bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1042: Diminished caspase 8 and c-Myc protein expression in human fibroblasts provides insight into normal cell resistance to TRAIL-mediated apoptosis
Authors: Crowder Roslyn N. , Dicker David T. , El-Deiry Wafik S. 
Published: February 2011

Abstract
TNF-related apoptosis-inducing ligand (TRAIL)-mediated cell death is currently being exploited in clinical trials for cancer therapy. However, the molecular basis of normal cell resistance to TRAIL-mediated apoptosis, and thus therapeutic index, remains largely unexplored. We found that normal HFF and WI38 fibroblasts expressed slightly lower levels of TRAIL receptor DR5 as compared to human lung and colon cancer cells. While normal and cancer cells showed comparable DcR2 expression, the WI38 and HFF expressed little DR4 and DcR1. Normal fibroblasts were examined for increased expression of proteins known to inhibit TRAIL-mediated cell death. Anti-apoptotic Bcl-xL and Mcl-1 expression in WI38 and HFF was comparable to expression found in cancer cells, while no XIAP expression was detected in the normal fibroblasts. c-Myc, a major determinant of TRAIL sensitivity in cancer cells, was found to be decreased in the normal fibroblasts and thus may be a contributing factor to their escape from TRAIL-induced cell death. NF-κB activation was assessed after 4 hours of TRAIL exposure, but minimal IκB degradation was observed in the normal fibroblasts, suggesting their resistance to TRAIL may not be mediated through induction of pro-survival factors by NFkB. Expression and activation of initiator caspases, required for complete TRAIL signaling, was investigated and although its levels were elevated, no caspase 10 activation was observed in normal WI38 and HFF cells after TRAIL treatment. Extremely low caspase 8 protein expression was detected in the normal human fibroblast lines, at levels barely detectable as compared to tumor cells that generally show robust caspase 8 expression. Reduced caspase 8 expression may be considered as another contributing factor to the resistance of normal cells to TRAIL. Expression and activation of effector caspase 3 was also examined. After TRAIL stimulation, expression of full length caspase 3 declined in normal and tumor cells. However, cleavage of caspase 3 substrate, PARP, was only seen in cancer cells. Our current studies are focused on further analysis of mediators of cell death signaling by TRAIL, whether treatment of normal fibroblasts with proteasome inhibitors, histone deacetylase inhibitors, and/or DNA methylation inhibitors might result in increased caspase 8 protein expression and susceptibility to TRAIL-mediated apoptosis. We are further investigating the effects of serum and growth factors to drive cell proliferation of normal cells on c-Myc expression and TRAIL sensitivity.
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 1042.
Abstract 1045: Enhancement of drug-induced apoptotic cell death in human hepatocellular carcinoma cells with knock-down of BNIP3
Authors: Yau Pak Lun , Tsang Tsun Yee , Co Ngai Na , Choi Siu Cheong , Yeung Chi Lam Au , Kwok Tim Tak 
Published: February 2011

Abstract
Although BNIP3 is known for its pro-apoptotic function by forming dimer to help the release of cytochrome c in apoptosis, its role in the cell death pathways was not yet well-defined. To investigate the role of BNIP3 in drug-induced apoptosis, stable transfectants were established from human hepatocarcinoma HepG2 cells transfected with pSilencer inserted with scramble oligos or BNIP3 siRNA. By MTT assay, knock-down of BNIP3 in HepG2 stable transfectant decreased cell survival towards vincristine, Taxol and doxorubicin. By DNA fragmentation assay and Annexin V binding assay, the level of drug-induced apoptosis in BNIP3i cells was elevated as compared with the control cells. Further analyses on caspases activation and mitochondrial cytochrome c release were done by Western blot analysis while the mitochondrial membrane depolarization was monitored by flow cytometry of JC-1 dye staining. By comparing with the control cells, the presence of vincristine or Taxol induced less cytochrome c release, mitochondrial membrane depolarization and activation of caspases-3, −8 and −9 in HepG2 BNIP3i cells. The results from present study indicated that BNIP3 might induce apoptosis by therapeutic drugs in HepG2 cells through a non-classical apoptotic pathway.
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 1045.
Abstract 1048: Homogenous, bioluminescent and HTS formatted assay for quantization of ADP production in kinase and ATPase reactions
Authors: Goueli Said , Hsiao Kevin , Zdanovoskaia Marina , Vidugiriene Jolanta , Zegzouti Hicham 
Published: February 2011

