bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4372: Mechanisms involved in MMP-2 downregulation in arsenic-exposed human urothelial cells
Authors: Wang Hsiu-Hua , Lee Te-Chang 
Published: February 2011

Abstract
Arsenic has been reported to induce aberrant gene expression through various mechanisms including genetic, epigenetic regulation and signaling transduction pathways. Our previous studies have shown that long-term exposure of human urothelial cell line SV-HUC-1 (HUC-1 cells) to low dose arsenic resulted in altered cell morphology, reduced cell migration activity, and suppressed expression of matrix metalloproteinase 2 (MMP-2). To explore how MMP-2 is suppressed in arsenic exposed HUC-1 cells (iAs cells), we found that MMP-2 gene expression could be partly reverted by treatment with either demethylating agent 5-aza-dC or TGF-β alone. The enhanced expression of MMP-2 was additive by treatment of iAs cells with in combination of 5-aza-dC and TGF-β. Although we confirmed that MMP-2 promoter was hypermethylated by MSP assay, we unexpectedly found that Smad2 and Smad4 proteins were significantly suppressed in iAs cells, indicating that the canonical TGF-β pathway was deficient in iAs cells. The negligible expression level of Smad4 was confirmed by aid of a luciferase reporter containing Smad4-binding element. Alternatively, TGF-β-induced MMP-2 gene expression in HUC-1 and iAs cells could be suppressed by PKC inhibitor. Our current results suggested that TGF-β may mediate through PKC activation to induced MMP-2 expression. Taken together, MMP-2 expression in iAs cells could be reactivated by 5-aza-dC and TGF-β, indicating that arsenic exposure may be through epigenetic and signaling pathway alteration to regulate the expression of MMP-2.
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 4372.
Abstract 4373: JNK1 participates in the VHL-independent HIF-1α degradation pathway by regulating Hsp90/Hsp70 turnover and the HDAC6-dependent chaperone activity
Authors: Zhang Dongyun , Cai Tongjian , Li Jingxia , Costa Max , Huang Chuanshu 
Published: February 2011

Abstract
Nickel has been proved to be a human carcinogen. Hypoxia induced factor-1α (HIF-1α) plays a key role in the pathological processes of cancers. Previous studies have shown that nickel can exert its carcinogenic effects through the induction of HIF-1α accumulation. However, the molecular mechanisms have not been well understood. The c-Jun N-terminal kinase 1 (JNK1) is implicated in several physiological processes, including proliferation, apoptosis and differentiation, which are thought to be involved in several cancer development. JNK1 is also known to regulate the level of Hsp90/Hsp70. Our present study was conducted to investigate the role of JNK1 in the accumulation of HIF-1α induced by nickel. In current studies, we demonstrated that JNK1 is required for such an Hsp-dependent HIF-1α regulation. HIF-1α stabilization was impaired in JNK1−/− cells, and could be rescued by reconstitutional expression of JNK1 in either hypoxia or chemical-mimicked hypoxia conditions. Accordingly, HIF-1-dependent transcriptional activity and its downstream gene's expression were dramatically reduced in JNK1-deficient cells. We further disclosed that in JNK1−/− cells the low expression level of Hsp90/Hsp70 proteins affected the protective roles of these chaperones in maintaining newly synthesized HIF-1α stabilization, and forced expression of Hsp90 or Hsp70 in JNK1−/− cells showed a notable increase in HIF-1α stability compared with that of parental cells. Furthermore, our studies found that defective HDAC6 expression and subsequently increased Hsp90 acetylation could account for the reduction of Hsp90 chaperon activity in JNK1−/− cells. Our studies for the first time disclose a novel function of JNK1 in the modulation of HIF-1ααstabilization under nickel mimicked chemical hypoxia conditions through regulation of Hsp90/Hsp70 expression as well as HDAC6-mediated Hsp90 acetylation modification. This novel function may contribute to JNK1-mediated carcinogenic effects in response to nickel exposure.
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 4373.
Abstract 4385: Testosterone induces DNA damage signaling in response to oxidative stress in prostate cancer cells
Authors: Ide Hisamitsu , Jingsong Yu , Yan Lu , Muto Satoru , Horie Shigeo 
Published: February 2011

