bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-241: Targeting cancer cells and anti-tumor effects of brucine immuno-nanoparticles on hepatocellular carcinoma in vivo
Authors: Qin Jianmin 
Published: August 2012

Abstract
BACKGROUND and AIMS: In vitro and in vivo studies have showed that brucine can inhibit the growth of liver cancer cells and animals with bearing cancer, and may be a promising anti-cancer drugs. However, high toxicity, poor water solubility, short half-life, narrow therapeutic window, close therapeutic and toxic dose limit its clinical application in malignant tumor treatment. In this study, we report on the preparation, in vivo disrtibution and anti-tumor effect of the brucine immuno-nanoparticles. METHODS: Anionic polymerization and chemical modification technology was used to prepare carboxylated polyethylene glycol-poly lactic acid copolymer carrier material, phacoemulsification technology was employed to prepare carboxylated polyethylene glycol-polylactic acid copolymer brucine nanoparticles and chemical coupling technology was utilized to develop anti-human AFP McAb-polyethylene glycol-poly lactic acid copolymer brucine immuno-nanoparticles. The nude mice in situ transplanted liver cancer model was established by surgical technique, and the brucine immuno-nanoparcitles was injected by caudal vein at indicated time. The liver and kidney function and AFP level were assayed, and the anti-tumor effect was observed after intravenous administration of the brucine immuno-nanoparticles.RESULTS: This results showed that in vivo application of brucine immuno-nanoparticles caused temporary liver and kidney functions damage and significantly reduced AFP secretion. Brucine immuno-nanoparticles had good slow releasing and tumor targeting properties. The brucine immuno-nanoparticles inhibited CD34 expression and angiogenesis of tumor tissues, induced tumor apoptosis, and inhibited tumor growth. CONCLUSIONS: The brucine immuno-nanoparticles has good tumor targeting and obvious anti-tumor effects, and is a promising targeted drug for liver cancer therapy in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-241. doi:1538-7445.AM2012-LB-241
Abstract LB-245: Investigating the role of BRCA1 in sensitivity to GRN163L, a telomerase template antagonist
Authors: Phipps Elizabeth A. , Gryaznov Sergei , Herbert Brittney-Shea 
Published: August 2012

Abstract
BRCA1 is a tumor suppressor gene with a variety of functions related to safeguarding genomic integrity. Regulation of telomere length is crucial in maintaining genomic stability, with critically short telomeres leading to telomere uncapping, end-to-end fusions, activation of the DNA damage response, and cell cycle arrest. Recent evidence suggests knockdown of BRCA1 in cell lines increases both telomerase activity and average telomere length, but likely results in more unstable telomeres compared to BRCA1 wild-type cell lines. The objective of this study was to determine whether GRN163L, a telomerase template antagonist currently in clinical trials, has enhanced activity in BRCA1 mutant breast or ovarian cancer cell lines compared to paired BRCA1 wild-type breast/ovarian cancer cell lines. In addition, we sought to determine whether BRCA1 cell lines have shorter average telomere lengths than other cancer cell lines, making them more amenable to inhibition of telomerase activity. We utilized a panel of breast and ovarian cancer cell lines harboring both N-terminal and C-terminal BRCA1 mutations, in addition to matched cells expressing exogenous wild-type BRCA1, and assessed the effects of GRN163L or a mismatch oligonucleotide on telomerase activity and telomere length using the TRAP (Telomere Repeat Amplification Protocol) and TeloTAGGG assays, respectively. All cell lines tested exhibited a dose-dependent response to treatment with GRN163L, but not a mismatch control oligonucleotide. In addition, we observed differential sensitivity between BRCA1 mutant and BRCA1 wild-type cell lines tested to clinically relevant concentrations of GRN163L in both TRAP and clonogenic survival assays. Of interest, the majority of the cell lines tested showed gross morphological changes as early as 12 hours following inhibitor treatment. We found UWB1.289 cells have a shorter average telomere length at baseline compared to their BRCA1 wild-type counterpart cells, and saw progressive telomere shortening over a three-week period of treatment with GRN163L, but not with mismatch oligonucleotide. Furthermore, long-term (12 week) treatment with GRN163L preferentially induced complete cell death in the HCC1937 (BRCA1 mutant) breast cancer cell population compared to the HCC1937 cells reconstituted with wild-type BRCA1. Finally, we demonstrate that pretreatment with GRN163L acts synergistically with cis-platin in UWB1.289 and UWB1.289+BRCA1 ovarian cancer cells. In summary, this work provides insight into the role of BRCA1 mutations in cancer cells and their impact on sensitivity to the cellular effects of telomerase antagonism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-245. doi:1538-7445.AM2012-LB-245
Abstract LB-246: Epithelial-mesenchymal transition (EMT) does not necessarily decrease the sensitivity of cancer cells to chemotherapeutic agents
Authors: Mezencev Roman , Jabbari Neda , McDonald John F. 
Published: August 2012

