bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 465: NEDD9 adaptor protein in glioblastoma cell migration and invasion
Authors: Zhong Jessie , Turner Kylie , O'Neill Geraldine M. ,   Discipline of Paediatrics and Child Health of Sydney University
Published: August 2012

Abstract
Gliomas are characterised by extensive infiltration of the surrounding normal brain parenchyma using neurite-like extensions. Significantly, glioma locomotion is highly similar to invading neural precursor cells. Earlier work has shown that the adhesion adaptor protein NEDD9 promotes active membrane extension in non-neuronal cells, is implicated in neuritogenesis and is enriched in neural precursor cells. Critically, NEDD9 depletion significantly inhibits neural precursor cell migration in vivo and reduces U87MG glioblastoma cell invasion through a brain homogenate. Therefore, we have sought to determine NEDD9 function in glioma cell morphology and 3D cell migration. We first categorized glioblastoma cell lines into mesenchymal, pro-neural and proliferative subtypes via expression of YKL-40 and DLL3. We then used representatives from each that expressed NEDD9 to investigate glioma cell morphology and behaviour. In two-dimensional (2D) culture, NEDD9 depletion caused the loss of microtubule-rich membrane protrusions that were observed in proliferative and mesenchymal cell types. Further, NEDD9 depletion caused increased cell size in 2D and reduced migration speed and persistence in 3D culture in all lines examined. Quantification of morphologies in 3D culture following either NEDD9 depletion or Rac GTPase inhibition revealed no detectable change in rounded versus elongated morphologies. To determine which partner molecules are required for NEDD9 maintenance of cell speed, we screened interacting partners in invading glioblastoma cells. We identified and confirmed the adaptor protein CIN85 as a novel interacting partner of the NEDD9 Src Homology 3 (SH3) domain. Immunofluorescence staining revealed that CIN85 localised to structures involved in cell migration. Our study has revealed that NEDD9 depletion can inhibit migration of lines derived from mesenchymal, pro-neural and proliferative glioblastoma cell types. These findings highlight NEDD9 signalling in glioma as potentially playing a role in the migration of different glioblastoma tumour subtypes.
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 465. doi:1538-7445.AM2012-465
Abstract 4650: Inhibiting oncogenic signaling by sorafenib activates PUMA via GSK3β and NF-κB to suppress tumor cell growth
Authors: Dudgeon Crissy , Buchanan Monica E. , Peng Rui , Wang Peng , Sebastiani Andrea , Yu Jian , Zhang Lin 
Published: August 2012

Abstract
Aberrant Ras/Raf/MEK/ERK signaling is one of the most prevalent oncogenic alterations and confers survival advantage to tumor cells. Inhibition of this pathway can effectively suppress tumor cell growth. For example, sorafenib, a multi-kinase inhibitor targeting B-Raf and other oncogenic kinases, has been used clinically for treating advanced liver and kidney tumors, and also has shown efficacy against other malignancies. However, how inhibition of oncogenic signaling by sorafenib and other drugs suppresses tumor cell growth remains unclear. In this study, we found that sorafenib kills cancer cells by activating PUMA, a p53 target and a BH3-only Bcl-2 family protein. Sorafenib treatment induces PUMA in a variety of cancer cells irrespective of their p53 status. Surprisingly, the induction of PUMA by sorafenib is mediated by IαB-independent activation of NF-κB, which directly binds to the PUMA promoter to activate its transcription. NF-κB activation by sorafenib requires GSK3β activation, subsequent to ERK inhibition. Deficiency in PUMA abrogates sorafenib-induced apoptosis and caspase activation, and renders sorafenib resistance in colony formation and xenograft tumor assays. Furthermore, the chemosensitization effect of sorafenib is dependent on PUMA, and involves concurrent PUMA induction through different pathways. Enhanced PUMA expression or BH3 mimetics potentiate the anticancer effects of sorafenib, and restore sorafenib sensitivity in resistant cells. We also developed a high-throughput screening assay for identifying anticancer compounds based on the activation of PUMA by sorafenib. Together, these results demonstrate a key role of PUMA-dependent apoptosis in therapeutic inhibition of Ras/Raf/MEK/ERK signaling. They provide a rationale for manipulating the apoptotic machinery to improve sensitivity and overcome resistance to the therapies that target oncogenic kinase signaling.
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 4650. doi:1538-7445.AM2012-4650
Abstract 4651: Sorafenib and its derivatives induce apoptosis and autophagy in canine mammary tumor cells
Authors: Lee Yi-Yen , Chen Kuen-Feng , Chou Chung-Hsi , Lin Chen-Si 
Published: August 2012

