bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5089: Survivin safeguards chromosome numbers and protects from aneuploidy
Authors: Wiedemuth Ralf , Klink Barbara , Schroeck Evelin , Schackert Gabriele , Temme Achim 
Published: May 2015

Abstract
Survivin, belonging to the family of Inhibitor of Apoptosis proteins (IAP), is overexpressed in a broad variety of different tumor entities. Besides its role and function in apoptosis, Survivin forms in mitosis with its partners Borealin, inner centromere protein (INCENP) and the enzymatically active member Aurora B kinase the chromosomal passenger complex (CPC). The main function of this complex is sensing and correcting non-bipolar microtubule-kinetochore interaction, regulating chromosome segregation and cytokinesis. Some evidence points to a role of Survivin in connecting mitosis with control of cell cycle arrest. In this study, we assessed the role of Survivin in ensuring chromosomal stability and DNA integrity in HCT116, MCF-7, U87-MG and corresponding isogenic p53-deficient cells.
Knock down of Survivin, using retroviral short-hairpin RNAs, caused in all tested cell lines a heavily impaired cytokinesis resulting in polyploidy and poly-merotelic kinetochore spindle assemblies, irrespective of the p53 status. Surprisingly, cells with wild type p53 showed after Survivin RNAi an activation of p53 and accumulation of p21waf/cip and Cyclin D1, indicating G1 arrest. A detailed Flow Cytometry analysis revealed a correlation between the increased p21waf/cip expression and increasing DNA content in Survivin-depleted wild type cells compared to p53-deficient cells. Conversely, BrdU incorporation in wild type cells decreased with DNA content compared to p53-deficient cells with knock down of Survivin. Nonetheless, polyploid wild type cells even with a DNA content larger 4n were still able to incorporate BrdU, indicating transient G1 arrest after Survivin knock down. Furthermore, Survivin RNAi led in all tested cell lines to an induction of DNA lesions and caused a DNA damage response. SKY-analysis revealed numerical aberrations and a significant higher frequency of structural chromosomal aberrations indicative for DNA double strand break repair, only in Survivin-depleted cells.
In conclusion, our results highlight the important role of Survivin as a chromosomal passenger protein which in concert with its molecular partners Aurora B, INCENP, and Borealin, controls chromosomal segregation by regulating bipolar spindle attachment and cytokinesis and protects cells from polyploidy and chromosomal instability.
Citation Format: Ralf Wiedemuth, Barbara Klink, Evelin Schroeck, Gabriele Schackert, Achim Temme. Survivin safeguards chromosome numbers and protects from aneuploidy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5089. doi:10.1158/1538-7445.AM2014-5089
Abstract 5092: Geminin regulates pre-replicative complex formation through the stabilization of CDT1 in mitosis
Authors: Kudo Yasusei , Tsunematsu Takaaki , Ishimaru Naozumi 
Published: May 2015

Abstract
Geminin, a factor essential to DNA replication, directly binds to the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation to avoid re-replication. Geminin protein expression is necessary during S, G2 and M phases of the cell cycle. In G1, geminin levels are kept in check by the anaphase-promoting complex/cyclosome ubiquitin ligase complex and its activator (APC/CCdh1), which targets geminin for proteasomal degradation to allow pre-RC formation. Conversely, from S to G2 is stabilized by the APC/C inhibitor Emi1 to ensure inhibition of Pre-RC formation. In this study, we found that Aurora-A phosphorylated geminin at Thr25 in M phase and the Aurora-A-mediated phosphorylation stabilized geminin by preventing its degradation via APC/C during mitosis. Aurora-A-mediated stabilization of geminin may further give rise to that of CDT1 protein to ensure pre-RC formation in the ensuing S phase. The Aurora-A-geminin-CDT1 axis, thus, represents a critical function for regulating proper DNA replication.
Citation Format: Yasusei Kudo, Takaaki Tsunematsu, Naozumi Ishimaru. Geminin regulates pre-replicative complex formation through the stabilization of CDT1 in mitosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5092. doi:10.1158/1538-7445.AM2014-5092
Abstract 5094: Investigating the role of CDC25B in inhibition of cellular proliferation
Authors: Lee Caleb C. , Manfredi James 
Published: May 2015