Abstract
Epithelial to mesenchymal transition (EMT) has been recently associated with metastatic competence and therapy resistance of cancer cells and the need for development of EMT-targeted therapies has been emphasized. In this report we address the differential responses of breast cancer cell lines with epithelial and mesenchymal phenotypes to anticancer agents using pharmacoinformatics and experimental approaches. First, we identified breast cancer cell lines with epithelial-like and mesenchymal-like phenotypes among the National Cancer Institute (NCI) panel of 60 cell lines and analyzed their differential responses to 10,081 anticancer agents. Second, we evaluated chemotherapeutic response of a mesenchymal-like isogenic breast cancer cell line (MCF-7-Snail) stably transfected to express the EMT-inducing Snail transcription factor and its epithelial-like precursor cell line transfected with the control plasmid (MCF-7-neo). The results of both approaches are inconsistent with the claim that mesenchymal-like cancer cells are generally more resistant to anticancer agents. We found that most of the 10,081 agents examined did not display significantly different potencies between epithelial-like and mesenchymal-like cells. Of the 10,081 anti-cancer agents examined, only 78 displayed consistent differences in effect between epithelial-like and mesenchymal-like cells and all of these agents displayed a more potent effect against mesenchymal-like cell lines. MCF-7-Snail cells were found to be more sensitive to the cytotoxic effects of doxorubicin, 5-FU and methotrexate, while MCF-7-neo cells were more sensitive to gemcitabine and docetaxel and both of these isogenic cell lines were equally responsive to mitomycin C and vincristine. The relatively lower sensitivity of MCF-Snail cells to docetaxel and gemcitabine can be explained by their overexpression of TUBB4 and RRM1, respectively, as demonstrated by gene expression analysis (U133 Plus 2.0 Affymetrix microarrays). In contrast, the higher sensitivity of MCF-7-Snail cells to 5-FU may be due to the down-regulation of the DPYD gene in these cells. Compared to isogenic epithelial cells, MCF-7-Snail cells display down-regulation of the anti-apoptotic genes XIAP, BCL2L1 and NAIP. Collectively, our results indicate that EMT per se does not generally result in a greater resistance of cancer cells to chemotherapeutic agents, but it may, in some instances, result in increased sensitivity of cancer cells to specific chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-246. doi:1538-7445.AM2012-LB-246
Abstract LB-25: Activation of AMPK by ATM in reponse to AICAR and metformin
Authors: Yang Da-Qing , Cleary Margot P. 
Published: August 2012