Abstract
Canine mammary tumors (CMTs) are the most common neoplasms in intact female dogs. Radiation treatment, chemotherapy and surgical removal are conventionally applied for treating CMTs; however, the efficacy is limited and a study showed around 48% of dogs died or were euthanized within one year due to recurrence or metastasis of the tumor after surgical removal. Recently, Sorafenib (Nexavar®), a multiple kinase inhibitor, has shown survival benefits in human patients with human hepatocellualr carcinoma (HCC) and is the first clinically approved drug for treating HCC. Except HCC, Sorafenib also showed certain effect on the treatment of human renal cell carcinoma, thyroid cancer, and, also, breast cancer. In this study, derivatives of sorafenib (SC-1 & CY-13) made by depleting the kinase inhibitory activities were investigated for their therapeutic efficacy in canine mammary tumors. Three CMT cell lines including CMT-1, CF41.mg and MPG were treated with sorafenib, SC-1 and CY-13. The results showed SC-1 owned stronger potency than other two compounds in suppressing tumor cell growth. Lower LD50 and earlier onset of cell death were found in SC-1-treated groups. The SC-1-mediated CMT cell death was through both apoptosis and autophagy since DNA fragmentation and autophagosome were observed in treated cells. These sorafenib derivatives were previously reported as novel inhibitors for STAT3. Here we also found that SC-1 down-regulated phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested CMT cells. Expression of STAT3-driven genes, including cylcin D1 and survivin, was also repressed by SC-1. Although the in vivo anti-tumor efficacy of SC-1 will be soon evaluated, our preliminary results have provided a lead for drug development of canine mammary tumors.
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 4651. doi:1538-7445.AM2012-4651
Abstract 4653: 5F203-induced reactive oxidative species, DNA damage and apoptosis involves aryl hydrocarbon activation in ovarian cancer cells
Authors: Callero Mariana A. , Luzzani Gabriela , Bradshaw Tracey D. , Pérez Andrea I. Loaiza 
Published: August 2012

Abstract
Ovarian cancer is the 2nd cause of death by gynecological malignancies after breast cancer. These tumors have poor prognoses because they are detected at advanced stages of disease and show acquired or intrinsic resistance to therapy.Benzothiazoles, agents with preclinical antitumor activity against ovarian and breast cancer models, belong to a novel mechanistic class which bind to the arylhydrocarbon receptor (AhR). Phortress the lysylamide prodrug of 2-(4-amino-3-methylphenyl)-5- fluorobenzothiazole (5F203) is currently under phase I clinical evaluation. We previously demonstrated that these compounds activate AhR signaling in sensitive breast cancer cells, the goal of this project was to evaluate the role of AhR in 5F203 activity in two human ovarian cell lines: IGROV-1 sensitive to 5F203 and SKOV-3 resistant to this agent. We observed by MTS assay IGROV-1 cell growth inhibition of 31.9±12.2% by 0.01 μM 5F203 and almost total growth inhibition (91.9±3.4%) after treatment of IGROV-1 cells with 1 μM 5F203. Pre-incubation with the AhR inhibitor ΔNF (1 μM), partially blocked the effect of 5F203 (inhibition of 21.6±4.7% and 27.7±5.3% respectively). In contrast, 5F203 failed to inhibit growth of SKOV-3 cells.5F203 (1 μM) induced AhR translocation from cytosolic to nuclear fractions evaluated by Western blot and confocal microscopy in IGROV-1 cells only. Moreover, activation of CYP1A1 related promoter sequences and EROD activity further indicated activation of AhR signaling. 5F203 treatment for 1h increased ROS and induced NFκB nuclear translocation only in IGROV-1 cells, effects which were attenuated by pre-treatment with ΔNF. Detection of γH2AX revealed DNA double strand breaks 2h post 5F203 treatment of IGROV-1 cells only. After 24h exposure, 5F203 resulted in increased IGROV-1 cell apoptosis, evaluated by DAPI staining of apoptotic bodies, increased pP53, caspase 3 and PARP cleavage. We also observed G1 cell cycle arrest, increased P21 expression and decreased cyclin D1 expression induced by 5F 203. We conclude that the antitumor/pro-apoptotic effects of 5F203 observed in IGROV-1 cells is mediated by AhR which may be a new molecular target in the treatment of ovarian tumors and that this agent may represent a potential novel treatment for ovarian 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 4653. doi:1538-7445.AM2012-4653
Abstract 4663: The cyclooxygenase-2 inhibitor, celecoxib, suppresses proliferation and induces apoptosis in endometrial cancer cells
Authors: Schuler Kevin M. , Suri Anuj , Zhou Chunxiao , Bae-Jump Victoria A. , Gehrig Paola A. 
Published: August 2012