Abstract
Because of its versatility (all types of substrates), robustness (Z’&gt;0.8), rapid performance, and its ease of use, the luminescence based Kinase GloTM assays platform have gained wide acceptance in many drug screening programs for protein kinase inhibitors. We have attempted to extend our strategy by now monitoring ADP product formation in the kinase reaction. The new assay we developed (ADP Glo) maintains all the positive features of Kinase GloTM such as universality, and applicability to all kinds of kinase substrates regardless of their nature with no prior modification (peptides, protein, polymer, lipids, and sugars) but In stead of measuring ATP depletion, it monitors ADP production. It detects ADP at early stages of enzyme reactions with very high signal to background (SB) ratio. It can be run at a wide range of ATP concentrations (low micromolar to millimolar), is sensitive to low ADP concentrations (0.1 pmol), and it can be carried out in high density plate formats. This assay is robust and homogenous, and does not require antibodies or custom synthesized substrates. It is ideal to search for optimal substrates in a collection of peptides, proteins, or lipids in a single assay format, and to screen for ATP competitive and Non competitive inhibitors. Because of the high dynamic range and more importantly, the high SB values even at low % ATP to ADP conversion, the assay allows the use of low amounts of enzyme during high-throughput screening. Evaluation of this assay in a screen of a large chemical library showed minimal false hits attesting to the quality of this system. The ADP-GloTM assay is applicable to all types of kinases, ATPases, multidrug resistant proteins such as MDR1-Pgp, helicases, topoisomerases, and heat shock proteins and as well as many other ADP producing enzyme reactions.
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 1048.
Abstract 1049: Akt1 and Akt2 are associated with poor outcome in glioblastoma multiforme
Authors: Joy Anna M. , Smirnov Ivan , Nakada Mitsutoshi , Feuerstein Burt G. 
Published: February 2011

Abstract
The Akt pathway is implicated in progression of astrocytic tumors. To refine the Akt pathway as a therapeutic target in glioblastoma multiforme (GBM) we determined activated Akt isoform(s) that mediate cellular behavior, and are associated with clinical parameters. Akt1 and Akt2 message is associated with worse clinical outcome while Akt3v1 message is associated with better clinical outcome. Silencing individual isoforms with shRNA gives different phenotypes. Bioinformatic analysis indicates that PI3K/Akt pathway components cluster with individual Akt isoforms and with tumor subtype suggesting that different arms of the PI3K/Akt pathway are associated with individual isoforms. Taken together, the data indicate that Akt3 function differs from Akt1 and 2 function, and support a role for Akt1 and 2 in the malignant behavior of glioma cells. Selective inhibition of Akt1 and/or 2, or their downstream effectors may be more effective and less toxic than general inhibition of Akt or PI3K. Supported by the Barrow Neurological Foundation (AJ and BGF).
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 1049.
Abstract 1050: CD109 expression promotes cell activity and enhances EGF signaling in human glioblastoma cells
Authors: Murakumo Yoshiki , Zhang Jing-min , Takahashi Masahide 
Published: February 2011