Abstract
AMPK is an AMP-activated protein kinase that plays a key role in regulating cellular energy homeostasis. Metabolic stress, such as heat shock and glucose starvation, causes energy deficiency in the cell and leads to elevated levels of intracellular AMP. This results in the phosphorylation and activation of AMPK. LKB1, a tumor suppressor, has been known as an upstream kinase of AMPK. We found that in response to treatment with 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside (AICAR), a LKB1-null cancer cell line, HeLa, still exhibited AMPK phosphorylation. This indicates the existence of an LKB1-independent AMPK protein kinase. ATM is a protein kinase that is deficient in the disease ataxia telangiectasia (A-T). We measured the activation of AMPK by AICAR in the normal mouse embryo fibroblast (MEF) cell line, A29, and the MEF cell line lacking the ATM protein, A38. In A38 cells, the level of AICAR-induced AMPK phosphorylation was dramatically lower than that found in A29 cells. Furthermore, phosphorylation of AMPK in HeLa and A29 cells was inhibited by an ATM specific inhibitor, KU-55933. Our results demonstrate that AICAR treatment could lead to phosphorylation of AMPK in an ATM-dependent and LKB1-independent manner. Similar to the results of AICAR treatment, our work also revealed that the metformin-induced phosphorylation of AMPK in A38 cells is significantly lower than that in A29 cells. We also examined the effect of ATM on AMPK in rat hepatoma cell line H4IIE. Inhibition of ATM by KU-55933 dramatically reduced the phosphorylation of AMPK in response to metformin in this cell line. Thus, ATM may act as a potential AMPK kinase in response to both AICAR and metformin treatment. Metformin is the most commonly prescribed pharmaceutical drug for type 2 diabetes (T2D). In addition, patients with T2D or obesity/insulin resistance who take metformin have reduced rates of cancer occurrence, including breast cancer. However, the mechanism underlying metformin's effect on cancer prevention and/or treatment is unclear (Nature, New & views, Feb. 2011; Science, News Focus, Jan. 2012). While ATM acts as a sensor of DNA damage by controlling cell cycle progression, it also has glucose regulatory function. Our results put ATM as a novel player in the AMPK signaling pathway in response to metformin. These findings provide new insights into the mechanisms by which metformin functions as a preventive and/or therapeutic agent for cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-25. doi:1538-7445.AM2012-LB-25
Abstract LB-261: A novel notch-AKT-NF-KB axis in triple negative breast cancer cells
Authors: Backus Kandis V. , Peng Y , Hicks C , Kumar S , Kundu G , Pannuti A , Miele L 
Published: August 2012

Abstract
BACKGROUND: Basal-like and claudin-low are two major subgroups of triple-negative breast cancers (TNBC). The clinical subtype claudin-low is represented by MDA-MB 231 cells. The Notch and NF-κB signaling pathways are known to regulate proliferation, differentiation, and apoptosis by regulating the transcription of target genes. Both pathways are commonly active in TNBC. There is strong evidence for cross-talk between these pathways: We previously published that in cervical cancer cells, Notch-1 can activate NF-kB through nuclear IKKα. We published that Notch-1 can activate the estrogen receptor alpha (ERα), also through nuclear IKKα and the IKK signalosome in T-LL cells. However, the mechanism(s) of IKK downstream of Notch remain unknown. Notch1 is highly expressed in TNBC, and Notch ligands Jagged1 and 2 correlate with poor prognosis. IKKα (CHUK) is expressed in all subtypes of TNBC. We investigated whether Notch-1 can activate NF-kB in TNBC cells of claudin-low and basal like subtypes, whether this requires IKKα and how IKKα is activated. METHODS: We used Retroviral RNAi transduction of MDA-MB231 cells to establish Notch1 siRNA. ChIP (chromatin Immunoprecipitation), CoIP (co-immunoprecipitation), Western blot, luciferase reporter assays, co-culture MDA-MB 231 cells with LTK-JAG mouse fibroblasts, qPCR, xenograft tumors in nude mice. RESULTS: We have determined that phosphorylation of Akt is mediated through a non-canonical Notch signaling pathway and this is dependent on PTEN status. Unlike the canonical Notch pathway, Notch activation by Jagged1-expressing stroma cells leads to phosphorylation of Akt within minutes of contact between Jagged1-expressing stroma cells in PTEN wt, MDA-MB 231 cells through a non-transcriptional mechanism. Our data suggest that Notch complexes with PI3K subunits, p85 and p110, after ligand-mediated activation. Inhibition of Notch activity through GSIs (γ-secretase inhibitors) leads to decreased phosphorylation of Akt. Dominant-negative AKT abolishes IKKα phosphorylation. Additionally, the combination of the AKT inhibitor, perifosine and gamma-secretase inhibitor MRK-003 is synergistic in vitro and highly active in MDA-MB231 xenografts. CONCLUSIONS: Our findings suggest a novel non-canonical cross-talk mechanism including Jagged, Notch, AKT and IKKα connecting three major oncogenic pathways in TNBC: Notch, AKT and NF-kB. Moreover, our findings suggest that Akt inhibitors may be combined with GSI for therapeutic purposes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-261. doi:1538-7445.AM2012-LB-261
Abstract LB-266: Expression of AGR2 in lung cancer cells needs an active Hippo pathway co-activator, YAP1
Authors: Dong Aiwen , Tun May , Wodziak Dariusz , Gupta Aparna , Lowe Anson 
Published: August 2012