Abstract
Introduction: In prostatic tissues, DNA damage response is specially activated in prostatic intraepithelial neoplasias (PINs) that are generally regarded as precursors of prostate cancer. The process of oncogenic transformation leads to enhanced DNA damage and activates the checkpoint network as an inducible barrier against cancer progression. In this study we analyzed the effects of testosterone under oxidative stress in DNA damage response to understand the biological function and the network of this signaling.
Methods: We tested the expression level of PSA and the activation of DNA damage response proteins including ATM (ataxia-telangiectasia-mutated kinase), H2AX (histone H2AX variant) and Chk2 (checkpoint kinase2) in prostate cancer cell lines (LNCaP and PC-3) with various concentration of H2O2. Apoptosis is quantified by flow cytometry and PARP cleavage.
Results: H2O2 induces apoptosis and the phosphorylation of ATM, H2AX and Chk2 in LNCaP cells. ATM inhibitor Ku55933 can block the phospholyration of H2AX and Chk2, but induced the activation of alternative pathways, p38 and ERK. Activation of DNA damage response and PARP cleavage was increased by testosterone. H2O2 did not induce phosphorylation of ATM, CHK2 and H2AX in PC-3 cells because of losing their expression. ATM inhibitor Ku55933 can reduce the apoptotic cells in LNCaP cells but PC-3 cells by the treatment of H2O2. Conclusion: Oxidative stress has been associated with tumor formation. On the other hand, DNA damage pathway plays important roles in the maintenance of the cell homeostasis in response to oxidative stress. Our results indicate that androgen signaling have tumor suppressive effects in prostate carcinogenesis through DNA damage response pathways under oxidative stress.
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 4385.
Abstract 4387: Reactive oxygen species-mediated cell death by psoralidin in prostate cancer cells
Authors: Sowmyalakshmi Srinivasan , Kumar Raj , Pahari Pallab , Rohr Jurgen , Damodaran Chendil 
Published: February 2011

Abstract
Modulating reactive oxygen species (ROS) levels may lead to either cell proliferation or death based on the cell type. It is well established that in cancer cells the basal levels of ROS is significantly higher when compared to their normal counterparts. Thus, identifying non-toxic small molecules which induces ROS specifically in cancer cells may be of enormous importance in cancer therapy. We have previously shown that psoralidin, a natural compound derived from Psoralea corylifolia specifically induces apoptosis in prostate cancer (PCa) cells (PC-3, DU-145, LNCaP and C4-2B). In this study we dissected the role of ROS in psoralidin-induced cell death in PCa. Our results suggested that psoralidin significantly induces ROS generation in both androgen-responsive (LNCaP) and -refractory (PC-3, DU-145 and C4-2B) PCa cells when compared to normal prostate epithelial cells (PzHPv7); leading to loss of mitochondrial membrane potential and release of cytochrome-c, caspase activation (9 and 3) and induction of apoptosis. In addition, induction of ROS downregulates pAkt expression and kinase activity, NF-κB (p65, p50 and p55) and mTOR (pp70S6K and p4E-BP1)-mediated pro-survival signaling in PCa cells. On the other hand, inhibition of ROS generation by N-acetylcysteine (NAC) prevented psoralidin-mediated anticancer effects on PCa. Collectively, our results suggest that psoralidin-mediated ROS generation in PCa cells causes inhibition of survival/proliferation and induction of apoptosis. Further investigation of the mechanism of action of psoralidin may facilitate initiation of clinical trials using psoralidin for the treatment of PCa.
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 4387.
Abstract 4388: beta-Carotene's oxidative breakdown inhibits p53 conformational folding and function
Authors: Bentz Brandon G. , Ring Terry A. , Murtaugh Maureen A. , Burnett David M. , McClane Robert , Fitzpatrick Frank A. 
Published: February 2011

Abstract
Lipophilic electrophiles have been found to have the ability to inhibit wild-type p53 protein function through a thioredoxin-dependent inhibition of functional protein folding. One potential extension of this line of research may help to explain the curious findings of certain carotenoid-based chemopreventive clinical trials that found that beta-carotene may be a contributory causal risk of cancer development in patients who actively smoke. Chemical precepts dictate that wild-type p53 function may be inihibited through a similar mechanism by other other lipophilic compounds such as carotenoids within a high redox milieu of ongoing smoking. We ask the question whether the oxidative breakdown of beta-carotene could inhibit p53 function via a similar post-translational mechanism. Using resonance Raman spectroscopy, HPLC, spectrophotometry, and Western blot analysis, we exposed isolated cell-free and intracellular beta-carotene to various oxidant sources such as nitric oxide (NO·), superoxide (O·), and/or the combination of NO· and O· [i.e. SNAP (NO+ donor), Spermine-NONOate (NO. donor), and SIN-1 (NO·/O· donor), and Angeli's salt (an NO[[Unsupported Character - Codename &shy;]]- donor)] as a model of ongoing oxidative stress. Our results demonstrate that the oxidative breakdown of beta-carotene specifically by SIN-1 (the donor of NO·/O· causes stabilization of p53, attributable to the accumulation of both “functional” and “non-functional” conformational folding. Finally, we demonstrate that the oxidative breakdown products of beta-carotene can inhibit thioredoxin function, thus providing a biochemical mechanism for the inhibition of wild-type protein folding. Taken together, these data support the hypothesis that ongoing oxidation of beta-carotene can inhibit this key cancer-related molecular pathway, through the post-translational inhibition p53 folding and function. These data may provide one biochemical mechanism for the surprising results of initial carotenoid-based chemopreventive cancer trials.
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 4388.
Abstract 4395: SEA technology: A novel strategy for enhancing antibody effector function
Authors: Alley Stephen C. , Sussman Django R. , Jeffrey Scott C. , Torrey Lindsay , Burke Patrick J. , Setter Jocelyn , Gfeller Brian , Klussman Kerry , Okeley Nicole M. , Senter Peter D. , Benjamin Dennis R. 
Published: February 2011

