bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1481: Srx-Prx IV axis is required for human lung cancer cell maintenance, migration, and invasion
Authors: Wei Qiou , Jiang Hong , Xiao Zhen , Stephen Andrew , Baker Alyson , Young Matthew R. , Veenstra Timothy D. , Colburn Nancy H. 
Published: February 2011

Abstract
Sulfiredoxin (Srx) is a novel antioxidant protein that has been shown to reduce the hyper oxidized Peroxiredoxins (Prxs). Our previous study has demonstrated that Srx is required for tumor promoter induced cell transformation and is highly expressed in certain types of human skin cancers (Wei et al PNAS 2008). In this study, our goal is to further examine the expression of Srx in a broad range of human tumors and to explore its functional significance and molecular mechanisms in human cancer development. We found that Srx is highly expressed in several types of human lung cancers and its level is correlated with cancer malignancy and metastasis. Using human lung cancer A549 cell in culture, we found that knockdown of Srx significantly reduces anchorage independent growth in soft agar, cell migration in a wound-healing assay and cell invasiveness in a matrigel invasion assay. In an effort to discover downstream mediators of Srx-signaling pathway, we used affinity-based pull down and mass spectrometry methods to identify proteins that interact with Srx. To our surprise, Prx IV was found to be the most abundant protein that interacts with Srx in at least three different cell lines and the preferential interaction occurs independently of its expression levels. To characterize the Srx-Prx IV interaction, bacterial expressed recombinant Srx, Prx I, II, III and IV were individually purified. In an in vitro binding assay using Surface Plasmon Resonance technique, we confirmed that purified Srx has a much higher binding affinity to Prx IV than to Prx I, II or III. With a lentiviral based shRNA technology, each individual Prx was specifically knocked down in A549 cells. The phenotypic changes of these cells were compared to the Srx knockdown cells. We found that knockdown of Prx IV, but not other Prxs, was sufficient to recapitulate the attenuation of tumor phenotype and progression of Srx knockdown cells. In addition, we also confirmed that Prx IV undergoes rapid hyperoxidation in the presence of oxidative stress and is preferentially reduced by Srx in A549 cells. Overall our data indicate that Srx is highly expressed in human lung cancers and Srx-Prx IV axis is critical for human lung cancer cell maintenance, migration and invasion.
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 1481.
Abstract 1482: Autocrine IL-1α mediates NF-κB activation by oncogenic ras in keratinocytes
Authors: Cataisson Christophe , Salcedo Roselba , Hakim Shakeeb , Barrett Andrea , Lyakh Lyudmila , Trinchieri Giorgio , Yuspa Stuart H. 
Published: February 2011

Abstract
Inflammation is a complex process evolved to protect us against pathogens. There is increasing evidence that chronic inflammation can be a major cancer risk. Clinical and epidemiological evidence link inflammation with epithelial skin cancer. One of the best established models linking inflammation with the development of skin cancer is the classical two stage skin carcinogenesis in mice. MyD88 is a crucial intermediate in the signaling from pro-inflammatory receptors. Mice ablated for MyD88 or the IL-1R are resistant to topical skin carcinogenesis and MyD88 deficient ras -transduced keratinocytes form only small tumors in orthotopic grafts. In the skin model the clonal benign tumor defines the phenotype of the initiated cell. High proliferation, resistance to terminal differentiation and altered gene expression are hallmarks of that phenotype. Our previous studies have revealed that Ras activation is sufficient to produce this complete phenotype and fully initiate tumor formation. We recently reported that Ras induction of CXCR2 ligands was mediated by autocrine activation of EGFR and NF-κB and that activation of CXCR2 on ras transformed keratinocytes has both pro-migratory and pro-tumorigenic functions. In MyD88 deficient cells, transduction of ras activates the EGFR loop, but these keratinocytes do not upregulate CXCR2 ligands. Using both genetic and pharmacological approaches we have demonstrated that IL-1α autocrine signaling is activated downstream of EGFR in ras transformed keratinocytes. We further demonstrate that IL-1α is responsible for NF-κB mediated activation of CXCR2 ligands in those keratinocytes. Collectively, those results demonstrate that ras activation converts normal keratinocytes to a tumor phenotype through a series of feedback signals that provide therapeutic opportunities.
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 1482.
Abstract 1484: Aldose reductase inhibition prevents breast cancer cell growth and restores breast cancer cell hormone dependency
Authors: Reddy Aramati Bindu M. , Nair Hareesh B. , Ramana Kota V. , Ansari Naseem H. , Tekmal Rajeswar R. , Srivastava Satish K. 
Published: February 2011