Abstract
Background/Objective: We have previously established that Anterior Gradient-2 (AGR2) affects cancer cell growth by activating YAP1 of the Hippo pathway and inducing AREG of the EGF pathway. Although significant advances have been made concerning the growth promoting effects of AGR2 on cancer cells, including those derived from the pancreas, lung and esophagus, little is known about how AGR2 expression is regulated. Because of AGR2's potential role in human cancer and its established role in organ development in lower vertebrates, we explored the mechanisms responsible for its expression. Methods: ShRNA mediated specific knockdown of YAP1 was conducted in H460 human lung cancer cells. Quantitative real-time PCR was performed to confirm the knockdown efficiency. The expression of AGR2, AREG, and the YAP1-induced genes CTGF, CYR61, COL8A1 was assayed by quantitative real time PCR after YAP1knockdown. The effect of YAP1 knockdown on AGR2 protein was evaluated by immunoblotting. Finally, an AGR2 expression reporter based on the firefly luciferase gene was employed to evaluate whether YAP1 acts on AGR2 promoter activity. Results: Reduced YAP1 expression by lentivirus mediated shRNAmir transduction was further confirmed by western blotting and was also supported by the decrease of YAP1 readouts, such as CTGF. A 95% knockdown of YAP1 expression in H460 cells resulted in a significant morphological change and a 275-fold decrease in AGR2 mRNA. As demonstrated in previously published work, AREG expression was also decreased by 40-fold. Western blots showed that in YAP1 knockdown cells (YAP1KD), there was only negligible levels of AGR2 protein. The data suggested that active YAP1 protein is required for AGR2 expression. The decrease of AGR2 mRNA expression by YAP1KD could be transcriptional or posttranscriptional. To address this question, an AGR2 promoter assay to answer whether YAP1 affects AGR2 transcription. Our AGR2 reporter assay showed that there was more than 5 times more luciferase activity in YAP1KD cells compared to cells infected with the control lentivirus not targeting to any known gene, suggesting that AGR2 expression is regulated in a post-transcriptional manner. Conclusion: YAP1 decreases AGR2 mRNA through a post-transcriptional mechanism, which may include microRNAs. There are four potential miRNA binding sites in the 3-UTR region of AGR2 transcripts. Future experiments will explore if any of these miRNAs are induced upon YAP1 knockdown. This work provides insight into the crosstalk between YAP1 and AGR2, which may have significant implications in lung cancer carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-266. doi:1538-7445.AM2012-LB-266
Abstract LB-273: Transcriptional regulation by androgen receptor in prostate cancer
Authors: Zhao Jonathan , Runkle Christine , Wu Longtao , Jin Hong-Jian , Yu Jindan 
Published: August 2012