Abstract
INTRODUCTION: Obesity is associated with increased risk and worse outcomes for women with endometrial cancer. Inflammation may play a critical role in obesity-driven cancers; thus, the anti-inflammatory effects of COX-2 inhibitors may be a novel treatment strategy that is particularly beneficial in endometrial cancer patients. As a result, our objective was to evaluate the effect of COX-2 inhibitors on proliferation and apoptosis in endometrial cancer cell lines. METHODS: Two endometrial cancer cell lines (ECC-1 and Ishikawa) were used in these studies. Cell proliferation was assessed by MTT assay after exposure to the COX-2 inhibitor, celecoxib. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3. hTERT mRNA expression was assessed by real-time PCR. Western immunoblotting was performed to determine the effect of celecoxib on COX-2 expression in the endometrial cancer cell lines. RESULTS: Celecoxib significantly inhibited proliferation in a dose-dependent manner in both endometrial cancer cell lines (IC50 5-10 μM for ECC-1, 10-20 μM for Ishikawa; p&lt;0.005 for each). Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis and inhibition of hTERT mRNA expression. Western immunoblot analysis demonstrated that celecoxib treatment suppresses COX-2 expression in both endometrial cancer cell lines. CONCLUSION: Celecoxib potently inhibits cell growth via G1 arrest, decreases telomerase activity and increases apoptotic cell death in endometrial cancer cells. This work suggests that celecoxib may be a novel chemotherapeutic agent for endometrial cancer prevention and treatment, especially given the interplay between obesity, inflammation and cancer risk.
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 4663. doi:1538-7445.AM2012-4663
Abstract 4673A: DAPK-mediated phosphorylation of HSF1 enhances apoptosis level upon TNF in colorectal carcinoma cells
Authors: Benderska Natalya , Rau Tilman , Ivanovska Jelena , Chakilam Saritha , Gandesiri Muktheshwar , Ziesche Elisabeth , Agaimy Abbas , Schulze-Luehrmann Jan , Distel Luitpold , Fischer Thomas , Sticht Heinrich , Schneider-Stock Regine 
Published: August 2012

