bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1694: Selective formation of the γ isomer of 1,N2-propanodeoxyguanosine adducts of acrolein through interactions with amine-containing molecules
Authors: Chung Fung-Lung , Wu Mona Y. , Dyba Marcin D. , Nath Raghu G. 
Published: February 2011

Abstract
Acrolein (Acr) is a highly reactive α,β-unsaturated aldehyde found ubiquitously in the environment and also formed endogenously as a major product from oxidation of polyunsaturated fatty acids. Acr can bind to deoxyguanosine (dG) to form two regioisomers of 1,N2-propanodeoxyguanosine adducts (α- or γ-Acr-dG depending on the position of the OH group). However, in most cases γ-Acr-dG is the major adduct detected in rodent and human tissues and Acr-treated cells. Our LC-MS/MS analyses of seven human lung and liver tissues confirmed previous findings that γ-Acr-dG is the major isomer. The reasons for the apparent prevalence of γ-Acr-dG in vivo are unclear. To determine whether the reaction of Acr with cellular molecules alter isomer formation, the soluble fraction of BEAS-2B cell lysate was reacted with equimolar concentrations of Acr and dG in 100 mM sodium phosphate buffer (pH 7.4) at 37° C for 24 h. Acr-dG was detected and quantified via HPLC-UV. In reactions without cell lysate, α- and γ-Acr-dG were detected in approximately equivalent amounts; however, in the presence of cell lysate the amount of α-Acr-dG decreased compared to γ-Acr-dG in a concentration-dependent manner. Similar results were obtained in the reactions with amino acids, histones, and polyamines under the same conditions or with a Tris buffer instead of a phosphate buffer. Additionally, LC-MS/MS analysis of reactions of these compounds with calf thymus DNA rather than dG yielded similar results. These results suggest that amino compounds are needed for the selective formation of the γ isomer. To investigate the intermediate(s) involved, Acr was reacted with arginine in 100 mM sodium phosphate buffer (pH 7.4). Analyses by HPLC-UV show that an initial compound forms quickly, but decomposes over time to give rise to a stable compound. These compounds were collected separately and reacted with dG. While Acr-dG was not detected in reactions with the stable compound, the initial compound predominately gave rise to γ-Acr-dG. It is likely that a similar or related unstable intermediate formed between Acr and an amine-containing molecule is responsible for the formation of DNA adducts in vivo. (Supported by NCI grant CA043159.)
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 1694.
Abstract 1695: Mechanisms of cytotoxicity of diepoxybutane, epichlorohydrin, and (1-chloroethenyl) oxirane
Authors: Bartley Bethany L. , Silvestri Vanesa L. , Ng Christopher , Hirsch David C. , Millard Julie T. 
Published: February 2011

Abstract
The bifunctional alkylating agents are an important class of drugs for the treatment of cancer, psoriasis, and some anemias. These compounds are widely believed to exert their cytotoxic effects through reactions with biological nucleophiles, with DNA interstrand cross-links considered to be the most lethal lesions. Indeed, for many families of bifunctional alkylators, DNA interstrand cross-linking correlates with cytotoxicity. Moreover, apoptotic potential may play a role in antitumor chemotherapeutic utility. We have established previously that diepoxybutane (DEB) and the structurally related compounds epichlorohydrin (ECH) and 1-(chloroethenyl)oxirane (CEO) form DNA interstrand cross-links in vitro. With the goal of elucidating the molecular and cellular mechanisms by which this family of epoxides exerts its cytotoxic effects, we are determining the relationships between interstrand cross-linking, LD50 values, and apoptotic potentials for DEB, ECH, and CEO in chicken 6C2 and human HL-60 cells. Preliminary results in 6C2 cells suggest that cytotoxicity follows the order DEB &gt; CEO &gt; ECH. Furthermore, flow cytometry with Annexin V-FITC/PI dual staining has revealed that the apoptotic potentials follow the order DEB &gt;&gt; ECH &gt; CEO. Reverse-transcriptase real-time PCR analysis of HL-60 cells treated with DEB under conditions known to induce apoptosis suggests up-regulation of several key genes involved in the mitochondrial apoptotic pathway, including BAK1, BAX, DIABLO, and APAF1. Further work is underway to characterize the pathways by which ECH and CEO exert their apoptotic effects.
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 1695.
Abstract 1701: Elevated DNA adducts detected in human breast tumors than normal tissues from mammoplasty
Authors: Mungala Radha , Vadhanam Manicka , Chagpar Anees , Fleming Muffin , Fink Betsy , Gridley Mary , Vasconez Henry , Gupta Ramesh 
Published: February 2011

