bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A47: Fucoidan from Laminaria cichorioides inhibits AP-1 transactivation and cell transformation in mouse epidermal JB6 cells
Authors: Namgoog Gwang Mo , Cho Hae-Gook , Choi Hong Seok 
Published: May 2012

Abstract
Fucoidan, a sulfated polysaccaride extracted from brown seaweeds, has anticoagulant and antithrombotic activities. Unlike heparin, fucoidan is known to exhibit anticarcinogenic activities. However, the underlying molecular mechanisms of the chemopreventive activities of fucoidan are not understood. Here we report that fucoidan from L. cichorioides inhibited the epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic cell transformation, but had less cytotoxic effects on JB6 mouse epidermal cells. The EGF-induced phosphorylation of extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinases, and c-Jun was inhibited by fucoidan, resulting from the inhibition of phosphorylation of epidermal growth factor receptor (EGFR). Fucoidan dose-dependently attenuated the c-fos or c-jun transcriptional activity, and thereby inhibited the associated AP-1 transactivation activity. In vitro binding assay revealed that fucoidan directly interacted with EGF, suggested that anti-tumor promoting effect of fucoidan might be due to preventing the binding of EGF to its cell surface receptor (EGFR). These findings are the first to reveal a molecular basis for the anticarcinogenic action of fucoidan and may partially account for the reported chemopreventive effects of brown seaweeds.
Citation Information: Cancer Res 2009;69(23 Suppl):A47.
Abstract A52: Mechanisms of 1,25-dihdyroxyvitamin D-mediated growth arrest and apoptosis in transformed mammary cells
Authors: Keith Meggan E. , LaPorta Erika , Welsh JoEllen 
Published: May 2012

Abstract
1,25-Dihdyroxyvitamin D (1,25D), the biologically active form of vitamin D, exerts pro-differentiating and anti-proliferative actions on epithelial cells, but the exact role of the vitamin D receptor (VDR) in mediating these effects remains to be defined. The goal of this project is to link specific functional domains of the VDR with regulation of cancer cell proliferation, invasion, and apoptosis. Epithelial cell lines derived from DMBA induced mammary tumors generated in VDR knock-out (KO) mice and their wild-type (WT) littermates were characterized for growth arrest and apoptosis following 1,25D treatment. Cells derived from WT tumors expressed VDR and exhibited growth arrest and apoptosis in response to 1,25D. In VDR positive cells, 1,25D mediated apoptosis was associated with activation of multiple caspases and calpain, resulting in PARP cleavage. In contrast, cells derived from KO tumors lacked VDR and failed to undergo growth arrest and apoptosis upon 1,25D treatment. To recreate VDR signaling in KO cells, human VDR was stably expressed in the KO240 cell line, generating the KOhVDR cell line. KOhVDR cells expressed transcriptionally active VDR protein at levels comparable to that of WT cells. Re-introduction of VDR did not affect doubling time of KOhVDR cells in the absence of ligand, but did sensitize cells to growth arrest and apoptosis in response to VDR agonists. PCR screening arrays and independent qPCR validation were used to identify VDR target genes in this model system. In WT cells, 6-24h treatment with 100nM 1,25D induced PDGF-B (up to 10 fold) and VEGF-A (up to 5 fold). No changes in PDGF-B or VEGF-A expression were observed in KO cells treated with 1,25D, but both genes were inducible by 1,25D in KOhVDR cells stably expressing hVDR. Thus, 1,25D can activate either human or murine VDR to induce endogenous PDGF-B and VEGF-A gene expression in these murine cells. In summary, these data indicate that VDR does not exert ligand-independent effects on mammary cell growth, but is essential to trigger gene expression, growth arrest and apoptosis in response to 1,25D. Supported by NIH CA69700.
Citation Information: Cancer Res 2009;69(23 Suppl):A52.
Abstract A57: Nonsense-mediated decay escaping mutations in microsatellite-unstable colorectal cancer
Authors: Gylfe Alexandra , Niittymäki Iina , Ahonen Leena , Lehtonen Heli , Laakso Marko , Sirkiä Johanna , Nousiainen Kari , Pouwels Jeroen , Järvinen Heikki , Nuorva Kyösti , Mecklin Jukka-Pekka , Ristimäki Ari , Ørntoft Torben , Hautaniemi Sampsa , Karhu Auli , Kallio Marko , Aaltonen Lauri 
Published: May 2012