Abstract
CD109 is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein whose expression is predominantly detected in squamous cell carcinomas of esophagus, lung, uterus and oral cavity. In the previous study, we found CD109 expression in cell lines derived from human glioblastomas by Northern blot analysis, however, the role of CD109 expression in glioblastoma cells is unclear. Here, we describe our study on significance of CD109 expression in biology of human glioblastoma cells. CD109-overexpressing glioblastoma cells exhibit upregulation of cell growth, motility and invasion ability compared with control cells. Evaluation of intracellular signaling status revealed that the CD109-overexpressing cells showed enhanced phosphorylation of ERK, AKT, and p38MAPK. After epidermal growth factor (EGF) stimulation, strong and sustained phosphorylation of these molecules and EGF receptor (EGFR) was observed in the CD109-overexpressing cells. In addition, we found an interaction between CD109 and EGFR and colocalization of these molecules without EGF stimulation. However, the interaction and colocalization were abolished after EGF stimulation, and EGFR internalization was not affected by CD109 overexpression. These findings suggest that CD109 facilitates EGF signaling via binding to EGFR and its expression is associated with the malignant behavior of glioblastoma cells.
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 1050.
Abstract 1058: E-cadherin mutations contribute to gastric carcinogenesis by modulating multiple EGFR-dependent downstream signaling pathways
Authors: Heindl Stefan , Lang Christina , Böllner Claudia , Malinowsky Katharina , Becker Karl- Friedrich , Luber Birgit 
Published: February 2011

Abstract
Mutations in the gene encoding the cell adhesion molecule E-cadherin and overexpression of the epidermal growth factor receptor (EGFR) represent fundamental genetic alterations associated with diffuse-type gastric cancer. Mutations, e.g. in frame deletion of exon 8 (del 8), lead to loss of putative extracellular Ca2+-binding sites of E-cadherin, thereby impairing its functionality. Several studies have shown a bidirectional crosstalk between E-cadherin and EGFR. Functional wild-type (wt) E-cadherin inhibits ligand-induced EGFR activation, but mutations lead to a loss of its suppressive function, resulting in increased EGFR activation and recruitment of downstream signalling components. The phenotype of cells harboring such mutations is characterized by increased proliferation and elevated migratory and invasive potential.
Our project aims at studying the impact of somatic mutations of E-cadherin on EGFR-mediated signalling pathways, in order to identify signalling molecules of these pathways as molecular targets for selective therapies in gastric cancer.
Cell lines expressing wt or mutant E-cadherin (del 8) were EGF-stimulated and cellular lysates were analyzed by commercial proteome profiler antibody array (R&D Systems). The array allowed detection of the phosphorylation status of 48 signalling molecules and facilitated identification of differential activation. We found differential response to EGF stimulation of proteins involved in DNA damage and repair, such as p53 and CHK2, in both cell lines. As both proteins are tumorsuppressors, their dysfunction could contribute to tumor progression. Furthermore, Src-family kinases (SFKs) like Src, Yes, Fgr, Lck and Lyn exhibited different activation profiles in response to EGF-stimulation in both cell lines. As SFKs are key players in multiple cellular processes like cell growth, differentiation, cellular adhesion, migration and invasion, the impact of their differential activation on the cellular phenotype is subject of ongoing experiments. To determine the role of the identified targets in gastric carcinogenesis and the mechanisms of crosstalk between E-cadherin and EGFR a protein microarray platform was established, allowing analysis of multiple samples under the same experimental conditions. This approach will reveal new insights in EGFR-mediated signalling pathways contributing to gastric carcinogenesis and complete our data describing how tumor associated mutations of E-cadherin affect cellular signalling.
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 1058.
Abstract 1059: Neuroendocrine-derived peptides stimulate IGF-1R signaling to promote prostate cancer cell survival
Authors: DaSilva John O. , Amorino George P. , Casarez Eli V. , Pemberton Bradley , Parsons Sarah J. 
Published: February 2011