Abstract
CDC25B is a dual specificity phosphatase that activates cyclin-dependent kinases to trigger entry into mitosis and is required for re-entry into mitosis after DNA damage. As an oncogene, CDC25B is overexpressed in multiple tumor types. It has been specifically associated with prostate cancer, where overexpression is seen in prostate tumor tissues and higher levels correlate with increased tumor grade. In the prostate, in addition to its role as a cell cycle regulator, CDC25B acts as an androgen receptor coactivator increasing the response of reporter genes to the addition of androgen analogues. In a transgenic mouse model, overexpression of CDC25B in the mammary glands led to accelerated mammary epithelial proliferation resulting in hyperplasia, while in vitro, co-transfection of CDC25B with Ras allows for transformation of MEF's.
Surprisingly, given the establishment of CDC25B as an oncogene, colony formation assays using ectopic expression of CDC25B in transformed cell lines reveal an anti-proliferative effect. Our data reveal a role for Ras inhibition as a cause of this anti-proliferative effect. Co-transfection of CDC25B and Ras results in a dose-dependent decrease in expression of the ectopic Ras protein in several cell lines tested. Preliminary experiments suggest that while mRNA levels remain stable, CDC25B inhibits Ras protein expression. As Ras is pivotal in multiple tumors, this effect of CDC25B may be broadly applicable. These data therefore reveal a new role for CDC25B, which may need to be overcome to allow transformation of tumor cells.
Citation Format: Caleb C. Lee, James Manfredi. Investigating the role of CDC25B in inhibition of cellular proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5094. doi:10.1158/1538-7445.AM2014-5094
Abstract 5095: Real-time FUCCI imaging of cell cycle phase in tumors demonstrates why cancer chemotherapy is not effective in solid cancers
Authors: Yano Shuya , Tome Yasunori , Zhang Yong , Hiroshima Yukihiko , Miwa Shinji , Uehara Fuminari , Suetsugu Atsushi , Kishimoto Hiroyuki , Tazawa Hiroshi , Zhao Ming , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: May 2015

Abstract
The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. The present report describes technology to monitor real-time cell cycle dynamics of cancer cells throughout a live tumor in vivo using a fluorescence ubiquitination cell cycle indicator (FUCCI). In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G0/G1 and 70% in S/G2/M. In contrast in an established tumor, approximately 90% of cancer cells in the center are in G0/G1 phase. Similarly, approximately 75% of cancer cells far from (&gt;100 µm) tumor blood vessels are in G0/G1. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface of tumors and, in contrast, had little effect on quiescent cancer cells that are the vast majority of an established tumor. Moreover resistant quiescent cancer cells that moved to the tumor surface restarted cycling after the cessation of chemotherapy. Most drugs currently in clinical use target cancer cells in S/G2/M which our results show are a small minority in established tumors, thereby accounting, at least in part, for poor efficacy of cytotoxic drugs in solid cancer. Our results also suggest that drugs that target quiescent cancer cells are urgently needed.
Citation Format: Shuya Yano, Yasunori Tome, Yong Zhang, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Toshiyoshi Fujiwara, Robert M. Hoffman. Real-time FUCCI imaging of cell cycle phase in tumors demonstrates why cancer chemotherapy is not effective in solid cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5095. doi:10.1158/1538-7445.AM2014-5095
Abstract 5110: The role triptolide in sensitizing lung tumor cells to cisplatin-induced apoptosis
Authors: Wang Gan , Xu Xiaoxin Susan , Zhang Yi 
Published: May 2015