Abstract
Genomic instability drives tumorigenesis by allowing the accumulation of genetic alterations that provide cells with growth advantage. Microsatellite-instability (MSI) and the underlying mutator phenotype caused by a defect in mismatch repair (MMR) functions is the hallmark of Lynch syndrome, and is also observed in a subset of all colorectal cancers (CRC). In cells with a defective MMR system, spontaneous length changes of repetitive microsatellite sequences accumulate all over the genome at highly increased rates. At coding regions instability may lead to frameshift mutations and altered protein products. Genes that mutate this way under MMR deficiency giving selective advantage to cells in tumorigenesis are called MSI target genes. It is generally anticipated that the frameshift mutation-containing transcripts that lead to prematurely terminated proteins undergo nonsense-mediated decay (NMD), followed by a reduction in gene expression levels. However, when a premature stop occurs in the carboxyl-terminal end of the gene it might escape decay mechanisms, which may lead to either dominant-negative or oncogenic effects. Aim of this study was a genome-wide unbiased identification of new MSI CRC target genes that escape NMD. By combining bioinformatic search to expression profiling, we created a list of 330 genes that contained mononucleotide repeats from 6 to 10 base pairs and were likely to be translated despite potential mutations. A novel frameshift predictor software was developed to search all repeat-containing transcripts in the human genome that would escape NMD after one nucleotide deletion. To enhance the odds of identifying oncogenic mutants, the analysis was restricted to genes that were overexpressed in MSI CRC versus normal colonic mucosa. All of these genes were screened initially by sequencing the given repeat in a panel of 30 MSI CRCs.Whenever the mutation frequency exceeded 20% in the tumor set, which was considered evidence for possible selection in MSI tumorigenesis, an additional set of 70 MSI CRCs was sequenced. The great majority of the successfully sequenced genes had no mutations. Altogether four genes were mutated in over 20% of the samples in the extended 100 MSI tumor panel. These candidate driver target genes are being evaluated further by various methods, including sequencing of MSI CRC cell lines and microsatellite-stable (MSS) CRCs, statistical analyses, and functional in vitro experiments.
Citation Information: Cancer Res 2009;69(23 Suppl):A57.
Abstract A62: Phosphorylation of Ser205 by the protein kinase CK2 persists on Pax3-FOXO1, but not Pax3, throughout myogenic differentiation
Authors: Dietz Kevin N. , Miller Patrick J. , Hollenbach Andrew D. 
Published: May 2012

Abstract
The myogenic transcription factor Pax3 plays an essential role in early skeletal muscle development and is a key component in Alveolar rhabdomyosarcoma (ARMS), a childhood solid muscle tumor. ARMS, which is associated with a four year survival rate of only 17%, is most commonly characterized by a t(2;13) chromosomal translocation resulting in the fusion of the 5′ Pax3 sequences to the 3′ FOXO1 sequences to encode the oncogenic fusion protein, Pax3-FOXO1. Posttranslational modifications such as phosphorylation are common mechanisms by which transcription factors are regulated. Consistent with this fact, we demonstrated in a previous report that Pax3 is phosphorylated on Ser205 in proliferating, but not differentiated, primary myoblasts. However, the kinase that mediates this phosphorylation event has yet to be identified. More recently it was demonstrated that Pax3-FOXO1 is also phosphorylated at unidentified sites in non-physiologically relevant cells. Despite this information, it is not known whether Pax3-FOXO1 is phosphorylated at Ser205 or how the phosphorylation of the fusion protein changes during myogenic differentiation. In this report, we use standard in vitro kinase assays to identify CK2 (formerly termed “casein kinase II”) as the kinase responsible for phosphorylating Pax3 and Pax3-FOXO1 at Ser205 in proliferating mouse primary myoblasts. Furthermore, we use standard Western blot analysis to demonstrate that in contrast to wild-type Pax3, phosphorylation at Ser205 persists on Pax3-throughout early myogenic differentiation. Finally, we use standard Western blot analysis to show that Pax3-FOXO1 is phosphorylated at Ser205 in a variety of translocation-containing ARMS cell lines. The results presented in this report not only suggest a possible mechanism by which the disregulation of Pax3-FOXO1 may contribute to tumorigenesis, but also identifies a novel target for the development of therapies to be used for the treatment of ARMS.
Citation Information: Cancer Res 2009;69(23 Suppl):A62.
Abstract A71: Distinct functions of epithelial growth factor receptor (EGFR) pathways in pancreatic acinar cell differentiation and initiation of pancreatic ductal adenocarcinoma
Authors: Shi Guanglu , DiRenzo Daniel , Konieczny Stephen F. 
Published: May 2012