Abstract
A common feature of the most aggressive hormone-refractory prostate cancers is the accumulation of cells with neuroendocrine characteristics that produce paracrine growth factors, and may provide a proliferative advantage to cancer cells during disease progression. We have previously shown that neuroendocrine-derived peptides transactivate EGFR and Src signaling to promote growth of prostate cancer cells under low concentrations of androgen. In this study we demonstrate that in addition to the transactivation of EGFR family of receptors, neuroendocrine-derived factors enhance IGF-1R signaling through the transcriptional regulation of downstream components of the pathway to promote cell survival.
cDNA microarray analysis to compare the gene expression profile of LNCaP cells in the presence or absence of neuroendocrine-derived conditioned medium (NE-CM) revealed differential regulation of multiple IGF-1R pathway signaling components including the receptor protein tyrosine phosphatase (PTP-RF) and Akt. Quantitative RT-PCR confirmed the downregulation of PTP-RF upon treatment of LNCaP cells with NE-CM for 24 hours that was associated with a reduction in protein levels. IGF1-R and Akt phosphorylation levels were enhanced and sustained over the 24 hour period. Statistically significant changes in cell survival, cell death, and apoptosis were observed with various experimental approaches for both LNCaP and PC3 cells treated with NE-CM. In addition, NE-CM was able to protect the prostate cancer cells from docetaxel-induced apoptosis. The pro-survival effects of NE-CM were abrogated in part by specific antagonists of the neuropeptides neurotensin, bombesin, and PTHrP, as well as selective inhibitors of IGF-1R, EGFR and Src. These data support the hypothesis that neuroendocrine-like cells secrete factors that act upon PC cells to stimulate pro-survival signaling mediated in part by IGF-1R, EGFR, and c-Src.
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 1059.
Abstract 1061A: Role of protein tyrosine phosphatase PTPH1 in breast cancer
Authors: Zhi Huiying , Hou Song-wang , Li Rong-shan , Basir Zainab , Welsh Joellen , Chen Guan 
Published: February 2011

Abstract
Tyrosine phosphorylation, which is controlled by the balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), regulates critical cellular processes including proliferation and malignant transformation. While PTKs have a well-established role in breast cancer, the contribution of PTPs remains mostly unknown. Our recent studies demonstrated that the PTPH1 tyrosine phosphatase promotes K-Ras-dependent colon cancer growth through binding and dephosphorylating p38γ MAPK, and here we showed that PTPH1 increases breast cancer growth through the nuclear receptor VDR (vitamin D receptor). PTPH1 was shown to be over-expressed in about 50% of primary breast tumors and importantly its expression levels are significantly higher in HER-2 positive breast cancers. PTPH-forced expression increases breast cancer growth independent of its phosphatase activity and its oncogenic activity was further established by a growth inhibitory response through shRNA-mediated PTPH1 depletion. Mechanistically, PTPH1 was found to specifically induce the nuclear receptor VDR but not ER or PR expression and inhibition of endogenous VDR expression by shRNA or the genetic knockout completely blocks PTPH1-induced growth stimulation, which couples with an altered intracellular VDR localization. These results reveal a promoting role of a novel tyrosine phosphtase PTPH1 in breast cancer growth through signaling cross-talk with VDR, which may be a new target for breast cancer control.
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 1061A.
Abstract 1064: Numb, a progenitor cell fate determinant and intrinsic inhibitor of Notch signaling, is cell cycle regulated and required for proper mitotic entry and progression in melanoma cells
Authors: Schmit Travis L. , Setaluri Vijayasaradhi , Spiegelman Vladimir S. , Ahmad Nihal 
Published: February 2011