Abstract
Breast cancer is the most common cancer among women worldwide and the second leading cause of cancer-related death in women in the United States. The etiology of the majority of human breast cancers is unknown. Elevated levels of estrogen and exposure to environmental carcinogens have been suggested to be involved in human breast cancer development. Several studies have also provided evidence of the potential role of oxidative stress and lipid peroxidation in breast cancer etiology. Identification of DNA adducts and monitoring change in DNA adduct profiles/burden in normal and cancer tissue may provide clues for risk of breast cancer. In this study, we detected and compared the levels of a wide range of polar to lipophilic adducts in tumor (n= 23) and adjacent normal tissue (n= 30) from breast cancer patients with normal tissue (n=124) from mammoplasty using a 32P-postlabeling adductomics. Adducts were classified into polar (P-1, P-2a and P2b or 8-oxodG) and lipophilic (L-1) in descending order of their polarities. Our results indicated significantly elevated total DNA adduct levels in tumor and adjacent normal tissue of breast cancer patients compared to normal tissues from mammoplasty. The levels of most polar adducts (P-1) were not significantly different among the tumor, adjacent and normal breast tissue. However, relatively lesser polar adducts, i.e., P-2a, P-2b (8-oxodG) and L-1 adducts were significantly higher in tumor and adjacent normal tissues of breast cancer patients compared with normal tissues from mammoplasty. Thus, there is a clear trend of adduct accumulation in the breast tissues of cancer patients that could have acted as a precursor event in carcinogenesis process. Therefore, elevated oxidative DNA adducts such as 8-oxodG can be a possible biomarker for early detection of breast cancer risk and subjects with high DNA adduct load may potentially be at higher risk for cancer development, and could be stratified for chemopreventive intervention. (Supported from CA-90892 and Agnes Brown Duggan Endowment)
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 1701.
Abstract 1705: 14-3-3ζ is an androgen-regulated gene that activates the androgen receptor signaling and facilitates cell survival in prostate cancer
Authors: Murata Taro , Takayama Ken-ichi , Urano Tomohiko , Fujimura Tetsuya , Kumagai Jinpei , Horie-Inoue Kuniko , Ikeda Kazuhiro , Takahashi Satoru , Ouchi Yasuyoshi , Homma Yukio , Inoue Satoshi 
Published: February 2011

Abstract
The 14-3-3 proteins are a family of regulatory molecules that modulate the functions of their binding partners. They are involved in many processes including protein synthesis/degradation, cell cycle regulation, apoptosis, and tumor development. We have identified one of 14-3-3 protein isoforms 14-3-3zeta as a novel androgen target gene by chromatin immunoprecipitation (ChIP) coupled with microarray analysis. The expression of 14-3-3zeta was upregulated in LNCaP prostate cancer cells at both mRNA and protein levels by androgen stimulation. We generated LNCaP cells stably expressing 14-3-3zeta or control empty vector, and found that less etoposide-induced cell death was observed in 14-3-3zeta-expressing cells compared with control cells. Cell proliferation and motility were increased in 14-3-3zeta-expressing cells. Imunoprecipitation study showed that 14-3-3zeta binds to androgen receptor (AR) in these cells. Luciferase assay showed that androgen-dependent PSA promoter activity was significantly increased in 14-3-3ζ-expressing cells. Androgen-dependent PSA expression was also increased in 14-3-3ζ-expressing cells. siRNA-dependent 14-3-3zeta knockdown revealed that androgen-dependent AR transactivation was reduced in LNCaP cells. Taken together, the present study indicates that 14-3-3ζ is a bona-fide androgen-regulated gene that plays an important role in activating AR-dependent signaling, thereby promoting cell growth, motility and acquirement of apoptosis resistance in prostate 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 1705.
Abstract 1706: Impact of PARP1 on AR signaling and therapeutic response in prostate cancer
Authors: Schiewer Matthew J. , Goodwin Jonathan , Knudsen Karen E. 
Published: February 2011

Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) modifies various nuclear proteins by poly (ADP-ribose)-ylation, and has a known role in a multitude of chromatin-associated functions, including: transcriptional coregulation, modification of chromatin structure, regulation of insulators, and well-established activities in DNA repair. With regard to nuclear receptors, PARP1 promotes recruitment of topoisomerase IIβ (TopoIIβ) to estrogen-regulated promoters, leading to promoter DNA cleavage, factor exchange, and transcriptional activation. However, PARP1 function is known to be context dependent. Here, the impact of PARP1 on AR signaling was assessed under conditions of prostate cancer relevance. As will be discussed, key preliminary data strongly suggest that PARP1 function is critical for the pro-tumorigenic functions of AR. First, pharmacological inhibition of PARP1 enzymatic activity potently suppressed ligand-dependent AR transcriptional activity on target genes of clinical relevance. Second, the mechanism of PARP1-mediated AR regulation appears to be manifest at the level of chromatin, as inhibition of PARP1 failed to alter AR levels. This posit was assessed by chromatin immunoprecipitation assays to delineate the impact on AR signaling. Third, it was shown that suppression of PARP1 specifically inhibited AR-dependent prostate cancer cell proliferation in both early stage and late stage (castrate-resistant) models of disease. Lastly, it was observed that PARP1 inhibition cooperates with currently used genotoxic therapeutic modalities (IR and Docetaxel) in reducing cell survival, dependent on treatment scheduling.
In sum, our data identify PARP1 as a critical effector of AR activity at the level of chromatin, and suggest that abrogation of PARP1 function may cooperate with existing therapeutics to improve the response to therapeutic intervention.
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 1706.
Abstract 1707: Androgen responsiveness of the NKX3.1 gene is regulated by the proto-oncogene ETS1
Authors: Thomas Marc A. , Preece Darren M. , Bentel Jacqueline M. 
Published: February 2011

Abstract
Expression of the prostatic homeodomain protein NKX3.1 is androgen-regulated in both the normal prostate and in prostate cancer cells. Androgen responsiveness of NKX3.1 is mediated in part by the 3’ untranslated region (3'UTR) of the NKX3.1 gene, within which we have isolated 3 discrete regions of androgen-induced transcriptional regulatory activity including 2 androgen response elements (AREs). The proximal ∼2kb of the 5’ promoter of the NKX3.1 gene is incompletely characterised, however it is not androgen-responsive using conventional luciferase reporter assays. Investigation of the NKX3.1 proximal promoter has identified regulation of promoter activity by the ETS transcription factor, ETS1, which is mediated by an ETS binding site (EBS) located at −1008 relative to the NKX3.1 transcription start site. Overexpression of ETS1 in the LNCaP prostate cancer cell line results in upregulation of NKX3.1 protein levels, supporting a functional role of ETS1 in the regulation of NKX3.1 expression. ETS1 has been reported previously to transactivate the androgen receptor (AR) in a ligand-dependent manner on a subset of androgen-responsive promoters, suggesting cooperativity or co-regulation of AR and ETS1 signalling in prostate cancer cells. Treatment of LNCaP cells with 10−8M 5α-dihydrotestosterone (DHT) results in upregulation of endogenous ETS1 protein levels, while overexpression of exogenous ETS1 causes a concomitant increase in AR expression. A cooperative interaction between ETS1 and the AR on the NKX3.1 promoter is evident in LNCaP cells whereby overexpression of ETS1 is able to induce androgen responsiveness of the initial ∼2kb of the NKX3.1 promoter sequence and in particular the 76bp region surrounding the EBS. Reversal of DHT effects by the antiandrogen bicalutamide indicates an AR-mediated mechanism. ETS1 is overexpressed in a high proportion of prostate cancers with its expression aberrantly localised in the cytoplasm of a subset of prostate tumour cells. Findings of the present study support a complex mechanism of AR-mediated regulation of NKX3.1 expression via multiple regions of the NKX3.1 gene and modified by additional transcription factors in prostate cancer cells. Abnormal expression and/or function of these factors may contribute to the transcriptional deregulation of NKX3.1 expression and the downregulation of NKX3.1 protein levels that is frequently observed in advanced prostate tumours. Similarly, it is also feasible that upregulation of ETS1 contributes to the deregulation of AR signalling in advanced prostate cancers.
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 1707.
Abstract 1708: Telomerase as an important target of androgen-signaling blockade for prostate cancer treatment
Authors: Liu Shuang , Qi Yanfeng , Ge Yubin , Duplessis Tamika , Rowan Brian G. , Cheng Helen , Rennie Paul S. , Zhang Haitao , Dong Yan 
Published: February 2011