Abstract
The activity of monoclonal antibodies (mAbs) can be enhanced by a number of chemical and genetic strategies. We describe a novel strategy, Sugar Engineered Antibody (SEA) technology, for enhancing antibody-dependent cellular cytotoxicity (ADCC) through modification of the mAb carbohydrate. A series of small molecule fucose analogs were added to mAb-expressing Chinese hamster ovary (CHO) cells, with the resulting mAbs showing a significant reduction in their carbohydrate fucosylation. We demonstrate that these mAbs show markedly increased ADCC activity and improved CD16 binding. The fucose analogs inhibit GDP-mannose dehydratase (GMD), the first enzyme in de novo synthesis of GDP-fucose, and lead to global depletion of intracellular GDP-fucose. We also demonstrate that this strategy yields mAbs with significantly reduced fucosylation in large scale CHO cell culture and is broadly active across a variety of mAbs and expression systems. Since genetic modification of the mAb-producing cell line is not required, SEA technology can be readily applied from the mAb screening to manufacturing stage to generate effector function enhanced therapeutic antibodies.
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 4395.
Abstract 4396: Conjugation site modulates the stability and biological activity of antibody drug conjugates
Authors: Shen Ben-Quan , Xu Keyang , Liu Luna , Parsons Kathryn , Bhakta Sunil , Raab Helga ,   20 more Genentech Authors, Flagella Kelly , Spencer Susan D. , Kaur Surinder , Scheller Richard H. , Sliwkowski Mark X. , Polakis Paul , Junutula Jagath Reddy 
Published: February 2011

Abstract
Antibody drug conjugates (ADCs) are attractive targeted chemo-therapeutic molecules as they combine ideal properties of both antibodies and cytotoxic drugs by targeting potent cytotoxic drugs to the antigen-expressing tumor cells, thereby enhancing their anti-tumor activity. The successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency and mode of linker-drug conjugation to the antibody. Recently, we have developed antibodies with cysteine substitutions (THIOMABs) at sites where the engineered cysteines are available for conjugation but do not perturb immunoglobulin folding and assembly or alter antigen binding and effector functions (Junutula, et al., Nature Biotech., 26, 925-932, 2008). These THIOMABs can then be derivatized through the engineered cysteine thiol group to obtain ADCs with uniform stoichiometry (∼2 drugs per antibody). Studies with multiple antibodies against different antigens have shown that THIOMAB drug conjugates (TDCs) are as efficacious as conventional conjugates in xenograft models and are tolerated at higher doses in relevant preclinical models. To further understand improved therapeutic activity and in vivo metabolism of TDCs, we have engineered TDCs with drug attachment at different parts of the antibody (light chain-Fab, heavy chain-Fab and heavy chain-Fc). TDCs produced by THIOMAB technology provided an unique advantage over conventional ADCs to answer several unresolved questions in ADC therapeutics due to their homogeneity and site-specific conjugation to cytotoxic drugs. We will discuss novel findings that were observed with these TDC varaints and the influence of conjugation site in modulating stability and biological activity of antibody drug conjugates.
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 4396.
Abstract 4397: Development of antibody-drug conjugate technology based on novel linkers & DNA alkylating duocarmycin derivatives
Authors: de Groot Vincent F.M.H , Beusker Patrick , Joosten John , Spijker Henri , Coumans Ruud , Menge Wiro , Elgersma Ronald 
Published: February 2011