Abstract
Cisplatin is an anticancer drug used in treatment for many types of cancer, including lung cancer. The quick development of tumor cell drug resistance, however, greatly hindered the effectiveness of cisplatin in cancer treatment. Exploring new strategies that can sensitize tumor cells to cisplatin treatment, therefore, is essential for improving the effectiveness of cisplatin in cancer treatment. Triptolide is a bioactive ingredient isolated from Tripterygium wilfordii, a traditional Chinese herbal medicine that has been used to treat immune-related disorders. Recent studies revealed that Triptolide possesses potent antitumor properties through CDK7-depedent RNA polymerase II (Pol II) degradation and global transcription inhibition by binding to the XPB subunit of general transcription factor TFIIH and inhibiting its ATPase activity. We have studied the possibility of using Triptolide to sensitize lung tumor cell to cisplatin-induced apoptosis. Using both HTB182 and CRL5985 lung tumor cells, our caspase 3 activation studies demonstrated that the presence of low-level Triptolide greatly sensitized these lung tumor cells to cisplatin-induced apoptosis. Our western blots results indicated that the presence of low-level Triptolide increased the cisplatin-induced expression of PUMA but reduced expression of Bcl-XL in these lung tumor cells. Our immune-blotting studies revealed that the RNA Pol II level was not significantly affected by the presence of low-level Triptolide. Our real time PCR studies results indicated that expression levels of several tested genes also were not affected by the presence of Triptolide. These results suggest that the presence of low levels of triptolide sensitizes the lung cancer cells to cisplatin-induced apoptosis through binding to XPB of the TFIIH and inhibiting the DNA repair activity for cisplatin DNA damage, resulting in increased apoptosis of the lung tumor cells. Therefore, the presence of low levels of triptolide sensitizes lung tumor cells to cisplatin-induced apoptosis.
Citation Format: Gan Wang, Xiaoxin Susan Xu, Yi Zhang. The role triptolide in sensitizing lung tumor cells to cisplatin-induced apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5110. doi:10.1158/1538-7445.AM2014-5110
Abstract 5119: Smac mimetic inhibits tumorigenicity and growth of glioblastoma by promoting differentiation of glioblastoma cancer stem-like cells
Authors: Tchoghandjian Aurelie , Jennewein Claudia , Eckhardt Ines , Momma Stefan , Figarella-Branger Dominique , Fulda Simone 
Published: May 2015

Abstract
Inhibitors of apoptosis (IAP) proteins are often overexpressed in human cancers including glioblastoma (GBM) and are well characterized for their antiapoptotic properties. Recently, a broader role of IAP proteins in tumor biology has been described, as they also regulate several non-apoptotic signal transduction pathways. Therefore, we investigated the effect of non-toxic concentrations of small-molecule Smac mimetics, which antagonize IAP proteins, on differentiation of cancer stem-like cells (CSLCs) derived from primary GBM specimens. Since CSLCs have been implicated in resistance to chemo- and radiotherapy and tumor recurrence, they are considered as critical therapeutic targets in GBM. Here, we identify a novel function of Smac mimetic in regulating differentiation of GBM CSLCs by activating NF-κB. Smac mimetic at non-lethal doses stimulates morphological changes associated with differentiation of GBM CSLCs. Smac mimetic increases transcriptional activity, mRNA and protein levels of the astrocytic marker GFAP without altering expression of the neuronal marker β-III-tubulin, indicating that Smac mimetic induces astrocytic differentiation of GBM CSLCs. Molecular studies reveal that Smac mimetic triggers processing of the NF-κB subunit p100 to p52, nuclear translocation of p52 and p50 and increased NF-κB DNA-binding. Intriguingly, inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks the Smac mimetic-stimulated increase in GFAP and differentiation. Interestingly, this Smac mimetic-stimulated differentiation is associated with reduced expression of stemness markers such as CD133, Nanog and Sox2 in GBM CSLCs. In contrast, Smac mimetic does not alter cell morphology, differentiation and expression of stemness markers in non-malignant neural stem cells. Importantly, Smac mimetic treatment reduces clonogenicity of GBM CSLCs in vitro and in vivo, suppresses their tumorigenicity in orthotopic and subcutaneous mouse models of GBM and significantly increases the survival of mice bearing GBM. By identifying a novel role of Smac mimetic in promoting the differentiation of GBM CSLCs, these findings provide new insights into Smac mimetic-regulated non-apoptotic functions with important implications for targeting GBM CSLCs.
Citation Format: Aurelie Tchoghandjian, Claudia Jennewein, Ines Eckhardt, Stefan Momma, Dominique Figarella-Branger, Simone Fulda. Smac mimetic inhibits tumorigenicity and growth of glioblastoma by promoting differentiation of glioblastoma cancer stem-like cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5119. doi:10.1158/1538-7445.AM2014-5119
Abstract 5128: Different effect of irinotecan induced apoptosis in k-Ras wild and mutant type colon cancer cell lines
Authors: Kang Myoung Hee , Kim Jung Lim , Kim Bo Ram , Jang Yoo Jin , Lee Sun I. , Kim Jun Suk , Oh Sang cheul 
Published: May 2015