Abstract
Transcriptional regulation by the androgen receptor (AR) is critical to prostate cancer development and progression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, we have recently reported AR as a globally acting transcriptional repressor. This repression is mediated by androgen responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In addition, AR-repressed genes are enriched for developmental regulators controlling cell differentiation. They tend to get down-regulated in advanced prostate cancer probably accountable for stem cell-like de-differentiation and thus tumor progression. However, critical AR-repressed genes of functional relevance are yet to be identified and their roles to be carefully characterized. Through meta-analysis of several expression microarray data, we nominate one top candidate AR-repressed gene. Using this gene as a model, we present further evidence that AR directly inhibits gene expression through physically binding to the enhancer, establishing promoter-enhancer DNA looping, and inducing repressive chromatin remodeling. Further, overexpression of this gene inhibits prostate cancer cell growth, migration, and invasion in vitro and xenograft tumor growth in mice, thus exhibiting a tumor suppressive role. In addition, the loss of this gene drives castration-resistant prostate cancer. Therefore, our findings support that AR-mediated inhibition of tumor suppressors plays important roles during prostate cancer progression. Our study provides an innovative mechanism for AR in castration resistance, which may eventually lead to novel therapeutic targets for treatment of advanced prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-273. doi:1538-7445.AM2012-LB-273
Abstract LB-274: Mutant p53 cooperates with ETS2 to promote etoposide resistance
Authors: Martinez Luis A. , Do Phi M. , Varanasi Lakshman 
Published: August 2012

Abstract
Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms including disabling pro-apoptotic proteins and by regulating gene expression. Analysis of promoter regions identified through CHIP-on-CHIP and CHIP-seq platforms reveal that the ETS motif (EBS) is prevalent within predicted mtp53 binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters, and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5′-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53 expressing cells to etoposide, and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially “druggable” component of mtp53's gain-of-function activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-274. doi:1538-7445.AM2012-LB-274
Abstract LB-278: MicroRNA control of GNA13 expression and cancer cell invasion
Authors: Rasheed Suhail Ahmed Kabeer , Teo Cui Rong , Beillard Emmanuel , Voorhoeve P. Mathijs , Casey Patrick 
Published: August 2012

Abstract
Heterotrimeric guanine nucleotide binding proteins (G proteins) transmit a variety of extracellular signals from cell surface G protein-coupled receptors (GPCRs) to intracellular effector molecules. Heterotrimeric G proteins are classified according to the α subunit into four subfamilies: Gs, Gi, Gq, and G12. The G12 subfamily, which is comprised of two members, Gα12 (GNA12) and Gα13 (GNA13), has been implicated in cancer cell invasion and metastasis. G12 signaling promotes prostate, breast and ovarian cancer cell invasion in vitro, and these proteins are highly expressed in metastatic cancer tissues. As part of a program to elucidate the mechanisms by which GNA12 and GNA13 expression is upregulated in cancer cells, we assessed the potential involvement of micro-RNAs (miRNAs) in post-transcriptional control of GNA13 expression. The initial focus was on prostate cancer; LnCAP (with the lowest GNA13 protein level) and PC3 (with the highest GNA13 level) were employed as the model system. Expression analysis of miRNAs predicted to bind the 3′UTR of GNA13 revealed that miR-182 and miR-141/200a showed an inverse correlation to the protein expression in LnCAP and PC3 cells. Ectopic expression of miR-182 and miR-141/200a in PC3 cells significantly reduced mRNA and protein levels, as well as GNA13 3′UTR- reporter activity. Further, expression of these miRNAs significantly inhibited PC3 cell invasion in an in vitro matrigel invasion assay, and this effect was blocked by overexpression of GNA13 in these cells. Importantly, inhibition of miR-182 and miR-141/200a in LnCAP cells using specific miRNA inhibitors (anti-miRs) elevated the expression of GNA13 and enhanced the basal invasion of these cells. These data provide strong evidence that GNA13 expression is regulated by post-transcriptional mechanisms involving miR-182 and miR-200 family members. Further studies are being performed to identify the role of these miRNAs in cancer progression and to determine the importance of impact on GNA13 expression as an important mediator of this effect.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-278. doi:1538-7445.AM2012-LB-278