Abstract
Significance: Pancreatic ductal adenocarcinoma (PDA) is one of the most fatal malignancies, partially due to the lack of early detection methods.
Background: Efforts to understand the early stages of PDA progression have led to identification of Kras mutations as the initiating event and pancreatic intraepithelial neoplasias (PanINs) as one of the cellular precursors of PDA. Recently, several labs have demonstrated that PanINs can be generated from pancreatic acinar cells upon expression of Kras mutants in mouse models. This dramatic shift from differentiated acinar cells to duct-like PanIN cells, generally termed acinar-ductal metaplasia (ADM), is accelerated by loss of Mist1, an acinar-restricted basic helix-loop-helix transcription factor. Despite this recent progress, the transcription and signaling networks that regulate ADM remain largely unknown.
Results: To study these networks, we employed a collagen-based 3-dimensional (3D) culture model of ADM, where primary acinar cells can be transformed into duct-like cysts when treated with transforming growth factor-alpha (TGF-α). A similar acinar-to-ductal conversion was observed with primary acinar cells that express the KrasG12D mutant. Initial characterization of the ADM process revealed that the MAPK pathway is required in both settings. However, EGFR activity is required for TGF-α-induced conversion but not for KrasG12D-induced conversion. Consistent with previous data generated from mouse models, loss of Mist1 accelerates KrasG12D-induced conversion to ductal cysts in vitro. This accelerated ADM formation can be reversed by inhibition of EGFR, without affecting the basal level conversion induced by KrasG12D, suggesting that loss of Mist1 promotes transformation through an EGFR-dependent pathway. Further investigation has revealed that Mist1 directly activates transcription of the epidermal growth factor (EGF) gene, which encodes a classic ligand of EGFR.
Conclusion: These data suggest that EGFR has a complex role in this ADM model. EGFR activity either promotes maintenance of acinar differentiation, or cooperates with KrasG12D-induced transformation, possibly depending on the functional specificity of different ligands.
Citation Information: Cancer Res 2009;69(23 Suppl):A71.
Abstract A74: Estrogen receptor α-regulated growth and transcription is dependent on X-box binding protein-1 in breast cancer cells
Authors: Kiewlich David , Rosser Mary , Kretschmer Peter , Zajchowski Deborah 
Published: May 2012

Abstract
This study was designed to investigate the impact of X-Box Binding protein 1 (Xbp1) mRNA knockdown on the estrogen-responsive growth and gene expression in an estrogen receptor α (ERα) positive breast cancer cell line model. Xbp1 is a basic leucine zipper-containing transcription factor that plays a key role in the unfolded protein response (UPR), a cell program that is activated by unfolded or misfolded proteins in the endoplasmic reticulum. MCF7 cells, a model of ERα positive breast cancer, express high levels of Xbp1 and are dependent on estrogen for growth and ERα regulated transcription. Previous studies have revealed that further overexpression of Xbp1 in ERα positive breast cancer cells leads to estrogen independent ERα regulated transcription and anti-estrogen resistance, suggesting that Xbp1 expression influences ERα regulated transcription. Unknown is whether ERα requires Xbp1 as a cofactor for transcription. Here we show that Xbp1 mRNA knockdown by specific siRNAs prevents estrogen responsive growth of MCF7 cells as well as ERα regulated gene expression, while non-specific control siRNAs had little effect. These results, together with the high expression of Xbp1 seen in ERα positive breast cancers, but not in normal mammary ductal cells, suggests that high levels of Xbp1 enable ERα tumor cells to use estrogen as a growth factor. Thus, high levels of Xbp1 expression could represent an early transformation step leading to ERα positive breast cancer, and could explain why normal ERα positive breast ductal cells have not been established as cell lines.
Citation Information: Cancer Res 2009;69(23 Suppl):A74.
Abstract A79: Genome-wide RNAi screen for tetraploid-specific lethality in cancer cells
Authors: Kuroda Taruho S. , Dagher Regina K. , Pellman David 
Published: May 2012

