover, we observed that some cell cycle-related genes, such as MAD2L1 and RFC4, altered their expression levels in response to SFRS10 knockdown as assessed by microarray analysis; cell cycle checkpoint pathways were significantly changed with network analyses. The alteration of gene expression levels were confirmed by real-time RT-PCR analyses.
[Conclusion]
These results suggested that SFRS10 may have an important role in regulation of cell proliferation and may control cell cycle checkpoints. Taken together, SFRS10 may be one molecule responsible for immortalization of cancer cells and the useful molecular target for cancer therapy.
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 1609.
Abstract 161: Discovery of novel methylation-based biomarkers for epithelial ovarian cancer using oligonucleotide microarrays
Authors: de Graeff Pauline , Wisman Bea , Fehrmann Rudolf SN , Crijns Anne PG , Meersma Gert Jan , Volders Haukeline H. , Blijdorp Iris , Mourits Marian JE , Hollema Harry , de Jong Steven , van der Zee Ate GJ 
Published: February 2011

Abstract
Objective: To improve current screening modalities, additional molecular markers that allow detection of ovarian cancer at an early stage are needed. The aim of the current study was to identify novel methylation-based biomarkers for ovarian cancer.
Methods: Genes frequently expressed at low levels were identified by comparing global expression levels from 232 primary ovarian cancers to Universal Reference RNA. Ten genes possessing a CpG island in the promoter region that showed frequent low expression in serous cancers and at least one other histological subtype were selected. The methylation status of candidate genes was verified in 50 sporadic ovarian cancers, 11 hereditary cancers, 13 borderline cancers and 12 cystadenomas using methylation specific PCR (MSP).
Results: Three candidate genes (IGFBP1, LIN28 and ZNF582) showed frequent methylation in cancers and were unmethylated in normal leukocyte DNA and human ovarian surface epithelial cells. Promoter methylation of any of the three candidate genes was observed in 88% of stage III/IV cancers and 72% of stage I/II cancers. In contrast, only 9% of hereditary cancers showed evidence of methylation for any of the three genes (p&lt;0.001). IGFBP1 was mainly methylated in stage III/IV cancers (88% vs. 12%, p&lt;0.001), while methylation of LIN28 and ZNF582 was more frequent in stage I/II cancers (8% vs. 44% and 8% vs. 48%, respectively; p&lt;0.05).
Conclusions: Using oligonucleotide microarray data, three novel methylation-based biomarkers for sporadic epithelial ovarian cancer were discovered. Further studies should elucidate the methylation status of these genes in larger cohorts of ovarian cancers and investigate their methylation status in serum.
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 161.
Abstract 1612: Validation of CSE1L/hCAS as a potential therapeutic target in pancreatic cancer
Authors: Husain Kazim , Coppola Domenico , Centeno Barbara , Helm James , Kooman John , Lawrence Nicholas , Sebti Said , Malafa Mokenge 
Published: February 2011

Abstract
Background: The nuclear export protein CSE1L/hCAS has recently gained attention as a putative oncogene, which is amplified in several human malignancies. The role of hCAS in pancreatic cancer is unknown. In this work, we sought to evaluate the expression of hCAS in pancreatic cancer cell lines and tumor tissue and to further explore the potential of hCAS as a therapeutic target.
Methods: The nuclear and cytosolic hCAS protein expression was determined in human pancreatic cancer cell lines and tumor tissues and compared with those of immortalized normal pancreatic ductal cells and normal pancreatic tissues. The cellular effects of hCAS knockdown using small interfering RNA oligonucleotides were investigated in MiaPaCa-2 human pancreatic cancer cells with regard to proliferation (MTT assay), cell death (Trypan blue and Flow cytometry), and malignant transformation (colony formation assay).
Results: hCAS protein expression increased in pancreatic cancer cell lines relative to the immortalized pancreatic ductal epithelial cell line. Immunohistochemical staining of a human pancreatic tumor tissue microarray showed that hCAS expression was higher in pancreatic tumors compared with their normal counterparts. There was increasing nuclear to cytoplasmic staining with progression from normal pancreatic duct to increasing grade of pancreatic intraductal neoplasia to invasive pancreatic cancer. Treatment with hCAS targeting small interfering RNAs effectively reduced pancreatic cell growth in tissue culture, induced apoptosis, and inhibited growth in soft agar.
Conclusion: This is the first report of hCAS expression and cellular distribution in human pancreatic cancer. Our data suggest that hCAS might be an attractive target for human pancreatic cancer prevention and therapy.
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 1612.
Abstract 1617: Potential therapeutic effect of glycogen synthase kinase 3β inhibition against human glioblastoma
Authors: Miyashita Katsuyoshi , Kawakami Kazuyki , Nakada Mitsutoshi , Shakoori Abbas , Fujisawa Hironori , Hayashi Yutaka , Hamada Jun-ichiro , Minamoto Toshinari 
Published: February 2011

Abstract
Purpose: Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3β (GSK3β), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma.
Experimental Design: The active fractionof GSK3β that is phosphorylated at the tyrosine 216 residue (pGSK3βY216) was identified in glioblastoma cell lines. GSK3β activity for phosphorylating its substrate was detected in these cells by nonradioisotopic in vitro kinase assay.
Results: Higher expression levels of GSK3β and pGSK3βY216 were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3β activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells in vitro. Inhibition of GSK3β was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type p53 and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation.
Conclusion: These results indicate thatGSK3β exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways (Clin Cancer Res 2009;15:887-97). Consequently, we propose that GSK3β provides a potential therapeutic target in glioblastoma (Minamoto T, inventor; National University Corporation Kanazawa University; assignee. Suppression of cancer and method for evaluating anticancer agent based on the effect of inhibiting GSK3β. International patent WO2006/073202. 2006 Jul 13. United States patent US 11/794,716. 2006 Jan 4. European patent EP1845094 2007 Oct 17. Japan patent 2006-550915 2007 Jun 21).
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 1617.