Abstract
Breast Cancer (BC) is the second leading cause of cancer deaths in the U.S. women. Hormone ablation therapy reduces the risk of cancer recurrence and improves the survival rate of most BC patients. Although BC initially responds to estrogen ablation therapy, as the cancer progresses, the cancer cells become hormone-independent and prone to metastasis, a major cause of mortality in BC patients. The few currently available drugs that restore hormone dependence are only partially effective and prohibitively costly. Hence there is an urgent need for novel therapeutic modalities. We have recently shown that aldose reductase (AR)-catalyzed GSH-lipid aldehyde conjugates such as GS-DHN induces growth factors-, cytokines- and chemokines-mediated signals that activate PKC, PLC and PI3K, which regulate transcription of NF-κB- and AP1-dependent inflammatory markers. Further, AR has been shown to be overexpressed in human breast cancers. We have investigated the efficacy of AR inhibition in preventing BC cells growth and reversing hormone dependency of BC cells. Our results indicate that pharmacological inhibition of AR or siRNA ablation of AR prevents growth factor -induced proliferation of BC cells (MCF-7) in culture. Similar results were observed when MDA-MB-231 and MDA-MB-468 BC cells were used. To further investigate how AR inhibitor prevents BC cell growth, we have examined the role of AR in resensitization of BC cells to letrozole. We found that combination of fidarestat with letrozole was very effective in inducing maximum cell death in LTLT-Ca cells when compared to fidarestat alone. The combination treatment not only restored estrogen receptor-α (ER-α) levels but also down-regulated HER2/MAPK-signaling proteins. Further, AR-siRNA - transfected MCF-7/Aro and MCF-7 cells upregulated ER-α in western blot and ER-functionality assays whereas in LTLT-Ca cells, ER-α levels were down-regulated as in fidarestat treated cells. Targeting the LTLT-Ca cells with PLG-based fidarestat nanoparticles having polyethylene glycol (PEG)-5000 as stabilizer and conjugated with FITC significantly prevented the aromatase activity in BC cells. Thus we have identified a novel role of AR in BC cell growth and estrogen-dependence of hormone insensitive BC cells and suggest the use of AR inhibitors either alone or in combination with letrozole to prevent as well as treat BC.
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 1484.
Abstract 1495: Analysis of p53 mutations in human esophageal cancer
Authors: Jackson Jonathan M. , Elespuru Rosalie K. 
Published: February 2011