Abstract
Cancer cells are often genetically unstable, resulting in aneuploid genomes. The consequences of aneuploidy are poorly understood, but have been suggested to play roles in tumor aggressiveness, chemotherapy resistance, and metastasis.
One important route to an aneuploid genome may be through doubling of the genome, leading to unstable tetraploid cells. Many cell division errors are ultimately manifest as a failure of cytokinesis. Especially in cells defective in p53 function, tetraploid cells proliferate, but generate both high rates of whole chromosome aneuploidy and defects in the maintenance of chromosome structural integrity. Our laboratory has demonstrated that, in p53-primary cells, tetraploidy promotes tumor development and the resulting tumors display markedly abnormal genomes (Fujiwara T. et al. Nature 2005, 437: 1043). It is now known that several human cancer-mutations — e.g. Rb loss or loss of the adenomatous polyposis coli tumor suppressor — also predispose cytokinesis failure and tetraploidy. These findings highlight a need to understand in detail the physiological changes that accompany tetraploidy.
To gain a comprehensive understanding of physiological alterations associated with tetraploidy in cancer cells, we have established tetraploid cell lines derived from a near diploid human colorectal cancer cell line HCT116. Using these paired tetraploid and diploid cell lines, we have performed a genome-wide RNAi screen to identify genes whose knock down selectively affect the viability of either diploids or tetraploid cells. We are currently validating the result of our ploidy-specific lethality screen and we would like to update our progress at this conference.
Citation Information: Cancer Res 2009;69(23 Suppl):A79.
Abstract A80: Somatic cancer mutations in human mtDNA show neutral and positive selection
Authors: Stafford Peter , Chen-Quin Estella B. 
Published: May 2012

Abstract
The majority of cancers exhibit somatic mutations in the mitochondrial chromosome (mtDNA). Whether these mutations play a causal role or are merely an effect is an issue of on-going uncertainty. To study the role of somatic mtDNA mutations in cancer, we present a meta-analysis of 356 tumor sequences of multiple cancer types from the literature. As tumor formation is a type of somatic evolution, we examine the mutation pattern for whether the cancer DNA variation is consistent with drift (random forces) or selection. We also compare the cancer mutation pattern to that observed at the organismal or population level in order to gain insight on the mutation process in cancer cells. Among germline sequences, all mtDNA genes show a strong deficiency of amino acid changes, reflecting negative selection during human history and consistent with functional constraints at the organismal level. In somatic cancer sequences, mtDNA genes show either relaxed negative selection relative to germline or a mutation pattern consistent with neutrality. ND3, CO3, and ND4L in particular show cancer missense mutation rates nine - 18 times that of their counterpart genes at the germline level. Bootstrap analysis of the cancer-specific missense mutations show Cytochrome B and ND6 to have changes occurring in positions of unusually high conservation, suggesting that tumors select for mutations in residues of high functionality. These results support relaxed negative selection or neutrality for somatic mtDNA mutations in cancer, with the later potential for positive selection of alterations that impair mitochondrial function.
Citation Information: Cancer Res 2009;69(23 Suppl):A80.
Abstract B1: Chemotherapy induces NEDP1-mediated destabilization of MDM2
Authors: Watson Ian R. , Li Bryan K. , Roche Olga , Blanch Alvaro , Ohh Michael , Irwin Meredith S. 
Published: May 2012

Abstract
MDM2 is an E3 ligase that promotes ubiquitin-mediated destruction of p53. Cellular stresses such as DNA damage can lead to p53 activation due in part to MDM2 destabilization. Here, we show that the stability of MDM2 is regulated by an ubiquitin-like NEDD8 pathway and identify NEDP1 as a chemotherapy-induced isopeptidase that deneddylates MDM2, resulting in MDM2 destabilization concomitant with p53 activation. Concordantly, RNA-imediated knockdown of endogenous NEDP1 blocked diminution of MDM2 levels and increased chemoresistance of tumor cells. These findings unveil the regulation of MDM2 stability via NEDP1 as a common molecular determinant governing chemotherapy-induced p53-dependent cell death.
Citation Information: Cancer Res 2009;69(23 Suppl):B1.
Abstract B17: Stepwise prostate carcinogenesis in vitro culture
Authors: Ke Xisong , Li Wencheng , Qu Yi , Hovland Randi , Rotter Varda , Akslen Lars A. , Øyan Anne Margrete , Kalland Karl-Henning 
Published: May 2012