Abstract
Irinotecan(IRI) prevents DNA from unwinding by inhibition of topoisomerase I. Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. Recent studies, those with
Irinotecan treatment has a synergistic effect appears. However, there is no study on the effect of the Irinotecan mono-treatment. In addition their roles and the underlying mechanism in anti-tumorigenic function of solid tumor, especially kras wild and mutant type colon cancer, are not yet known. Bax protein is a key mediator of apoptosis and might be related to chemosensitivity. In this work, we evaluated the anti-tumorigenic action of these Irinotecan anti-cancer agent with especially k-ras wild and mutant type colon cancer cell lines, and investigated their apoptosis-inducing effects as the potential mechanism in this process. The results show that the growth inhibitory effects of 5-fuorouracil (5-FU), Oxaliplatin(OX) produced a dose- and time dependent fashion in k-ras wild(HT29, Colo205) and mutant type(HCT116, DLD-1) colon cancer cell lines. Otherwise, Irinotecan(IRI) produced a cell growth of k-ras wild type cell lines were resistant versus that shown in the sensitive k-ras mutant type cell lines. Cell cycle analysis by FACS indicated that IRI-treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of colon cancer cells to IRI also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. The results by multiple in vitro experimental model, showed that IRI induce these k-ras mutant type colon cancer cells to undergo apoptosis with increased the Bax protein and a release of cytochrome C from mitochondria, the activation of caspase9, the cleavage of PARP. But Bax protein was inactivation in k-ras wild type colon cancer cell lines. Importantly, inhibition of ERK kinase activity demonstrated that IRI-induced apoptotic pathway was regulated by the ERK signaling cascade. These data indicate that Anti-cancer agent, Irinotecan, promotes
Bax-mediate apoptosis of colon cancer cell lines by sequential activation of the ERK signaling pathway followed by the up-regulation of intrinsic pathway of caspase 9.
Citation Format: Myoung Hee Kang, Jung Lim Kim, Bo Ram Kim, Yoo Jin Jang, Sun Il Lee, Jun Suk Kim, Sang cheul Oh. Different effect of irinotecan induced apoptosis in k-Ras wild and mutant type colon cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5128. doi:10.1158/1538-7445.AM2014-5128
Abstract 5138: Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1
Authors: Shahbazi Jeyran , Scarlett Christopher J. , Norris Murray , Liu Bing , Haber Michelle , Tee Andrew E. , Carrier Alice , Biankin Andrew V. , London Wendy B. , Marshall Glenn M. , Lock Richard , Liu Tao 
Published: May 2015