Abstract
Studies on p53 mutations occurring in human tumors have the potential to provide information on causes of human cancer. This is relevant for cancer risk assessment on new products. A database of p53 mutations in human tumors is maintained by Olivier and Hainaut at IARC. We analyzed esophageal squamous cell carcinoma (ESCC), a cancer with known geographic hot spots and life style associations. IARC search allows the rapid determination of sequence distribution, codon location, and strand bias of p53 mutations in tumors stratified by pathology, gender, and lifestyle factors such as tobacco and alcohol use. Although proportions of DNA sequence changes in tumors are provided in IARC profiles, the nature of sequence changes at each base pair is not. Of particular interest are the sequence changes at hot spots. We analyzed the DNA sequence changes among 1032 esophageal mutations occurring at hot spot codons 175, 248, 273, and 282. These are all CpG sites encoding arginine. However, the distribution of mutations was strikingly different at the different sites. At codon 175 (CGC) 98% of the mutations were CAC, virtually all showing strand bias, i.e. G to A from the G containing strand. At codon 248 (CGG), the mutation distribution was 49%TGG and 40% CAG, showing no strand bias, i.e. equally G to A or C to T. At codon 273 (CGT), the mutation distribution was 49% CAT, 33% TGT, and 12% CTT, demonstrating some strand bias but a broader distribution of sequence changes. At codon 282 (CGG), 92% were TGG, again showing striking strand bias. Codons 248 and 282 had identical target sequences but different distributions in the tumors, 282 showing strand bias and 248 showing equivalent distribution of mutations on both strands of DNA. A biased distribution of DNA sequence changes could be related to causal DNA lesions, asymmetric DNA repair, and/or selection of particular mutant phenotypes during tumor progression.
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 1495.
Abstract 1499: Gene therapy in a mouse model for malignant melanoma: Combining the activities of the p53/Arf and interferon pathways
Authors: Merkel Christian A. , Strauss Bryan E. 
Published: February 2011

Abstract
Background: Malignant melanoma cells typically maintain wild-type p53 in a non-functional state, due in part to the loss of ARF (p14ARF in humans, p19ARF in mice). Data have shown that interferon-β (IFNβ) can activate the transcription of p53 and interact with the ARF pathway as well. By using a p53-driven adenovirus, we sought to combine the action and regulation of p53, p19ARF and IFNβ for the treatment of malignant melanoma in an immunocompetent mouse model.
Methods: p53-responsive AdPG adenoviral vectors (Bajgelman and Strauss, 2008) containing p53, p19ARF and IFNβ were produced and expression verified by immunofluorescence and ELISA. In vitro evaluation of the antiproliferative effect of single or co-transduction of B16F10 cells (B16, p53 wild-type) was done by FACS after annexin/PI staining. C57/Bl6 mice were injected subcutaneously with B16 cells and tumors were allowed to develop (∼0.5 cm2). At this point, three consecutive intra-tumor injections (3 day interval between injections) of individual or combined adenoviral vectors were performed. Animals were then sacrificed and tumors collected and analyzed.
Results: The combination of IFNβ and p19ARF proved to be more effective in inhibiting proliferation of B16 cells than either treatment alone, both in vitro and in vivo. In vitro we observed that neither AdPGp19 nor AdPGIFNβ alone altered the cell cycle, though co-transduction with these vectors resulted in extensive cell death. Annexin-V staining was also increased by the combined, but not individual, treatments. Cell death was observed only after 90-120h of incubation, yet prior to this event, indicators of senescence (positive SA-βGal staining, loss of histone H3 acetylatation at Lys9) were revealed in both single and combined vector treatments. In vivo, we observed that the combined gene transfer strategy led to reduced tumor volume, reduced incorporation of BrdU and increased staining by TUNEL in the primary tumor. Assays are in progress to determine if the combined treatment is effective in reducing metastases and prolonging survival.
Conclusion: The use of p53-responsive vectors for the restoration of ARF expression in the presence of IFNβ represents a potential strategy for melanoma tumor suppression. While mechanistic studies are underway, we propose that the complementation of the p53/ARF and interferon pathways in the primary tumor may lead to reduction of metastases.
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 1499.
Abstract 1502: Adenoviral-mediated interferon α induces endoplasmic reticulum stress related cytotoxicity in human cancer but not normal cells
Authors: Zhang Xinqiao , Benedict William F. 
Published: February 2011