Abstract
The loss of epithelial characteristics and the acquisition of a migratory phenotype, referred to as epithelial to mesenchymal transition (EMT), is a crucial event in tumor metastasis. Our previous work reported an EMT model based on primary prostate epithelial cells (EP156T) which gave rise to mesenchymal cells (EPT1) without malignant transformation. To achieve transformed prostate cells, EPT1 cells were kept growing in extended saturation density culture to select for cells overriding quiescence. Many foci formed in EPT1 monolayers after 4 weeks at confluence, but foci never appeared in EP156T monolayers in parallel controls. Cells from the foci formed robust colonies in soft agar suggesting full malignant transformation. The transformed cells were named EPT2. In this stepwise transformation model, EPT2 cells showed much higher abilities to proliferation at confluence, migrated better and were less dependent on exogenous growth factors than EP156T and EPT1 cells. Foci were more easily derived from EPT1 cells at later passages following EMT. Gene expression profiling showed progressive downregulation of CDH1 from EP156T, through EPT1 to EPT2 together with a number of additional changes. Our findings provide a novel stepwise transformation model according to which EMT can occur independently of transformation, but can promote subsequent malignant transformation in prostate carcinogenesis.
Citation Information: Cancer Res 2009;69(23 Suppl):B17.
Abstract B18: A role for E2f3 in DNA damage-induced apoptosis
Authors: Martinez Luis A. 
Published: May 2012

Abstract
The E2F transcription factors have emerged as critical apoptotic effectors. Herein we report that the E2F family member, E2f3a, can be induced by DNA damage through transcriptional and post-translational mechanisms. We demonstrate that the post-translational induction of human E2f3a is dependent on the checkpoint kinases. Moreover, we show that human E2f3a is a substrate for the chk kinases and that mutation of the chk phosphorylation site eliminates the DNA damage inducibility of the protein. Furthermore, we demonstrate that all three activating E2Fs (E2f1, E2f2 and E2f3a) are transcriptionally induced by DNA damage. siRNA knockdown of E2f3 in human cells or E2f3 genetic deficiency in mouse embryonic fibroblasts eliminates the DNA damage induction of the transactivating E2fs. Finally, using both in vitro and in vivo approaches, we establish that E2f3 is required for DNA damage induced apoptosis, regardless of p53 status. Thus, our data reveal the novel ability of E2f3 to function as a master regulator of the DNA damage response.
Citation Information: Cancer Res 2009;69(23 Suppl):B18.
Abstract B20: Acetaminophen enhances the cytotoxicity of cisplatin in vitro and in a subcutaneous tumor xenograft model of human ovarian carcinoma
Authors: Wu Yingjen Jeffrey , Neuwelt Alexander J. , Muldoon Leslie L. , Neuwelt Edward A. 
Published: May 2012

Abstract
Background: High dose acetaminophen causes hepatotoxicity by depleting glutathione and increasing production of toxic metabolites. The objective of this study was to examine if these mechanisms of acetaminophen can enhance the cytotoxicity of cisplatin in human ovarian cancer cells both in vitro and in vivo.
Methods: In vitro studies (glutathione concentration, cell viability and immunoblotting assays) were performed using SKOV3 human ovarian cancer cells cultured in combinations of acetaminophen and cisplatin. For the tumor model, female nude rats were pre-treated with cyclophosphamide (i.p. 100 mg/kg) one day prior to subcutaneous inoculation of SKOV3 cells with matrigel on the left flank. At 7 days after implantation, rats were randomly assigned into vehicle, cisplatin, and acetaminophen plus cisplatin treatment groups (n=3–5 per group). Subcutaneous tumor volume was measured by dial caliper. Acetaminophen pharmacology and the toxicity of treatments were monitored.
Results: In vitro, acetaminophen decreased SKOV3 cellular glutathione level by approximately 30% over 2 hr time frame. Acetaminophen combined with cisplatin decreased cell growth and viability and enhanced apoptosis compared to cisplatin alone in vitro. In vivo, high dose acetaminophen showed uniform tissue distribution, but only decreased glutathione in the liver but not in the serum, brain, or subcutaneous tumor of nude rats. Acetaminophen pretreatment 2–4 hr prior to cisplatin enhanced cisplatin chemotherapeutic effect as determined by a reduction in subcutaneous tumor volume by 15–25% (55–85% vs 40–60%). Serum BUN and creatinine levels were elevated by the combination of acetaminophen with cisplatin treatment when compared to cisplatin alone (48.2±10.9 vs 24.4±4.1 mg/dL; 0.65±0.06 vs 0.30±0.04 mg/dL; p&lt;0.01).
Conclusions: Our results suggested that a chemotherapeutic regimen containing both high dose acetaminophen and cisplatin could be applied not only in hepatic tumors but also in ovarian or other tumor malignancies as a potentially promising approach for pre-clinical trial.
Citation Information: Cancer Res 2009;69(23 Suppl):B20.