Abstract
Objectives: Tumor necrosis factor ≤ (TNF) is an inflammatory cytokine, which is released upon different stimuli, including irradiation. Recently it has been shown, that the Death-associated protein kinase (DAPK) mediates TNF-induced apoptosis in colon cancer cells [1]. Here, we aimed to identify new DAPK binding partners and to characterize the functional role of novel protein interaction complexes during TNF-induced apoptosis in colon cancer cells. Methods/Results: HCT116 colorectal cancer cells were cultured for 6 to 48 hours in either normal or TNF-conditioned medium. For phosphopeptide microarray (PPM) whole cell lysates were incubated on peptide platforms with radioactive-labeled P33. Apoptosis was detected by Annexin V staining and caspase 3 cleavage in Western Blotting. PPM analysis revealed heat shock transcription factor 1 (HSF1) as a new potential substrate of DAPK phosphorylation under TNF-stimulation. DAPK Co-IP, co-immunofluorescence (Co-IF), and mass spectrometry showed that DAPK interacts with HSF1 after TNF-treatment. Phosphorylation on serine residues of HSF1 is necessary for HSF1 nuclear translocation and the initiation of transcription of its target genes. Among them, Ser 230 is part of a consensus phosphorylation motif for DAPK. Maximal level of pHSF1Ser230 was observed at the time point where massive apoptosis was induced. Co-IF microscopy confirmed enrichment of pHSF1Ser230 in the nucleus already after 24 hours of TNF-stimulation. EMSA and Chromatin-IP revealed that pHSF1Ser230 binds to the heat shock response element in the DAPK promoter region and enhances its transcriptional activity. Exogenous over-expression of HSF1 protein led to a significant increase in mRNA DAPK levels and consequently to an enforcement of apoptosis. As expected, DAPK knockdown cells did not show any variation in pHSF1Ser230 level, supporting again that DAPK is an important mediator of the TNF-driven signaling pathway in colorectal cancer cells. The significance of the DAPK/pHSF1Ser230 interaction for response prediction was evaluated by immunohistochemical staining on tissue microarrays of colorectal cancer before and after radiotherapy. Conclusion: Our data show a novel functional interaction between HSF1 and DAPK under TNF-stress and highlight a positive feedback mechanism in DAPK-regulation. These results help to understand cell death pathways in response to radiotherapy. [1].Bajbouj K.et al., Am J Pathol. (2009)
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 4673A. doi:1538-7445.AM2012-4673A
Abstract 4677: Slug is a potential target to restore transforming growth factor-β mediated apoptosis in lung cancer cells
Authors: Reka Ajaya Kumar , Goswami Moloy , Kurapati Himabindu , Kaza Viritha , Chen Jun , Keshamouni Venkateshwar G 
Published: August 2012

Abstract
Transforming growth factor-β (TGFβ) inhibits carcinogenesis at early stages by inhibiting cell growth and inducing apoptosis. Cancer cells acquire resistance to TGFβ induced apoptosis and divert the TGF-β signaling to stimulate tumor promoting processes such as Epithelial-Mesenchymal-Transition (EMT), immunosuppression and angiogenesis. Hence, the identification of molecular targets/ pathways enabling cancer cells to overcome TGFβ-mediated apoptosis is critical for exploiting tumor suppressive functions of TGFβ for therapy. We have identified slug (snai2), a zinc-finger transcription factor, as a critical regulator of TGF-β mediated apoptosis in lung cancer cells. In EMT models of lung cancer slug is up-regulated by several fold upon TGFβ treatment. Knock down of Smad 3 or Smad 4, but not Smad 2, completely abrogated the TGF-β induced up-regulation of Slug. Chromatin immunoprecipitation analysis revealed increased occupancy of Smad 3 to the slug promoter on TGFβ treatment indicating slug might be a direct target gene of Smad 3. Slug is often described as a potent E-cadherin suppressor and an important regulator of EMT along with other E-box proteins. In contrast siRNA knock-down of slug (slug KD) in lung cancer cells did not prevent TGFβ induced E-cadherin suppression or acquisition of mesenchymal markers such as N-cadherin, vimentin and fibronectin; instead lead to increased cell death. Slug KD cells on TGFβ treatment underwent apoptosis through the typical apoptosis cascade characterized by increased annexin-v staining and caspase-3 activation. This apoptotic cell death is abrogated by inhibitors of caspase-3 and caspase-9. Inhibition of caspase-8, an initiator of extrinsic apoptotic pathway or siRNA knockdown of RIP1 that promotes necroptosis did not inhibit the death of TGFβ treated slug KD cells. Together these finding suggests slug KD results in cell death via intrinsic apoptosis pathway in response to TGFβ. This study indicates slug induction during EMT allows cancer cells to escape from apoptotic functions of TGFβ and might function as a critical regulatory switch to shift TGFβ role from tumor suppressor to tumor promoter. Thus slug inhibition might serve as a potential mechanism to reinstate the apoptotic functions of TGFβ in lung cancer cells.
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 4677. doi:1538-7445.AM2012-4677
Abstract 4678: Silencing of TIMELESS induces growth suppression, apoptosis and enhanced cytotoxicity of cisplatin in H157 lung cancer cells
Authors: Yoshida Kenya , Sato Mitsuo , Hase Tetsunari , Oguri Tomoyo , Elshazley Momen , Yamashita Ryo , Kondo Masashi , Hasegawa Yoshinori 
Published: August 2012