Abstract
We have previously shown that adenoviral-mediated interferon α (Ad-IFNα) treatment is specifically cytotoxic to various cancer cells, not only to the cancer cells sensitive to the interferon protein (IFNα), but also to the cells which are resistant to IFNα. We also found that there is very little cytotoxic effect of Ad-IFNα on non-cancer cells. The cancer cell specific toxic effects of Ad-IFNα can be classified into three different mechanisms: 1. Expression and secretion of interferon α protein that results in kill of IFNα sensitive cancer cells; 2. Direct kill of IFNα resistant cancer cells by Ad-IFNα and 3. Cancer cell kill by Ad-IFNα produced bystander factors.
After Ad-IFNα infection, the host cells produce a large amount of IFN protein. We hypothesized that this protein over-load is cytotoxic to cancer cells and may be a major reason for Ad-IFNα direct effect. We now report that Ad-IFNα infection induces ER stress and ER stress related apoptosis in human cancer but not normal urothelial cells. In addition we found that the Ad-IFNα produced bystander cytotoxicity was not related to ER stress.
To investigate whether Ad-IFNα induced cancer specific cytotoxicity was correlated with the activation of ER stress pathways, the expression of several markers of ER stress was studied. Experiments utilized the interferon resistant human bladder cancer cell line, KU7, and the normal human urothelial cell line, TERT-NHU, for the studies. We found that three ER stress response pathways examined were activated in KU7 cells. In contrast, the ER stress response pathways remained silent in the normal TERT-NHU cells or in KU7 cells treated with conditioned medium from Ad-IFNα treated KU7 cells (to test the effect of bystander factor produced cytotoxicity) the ER stress response pathways remained silent. After 24hr of Ad-IFNα exposure, KU7 cancer cells produced spliced X-box binding protein 1 (sXBP1), activating transcription factor 4 (ATF4) and activating transcription factor (ATF6) protein, and evoked an ER stress response that contribute to Ad-IFNα induced apoptosis in cancer cells. In addition, we found GADD153/CHOP and GADD34 were also upregulated following the activation of the three ER stress pathways, thereby signaling downstream effectors in a pro-apoptotic manner.
Ad-IFNα recently has been used in Phase I clinical trial for patient with superficial bladder cancer. The results presented here could provide a mechanistic basis for Ad-IFNα action and support the positive clinical results obtained to date.
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 1502.
Abstract 1507: Aberrant oncolytic human adenovirus late mRNA translation causes failure of viral progeny production in murine cancer
Authors: Young Anna M. , McNeish Iain A. 
Published: February 2011

Abstract
Introduction. Oncolytic viruses have therapeutic potential in cancer by selectively replicating within malignant cells, causing death. Adenovirus type 5(Ad5) mutant dl922-947 contains a 24 bp deletion in E1A-CR2 and selectively replicates in cells with an abnormal Rb pathway - a feature of 90% human malignancies. dl922-947 has activity in human ovarian cancer following intraperitoneal (ip) delivery. Immunocompetent models are essential to evaluate the host immunological response as adenoviruses induce robust immune responses and CD8+ T cell infiltration has prognostic importance in ovarian cancer. However, adenoviridae are species specific and Ad5 fails to produce infectious progeny in murine tissue, preventing development of such models. We have investigated why human adenovirus replication fails in murine cancer.
Methods. dl922-947 lifecycle was examined in murine carcinoma cells CMT64 and MOVCAR7 and human epithelial ovarian cancer (EOC) cells OVCAR4.
Results. Infectivity, qPCR and sub-fractionation assays demonstrated no deficit in virion internalisation, genome replication or mRNA nuclear export in murine cells. E1A transcription and expression were similar in murine and human cells. However, there was marked failure of late viral capsid protein expression on immunoblot, which was not reversed by proteasome inhibition. TCID50 assay confirmed minimal infectious progeny production in murine cells (0.005-0.25 pfu/cell at MOI 10 in murine cells vs 104 pfu/cell in OVCAR4 cells 48h pi). Temporal differences in late gene transcription were seen between OVCAR4 and MOVCAR7 but not CMT64 cells, whilst late mRNA processing was qualitatively normal in murine cells. dl922-947 infection failed to induce global shut-down of host protein translation in murine cells on Coomassie staining. Transcription of L4 100K, important for preferential viral mRNA translation, was 1 log lower in murine cells than human controls, which may contribute to decreased production of infectious virions. Interestingly, co-infection of MOVCAR7 cells with dl922-947 and murine adenovirus type 1 (MAV-1) partially rescued late viral protein expression and increased dl922-947 cytotoxicity by MTT assay (&gt;50% reduction of EC50).
Conclusions: Failure of late viral mRNA translation results in failure of dl922-947 replication in murine cells. Current work focuses on the importance of the 5’ UTR tripartite leader sequence (TPL) common to all adenoviral late mRNAs. Specifically, sequence differences between human Ad5 and MAV-1 TPL may prevent adequate translation.
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 1507.
Abstract 1510: Improving replication kinetics by using a single shRNA p21/Waf-1 construct in backbone of prostate specific CRAd
Authors: Hoti Naser U. , Mustafa Sadaf , Chowdhury Wasim , Johnson Tamara , Lupold Shawn E. , Rodriguez Ronald 
Published: February 2011