Abstract
Myc oncoproteins and histone deacetylases (HDACs) exert oncogenic effects by modulating gene transcription. Paradoxically, N-Myc induces p53 gene expression. Tumor protein 53-induced nuclear protein 1 (TP53INP1) phosphorylates p53 protein at serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes and programmed cell death. We aimed to identify the mechanism through which N-Myc overexpressing p53 wild-type neuroblastoma cells acquired resistance to apoptosis.Gene and protein expression was analysed by real-time RT-PCR and immunoblot. Cell survival/death was examined by flow cytometry study of Annexin V-staining. The prognostic value of TP53INP1 expression in tumor tissues was investigated in three independent cohorts of neuroblastoma patients. TP53INP1 was one of the genes most significantly repressed by HDAC2 and N-Myc according to Affymetrix microarray gene expression datasets. HDAC2 and N-Myc reduced TP53INP1 gene expression by direct binding to the TP53INP1 gene promoter, leading to transcriptional repression of TP53INP1, p53 protein de-phosphorylation at serine 46, neuroblastoma cell proliferation and survival. Moreover, low levels of TP53INP1 expression in human neuroblastoma tissues correlated with high levels of N-Myc expression and poor patient outcome, and the BET bromodomain inhibitors JQ1 and I-BET151 reduced N-Myc expression and reactivated TP53INP1 expression in neuroblastoma cells. These findings identify TP53INP1 repression as an important co-factor for N-Myc oncogenesis, and provide further evidence for the potential application of BET bromodomain inhibitors in the therapy of
N-Myc-induced neuroblastoma.
Citation Format: Jeyran Shahbazi, Christopher J. Scarlett, Murray Norris, Bing Liu, Michelle Haber, Andrew E. Tee, Alice Carrier, Andrew V. Biankin, Wendy B. London, Glenn M. Marshall, Richard Lock, Tao Liu. Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5138. doi:10.1158/1538-7445.AM2014-5138
Abstract 5146: The histone demethylase KDM2A is a new promoter of tumorigenesis, drug target and negative prognostic biomarker for non-small cell lung cancer
Authors: Wagner Klaus W. , Alam Hunain , Dhar Shilpa S. , Giri Uma , Li Na , Wei Yongkun , Cascone Tina , Giri Dipak , Kim Jae-Hwan , Ye Yuanqing , Multani Asha , Chan Chia-Hsin , Erez Baruch , Saigal Babita , Lin Hui-Kuan , Wu Xifeng , Hung Mien-Chie , Heymach John , Lee MinGyu 
Published: May 2015

Abstract
The molecular etiology of non-small cell lung cancer (NSCLC) is heterogeneous and mostly dominated by alterations in kinase signaling pathways (i.e. KRAS, EGFR, EML4-ALK, PI3K, MEK1). Epigenetic modifiers, including histone methyltransferase and demethylases, have emerged as important regulators of oncogenic phenotypes in a small but growing number of tumor types, but the pathogenic role of histone methylation modifiers in NSCLC is largely unknown. We found that the histone H3 lysine 36 (H3K36) demethylase KDM2A is a novel oncogenic promoter of NSCLC. In our analysis KDM2A is frequently overexpressed in NSCLC cell lines and patient samples (≥14% in NSCLC tumors), and high expression levels of KDM2A correlate with poor prognosis in three independent patient populations from the USA and Asia.
KDM2A knockdown by RNAi in KDM2A overexpressing cell lines inhibits proliferation and invasiveness of NSCLC cells in vitro and in three mouse xenograft models (subcutaneous, intravenous, and orthotopic models). Consistently, KDM2A overexpression promotes these cellular characteristics in NSCLC cell lines with low endogenous KDM2A levels. Rescue experiments using KDM2A-depleted cells showed that ectopic expression of wild-type KDM2A, but not its catalytic mutant mKDM2A, restored proliferation and invasion. These results indicate that the effect of KDM2A on oncogenic phenotypes is largely dependent on its catalytic activity and validate it as drug target for development of small molecule inhibitors. Mechanistically, we uncovered, that KDM2A activates the MAPK signaling pathway (ERK1/2) by transcriptionally repressing the MAPK phosphatase DUSP3.
In summary, these novel findings indicate that KDM2A overexpression promotes NSCLC tumor growth and invasion. Our results provide new insights into how the dysregulation of an epigenetic enzyme can be coupled to activation of the ERK1/2 signaling pathway to promote NSCLC tumorigenesis and suggest that KDM2A is a promising anti-cancer therapeutic drug target for KDM2A-overexpressing NSCLC patients.
Citation Format: Klaus W. Wagner, Hunain Alam, Shilpa S. Dhar, Uma Giri, Na Li, Yongkun Wei, Tina Cascone, Dipak Giri, Jae-Hwan Kim, Yuanqing Ye, Asha Multani, Chia-Hsin Chan, Baruch Erez, Babita Saigal, Hui-Kuan Lin, Xifeng Wu, Mien-Chie Hung, John Heymach, MinGyu Lee. The histone demethylase KDM2A is a new promoter of tumorigenesis, drug target and negative prognostic biomarker for non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5146. doi:10.1158/1538-7445.AM2014-5146