Abstract
Background: TIMELSS (TIM) is a circadian clock gene in Drosophila, but its role in mammals in circadian clock systems is not well-understood. Mammalian TIM is involved in Chk1 activation and intra-S checkpoint through genotoxic stress (Unsal-Kaçmaz et.al, Molecular and Cellular Biology, 27(8), 3131-3142(2007)). TIM is also associated with doxorubicin-induced G2/M cell cycle arrest and TIM depletion sensitizes HCT116 colon cancer cells to doxorubicin-induced cytotoxicity (Yang et.al, Journal of Biological Chemistry, 285(5), 3030-3034(2010)). Mutations in TIM in breast cancer were reported (Sjöblom et.al, Science, 314(5797), 268-274(2006)). Methods and Findings: The mRNA expression levels of TIM in 17 non-small cell lung cancer (NSCLC) cell lines and 4 small cell lung cancer (SCLC) cell lines were analyzed by reverse transcriptase PCR. HCC44, H460, H157 (NSCLC), H146 and H740 (SCLC) expressed higher levels of TIM than cdk4/hTERT-immortalized normal human bronchial epithelial cell line HBEC4. Sequencing analysis of TIM revealed no mutation in 21 lung cancer cell lines. RNAi-mediated knockdown of TIM in H157 suppressed proliferation in WST-1 assay and clonogenic growth in liquid colony formation assay. Western blot analysis revealed increased level of cleaved caspase-3 after TIM-knockdown, suggesting that apoptosis was involved in growth inhibition. TIM-knockdown induced increased sensitivity to cisplatin in drug sensitivity assay using WST-1 (IC50 were 1.70μM and 0.91μM in TIM-knocked down H157 compared to 4.87μM in control). Conclusions: TIM inhibition causes growth suppression, apoptosis and enhanced cytotoxicity of cisplatin. Our results suggest that TIM inhibition has a potential utility in the treatment of lung 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 4678. doi:1538-7445.AM2012-4678
Abstract 4679: Betulinic acid inhibits deubiquitinases to increase the degradation of pro-survival proteins and enhance prostate cancer-specific apoptosis
Authors: Reiner Teresita , Parrondo Ricardo , de las Pozas Alicia , Palenzuela Deanna , Perez-Stable Carlos 
Published: August 2012

Abstract
Inhibition of the ubiquitin proteasome (UPS) pathway is a valid anti-cancer target but the alternative strategy to increase activity in order to degrade pro-survival proteins is much less developed. Betulinic acid (BA) is a naturally occurring small molecule with multiple mechanisms for increasing apoptosis in cancer cells, making it an attractive anti-prostate cancer agent. There is evidence that BA can activate the UPS pathway to degrade multiple pro-survival proteins such as androgen receptor (AR), but the mechanism is not clear. Our western blot data in prostate cancer (PC) cells indicates that 10 μM BA decreases the levels of multiple pro-survival proteins including AR, cyclins, and cyclin-dependent kinases. Inhibition of the UPS pathway with 1 μM MG132 blocks the BA-mediated decrease of AR and AKT proteins and lowers cell death, suggesting a dependence on the UPS pathway. In TRAMP transgenic mice, BA treatment (10 mg/kg) inhibits tumor growth, increases apoptosis, decreases angiogenesis and proliferation, and lowers AR and cyclin D1 protein levels (immunohistochemistry) without toxic side effects to normal tissues. However, BA does not increase UPS activity (Proteasome-Glo Chymotrypsin-like Cell-Based Assay; Promega) in LNCaP PC cells suggesting an alternative mechanism for increasing protein degradation. BA-mediated inhibition of deubiquitinase (DUB) activity, as determined by DUB-Glo Protease Assay (Promega) and DUB labeling with HA-ubiquitin vinyl sulfone, results in the accumulation of poly-ubiquitinated (Ub) proteins that are recognized by the UPS pathway and degraded. The cyclin D1 T286A mutant that cannot be degraded by the UPS pathway is resistant to BA-mediated degradation. In non-cancer BJ fibroblast, however, BA does not inhibit DUB activity nor increases total poly-Ub proteins and this is associated with no effect on cell death. Our data suggests that BA-mediated inhibition of DUBs and induction of apoptotic cell death specifically in PC but not in non-cancer cells will provide an effective non-toxic and clinically selective agent.
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 4679. doi:1538-7445.AM2012-4679