Abstract
Conditionally replicating adenoviruses (CRAds) represent a promising modality for the treatment of neoplastic diseases, including Prostate Cancer. Selectively replicative viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). We have previously reported the attenuated replication of these viruses by multiple cellular mechanisms. In this study we investigated the importance of p21/Waf-1, a cdk inhibitor on viral replication and tumor growth. Using RNA interference against p21/Waf-1 in prostate cancer cells we demonstrated an increase viral replication and viral oncolysis of the prostate cancer cells. Similarly CRAd viruses that carry p21/Waf-1 shRNA (Ad5-RV004.21) were able to prevent tumor outgrowth by inhibiting growth of established tumor xenografts that resulted in a marked increase in the mean survival time of tumor-bearing mice compared to CRAd with out p21/Waf-1shRNA (Ad5-RV004) or mock treated control groups. Furthermore in combinatory studies of Ad5-RV004.21 with Adriamycin a supra-additive effect was observed only in CRAds viruses that harbor shRNA against p21/Waf-1. Taken together these findings of enhance viral replication in prostate cancer cells by using RNA interference against the cdk inhibitor (p21/Waf-1) have significant implications in the development of prostate-specific CRAd therapies.
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 1510.
Abstract 1523: Caffeine antagonizes multidrug resistance by down-regulating ABCG2
Authors: Ding Rui , Shi Jia , Scotto Kathleen W. 
Published: February 2011

Abstract
ABCG2/BCRP (Breast Cancer Resistance Protein) is an ATP-binding-cassette (ABC) transporter that has been shown to confer multidrug resistance (MDR) in cancer cells, ultimately resulting in the failure of cancer chemotherapy. Accordingly, the downregulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. Caffeine and its analogs are a category of natural/synthetic and cell-permeable compounds that are used therapeutically in the treatment of occurring migraines and asthma, radiosensitization and obesity. In this study, we found that caffeine, at pharmacologically relevant concentrations, can dramatically decrease ABCG2 protein in cells that have either moderate (BeWo, a placental choriocarcimoma cell line) or high (MCF7/MX100 cells, a breast cancer drug resistant cell subline) levels of ABCG2 expression. This downregulation is time-dependent, dose-dependent, and reversible. Immunofluorescence studies revealed that caffeine treatment decreases membrane-localized ABCG2 protein and significantly increases the retentions of an established ABCG2 substrate in MCF7/MX100, but not in the parental cells, demonstrating that the caffeine-mediated downregulation of ABCG2 directly decreases drug efflux. Importantly, we found that caffeine can sensitize cells to the chemotherapeutic agent mitoxantrone (MX), where combination treatment with MX and caffeine decreased the IC50 of MX ∼10-fold and induced a greater degree of apoptotic cell death compared to MX treatment alone. Additionally, several caffeine analogs were tested and exhibited a similar ability to down-regulate ABCG2; theophylline (a metabolite of caffeine, also naturally found in tea) appeared to be the most potent. Taken together, these findings suggest that caffeine or caffeine analogs could be developed as combination therapy to improve the efficacy of drugs that are ABCG2 substrates.
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 1523.