Abstract
As the mainstay treatment for advanced prostate cancer, androgen-deprivation therapy (ADT) targets the action of androgen receptor (AR) by reducing androgen level and/or by the administration of anti-androgen that competes with androgens for binding to AR. Albeit effective in extending survival, ADT is associated with dose-limiting toxicity and the development of castration-resistant prostate cancer (CRPC) after prolonged use. Since CRPC is generally lethal and incurable, developing effective strategies to enhance the efficacy of ADT and circumvent resistance becomes an urgent task. Continuous AR signaling constitutes one major mechanism underlying the development of CRPC. The present study showed that methylseleninic acid (MSA), an agent that effectively reduces AR abundance, could enhance the cancer-killing efficacy of the anti-androgen bicalutamide in both androgen-dependent and castration-resistant prostate cancer cells. We found that combination of MSA and bicalutamide produced a robust downregulation of prostate-specific antigen and a recently identified AR target, telomerase and its catalytic subunit, telomere reverse transcriptase (hTERT). The downregulation of hTERT occurs mainly at the transcriptional level, through reducing AR occupancy of the hTERT promoter. Furthermore, apoptosis induction by the two agents is significantly mitigated by restoration of hTERT. Our findings thus indicate that MSA in combination with anti-androgen could represent a viable approach to improve the therapeutic outcome of ADT. Given the critical role of hTERT/telomerase downregulation in mediating the combination effect and the fact that hTERT/telomerase could be measured in blood and urine, hTERT/telomerase could serve as an ideal tumor-specific biomarker to monitor the efficacy of the combination therapy non-invasively. (Supported by the Department of Defense Prostate Cancer Training grant No. W81XWH-08-1-0291 (SL); the National Cancer Institute grant No. K01 CA114252 (YD); the American Cancer Society grant No. RSG-07-218-01-TBE (YD))
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 1708.
Abstract 1709: Activation of androgen signaling axis by NF-kappaB2/p52
Authors: Nadiminty Nagalakshmi , Lou Wei , Gao Allen C. 
Published: February 2011