Abstract
Proper regulation of the cell cycle, particularly DNA replication and cell division, are crucial for correct cell ploidy and genomic integrity. Loss of various regulators, often tumor suppressors, during these processes leads to either cell cycle arrest or unregulated progression through mitosis. This may result in aneuploidy and neoplastic transformation. Therefore, defining the mechanisms by which various tumor suppressors exert their regulatory functions is essential for understanding cancer development as well as developing novel target-based therapies to combat cancer progression. We found that Numb expression is cell cycle regulated and that its expression is required for proper mitotic entry and exit in melanoma cells. Using a double thymidine arrest and release protocol, we evaluated the expression of Numb during the cell cycle. Numb mRNA and protein expression was found to be maintained at a low steady state level in asynchronous A375 and HS294T melanoma cells. However, as cells entered S phase Numb levels were found to increase, peak during mitosis and then rapidly decline at mitotic exit when the cells reentered G1 Phase. This cycling of Numb mirrored the mitotic specific expression of both Plk1 and CyclinB1, however Numb showed an expression pattern with an increase beginning slightly earlier (as early as S phase). Plk1 inhibition (via shRNA as well as a small molecule inhibitor) and nocodazole-mediated mitotic arrest was also found to be accompanied with an increase in Numb expression. Additionally, we found that Plk1 and Numb co-immunoprecipitated and Plk1 was capable of phosphorylating Numb indicating a possible regulation of Numb by Plk1. Further, surprisingly, we found that lentiviral shRNA mediated knockdown of Numb resulted in a G2/M cell cycle arrest (using FACS analysis) and a significant reduction in cell growth (using Trypan blue exclusion) in both melanoma cell lines. Overall, our observations suggests that Numb is a regulator of proper cell cycle progression and may possess tumor suppressor functions.
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 1064.
Abstract 1067: FOXD3 is a B-RAFV600E-regulated inhibitor of G1/S progression in melanoma cells
Authors: Abel Ethan V. , Aplin Andrew E. 
Published: February 2011

Abstract
The forkhead box transcription factor FOXD3 is a stemness factor that prevents the production of melanocyte progenitors from the developing neural crest; however, its role in human cancers is not known. Here we demonstrate that FOXD3 levels are up-regulated following attenuation of B-RAF and MEK signaling in mutant B-RAF harboring human melanoma cells. This effect was selective since FOXD3 was not up-regulated following MEK inhibition in wild-type B-RAF melanoma cells and mutant B-RAF thyroid carcinoma cells. Ectopic FOXD3 expression potently inhibited melanoma cell growth without altering mutant B-RAF activation of ERK1/2. Inhibition of cell growth was due to a potent G1 cell cycle arrest that was largely dependent on p53 and, to a lesser extent, its downstream target p21Cip1. These studies demonstrate that FOXD3 is suppressed by B-RAF, uncover a novel role and mechanism for FOXD3 as a negative cell cycle regulator and have implications for the repression of melanocytic lineage cells.
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 1067.
Abstract 1069: The role of mammalian Ecdysoneless in cell cycle regulation and cancer
Authors: Gurumurthy Channabasavaiah B. , Kim Jun H. , Zhao Xiangshan , Naramura Mayumi , Band Hamid , Band Vimla 
Published: February 2011

Abstract
Our long term research goal is to understand biochemical mechanisms of immortalization of human mammary epithelial cells (hMECs) that represents an early step in breast cancer progression. We have generated several hMEC immortalization models using viral oncogenes, mutated cancer genes as well as radiation treatment of cells.
In one of such immortalization model, we identified Ecdysoneless (Ecd) protein as the human papilloma virus (HPV) E6 interacting protein. We have reported earlier that HPV16 E6 protein is highly efficient for hMEC immortalization. Here, we present evidence that Ecd, an evolutionarily conserved protein, is a novel regulator of the Rb/E2F pathway. We generated a conditional Ecd knockout mouse model and observed that complete deletion of Ecd leads to early embryonic lethality in mice. The experiments using conditional Ecd-null MEFs created from Ecdlox/lox revealed that lack of Ecd inhibits cellular proliferation by delaying G1-S cell cycle progression and down-regulates E2F target gene expression. Furthermore, Ecd directly binds to Rb at the pocket domain and disrupts the interaction of Rb with E2F, leading to impairment of repressive effect of Rb on E2F target promoters. Thus, we demonstrate that Ecd is an essential protein in embryonic development and a novel regulator of G1-S cell cycle transition by modulating Rb/E2F pathway. Consistent with these observations, overexpression of Ecd in hMECs hastens the exit of cells from G1 phase of the cell cycle. Significantly, immunohistochemical analyses showed Ecd is overexessed in ductal carcinoma in situ as well as in infiltrating ductal carcinoma of breast. In conclusion, Ecd plays an important role in cell cycle progression and its deregulation can lead to abnormal cell proliferation leading to breast cancer 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 1069.