Abstract
Antibody-Drug Conjugation (ADC) is gaining momentum as a next generation antibody therapeutics approach in oncology. Tumor specific delivery of the cell-killing agent maximizes the agent's potency while avoiding damage to healthy tissue resulting in a high therapeutic window. Syntarga's Potent Payload Technology comprises the combination of highly potent DNA-alkylating duocarmycin derivatives and suitable linker technologies. Duocarmycin analogs and the CC-1065 derivatives represent a class of highly potent, cell-killing, DNA-alkylating, minor groove binding agents. This class is suitable to target solid tumors and has not been associated with Multi-Drug Resistance (MDR). Strong in vivo Proof of Concept with Potent Payload ADCs has been obtained against multiple targets. In human tumor xenograft models, substantial efficacies have been obtained based on single dose treatments, with minimal or absent side effects. We discuss applicability and several other aspects of multiple, validated Potent Payload-based Antibody-Drug Conjugates (ADCs). Latest results of preclinical development progress (in vivo efficacy, safety, etc.) will be presented, including drug potencies, linker stability and therapeutic window aspects for ADCs directed against HER2.
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 4397.
Abstract 44: STAT1-dependent expression of genes and proteins involved in energy metabolism links tumor growth and radioresistance to the Warburg effect and predicts poor prognosis in cancer patients
Authors: Khodarev Nikolai N. , Pitroda Sean P. , Wakim Bassam T. , Golden Daniel W. , Beckett Michael A. , Mauceri Helena J. , Sutton Harold G. , Perakis Samantha , Malik Renuku , Wietholt Christian , Pelizzari Charles , Chen Chin-Tu , Weichselbaum Ralph R. 
Published: February 2011

Abstract
Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumor suppressor. Recent data have identified new functions of STAT1 associated with tumorigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumorigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis of tumor xenografts with stable Stat1 knock-down (KD) relative to tumors with wild type (wt) Stat1. We also compared previously described SCC61 and nu61 isologous tumors, where SCC61 is radiosensitive and nu61 is radioresistant counterparts with different expression of IFN/Stat1 pathway. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the MS/MS data by searching against the human subset of the UniProt database. Knockdown of STAT1 led to significant growth suppression in untreated tumors and radiosensitization of irradiated tumors. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC), and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumor-specific glycolysis. IR drastically suppressed the GG pathway in STAT1 KD tumors without significant change in STAT1 WT tumors. Using 18F-FDG-PET we observed significantly higher glucose uptake in nu61 compared to SCC61 post-irradiation (6Gy). The STAT1 and glycolytic pathways were co-expressed in human breast tumors, and expression of STAT1-linked glycolytic genes was highly predictive of poor prognosis. Our results identify a previously uncharacterized function of STAT1 in tumors: expressional regulation of genes and enzymes involved in glycolysis, the citrate cycle, and mitochondrial oxidative phosphorylation, with predominant regulation of glycolysis. STAT1-dependent transcriptional and translational regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.
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 44.
Abstract 440: Myoglobin in breast cancer: Regulation, function and relevance
Authors: Kristiansen Glen O. , Hu Junmin , Gerhardt Josefine , Fritzsche Florian , Theurillat Jean-Phillipe , Geisler Cordelia , Rose Michael , Stiehl Daniel , Gleixner Eva M. , Hankeln Tom , Gnaiger Erich , Moch Holger , Gassmann Max , Gorr Thomas , Dahl Edgar 
Published: February 2011

Abstract
Background
Following an accidental observation, we aimed to analyse expression, regulation and function of myoglobin (Mb) in breast cancer.
Methods
Immunohistochemistry/Immunofluorescence, microdissection, transmission electron microscopy, Western blot, qPCR, cell culture (under normoxia and hypoxia), shRNA and siRNA knockdown, in silico data mining, high resolution respirometry. Functional assays: proliferation, migration and colony formation.
Results
Mb protein is de novo expressed in 71% of invasive breast carcinomas (n=917) in association with the hypoxia inducible factor 2α (HIF-2 α), carbonic anhydrase IX and a better prognosis. Expression of Mb in breast cancer was confirmed on mRNA level and occurred irrespective of rhabdomyoid differentiation and was inducible by prolonged hypoxia in breast cancer cell lines (MDA-MB231, MDA-MB468, MCF7) with a median change fold of 3.4 after 72 hours. Interestingly, hypoxically induced MB mRNA originated from a novel, alternative transcription start site 6 kb upstream of the genuine ATG codon. Functionally, stable myoglobin knockdown in MDA-MB468 cells was associated with a stimulated O2 uptake during mild hypoxia, yet did not impact the O2 diffusion gradient in these small cells during limiting conditions. Knockdown of Mb also conferred a significant retardation of the cells’ in vitro motility to close an inflicted wound within the normoxic culture.
Conclusions
Regarding cancer cells, unconventional functions of myoglobin, not directly related to the transport of oxygen, thus need to be envisioned. These unprecedented findings may have fundamental implications for our understanding of non-muscle Mb in solid tumors.
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 440.