Abstract
INTRODUCTION: Castration-resistant progression of prostate cancer occurs in &gt;80% of patients after failure of hormonal therapy but the underlying mechanisms are incompletely understood. Emerging evidence implies that ligand-independent activation of the androgen receptor (AR) is of critical importance during this process. Our previous studies show that the levels of NF-κB2/p52 are elevated in prostate cancer cells and that active NF-κB2/p52 promotes prostate cancer cell growth in vitro and in vivo. In this study, we examined the role of NF-κB2/p52 in the aberrant activation of the AR during castration resistant progression, in contrast to the interaction between the AR and RelA/p65.
METHODS: The effects of NF-κB2/p52 on cell survival, growth and androgen responsiveness were examined in prostate cancer cells. Modulation of LNCaP tumor growth by p52 was examined in intact and castrated male nude mice. Effect of p52 or p65 on AR activation was examined using luciferase assays, EMSA, ChIP assays and ELISA.
RESULTS: Expression of NF-κB2/p52 enhanced androgen-sensitive LNCaP human CaP cell growth and clonogenic ability in androgen-deprived conditions in vitro. LNCaP cells expressing p52 exhibited protection from apoptotic cell death and cell cycle arrest induced by androgen-deprivation. Adenoviral mediated p52 expression in LNCaP cells induced tumor growth in castrated male nude mice. NF-κB/p52 induced the activation of the AR resulting in increased transactivation of AR-responsive genes such as PSA and NKX3.1 in a ligand-independent manner. NF-κB2/p52 enhanced nuclear translocation and transactivation of AR by interacting with its N-terminal domain and enhanced the recruitment of co-activators like p300 to the promoters of AR-dependent genes. These results were confirmed in 3 different prostate cancer cell lines: LAPC-4 (wild type AR), LNCaP (mutant AR) and C4-2 (androgen-insensitive). Transfection of p52 into LAPC-4 and LNCaP cells (which express low levels of p52) showed increased activation of the endogenous AR. Downregulation of endogenous p52 in C4-2 cells resulted in abrogation of AR constitutive activation. In contrast, we observed that p65 exhibited transcriptional repression of the AR, and did not induce expression of AR-responsive genes, PSA and NKX3.1.
CONCLUSIONS: These findings demonstrate that overexpression of NF-κB2/p52 induces castration-resistant growth and aberrant activation of the AR in LNCaP cells. NF-κB2/p52 may promote castration resistant progression by activating the AR under conditions of androgen deprivation.
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 1709.
Abstract 1716: BRCA1 expression modulates apoptosis and survival in response to retinoic acid in breast cancer cells
Authors: Pickholtz Itay , Papa Moshe Z. , Yarden Ronit I. 
Published: February 2011

Abstract
The vitamin A metabolite retinoic acid (RA) plays key roles in development, cell proliferation and differentiation. RA derivatives also display anti-cancinogenic activities. The different physiological effects of RA are mediated by retinoic acid receptors (RARs) and retinoid-X receptos (RXRs) that are transcription factors and members of the nuclear hormone receptor superfamily. Transcriptional activation by RA trigger cell cycle arrest, differentiation and apoptosis in certain tissues and cell types but in other tissues RA appear to promote rather than inhibit cell survival.
Recently, RA derivatives were shown to bind and activate the orphan nuclear hormone receptor, peroxisome proliferator-activated β/δ (PPARβ/δ) when it hetrodimerizes with RXR. The partitioning of RA between the RAR and PPARβ/δ receptors is regulated by the balance between two intracellular lipid binding proteins: cellular retinoic acid binding protein II (CRABPII) and fatty acid binding protein 5 (FABP5). While CRABP-II delivers RA to RAR-RXR and facilitates anti-proliferative effects, FABP5 shuttles RA to PPARβ/δ-RXR and promotes pro-survival functions.
Interestingly, the breast and ovarian tumor suppressor, BRCA1 and RA share the ability to direct cell-cycle arrest and apoptosis, and both BRCA1 and RA regulate transcription and chromatin structure. We hypothesize that BRCA1 and RA pathways work in concert to inhibit cell growth in breast cancer cells. We found that the inhibitory effects of all-trans RA (ATRA) and 9-cisRA correlate with BRCA1 expression. Both RA derivatives inhibited BRCA1-proficient MCF7 breast cancer cells growth by inducing apoptosis. ATRA and 9-cisRA did not inhibit the growth of BRCA1-null or BRCA1-silenced breast cancer cells despite similar levels of RA receptors (RAR and RXR) expression. We show here that in BRCA1-proficient cells, the FABP5/CRABP-II ratio is constant facilitating apoptotic cell death, while in BRCA1-deficient cells FABP5/CRABP-II ratio is elevated, and coincides with increased phosphorylation of the pro-survival factor, AKT, supporting RA-mediated cell survival. Additional apoptotic and cell cycle genes were differentially regulated between BRCA1-deficient and proficient cells in response to RA. However, RA-induction of the metabolic enzyme CYP26 gene expression was not altered between BRCA1-deficient and proficient cells, suggesting the cooperation between RA and BRCA1 is affecting cell proliferation but not necessarily all spectrum of RA signaling.
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 1716.