bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5104: Identification of cancer-specific COPI inhibitors and their associated apoptotic cell death pathways
Authors: Oliver David J. , Chaparala Anusha , Okafor Emeka , Camacho Carlos J. , Doemling Alexander S. , Wieland Felix T. , Roninson Igor B. , Shtutman Michael 
Published: May 2015

Abstract
The COPI complex is a heptameric complex involved in multiple aspects of intravesicular transport. Recently, Shtutman et al. identified the ζ1 subunit of the COPI complex as a potential target for cancer therapy1. The ζ subunit of COPI is coded for by two genes, COPZ1 and COPZ2. In normal tissue, both COPZ genes are expressed and the protein products are functional isoforms within the COPI complex. In numerous different cancers, COPZ2 is silenced and the cells must depend on the ζ1 isoform for COPI function. When ζ1 is inhibited by siRNAs, cancer cells undergo apoptotic cell death while normal cells, which retain the ζ2 isoform, survive. Thus, the ζ1 subunit of the COPI complex is a potential target for cancer therapy. Here we present our work to develop and test small molecule inhibitors of ζ1-containing COPI complexes, as well as the identification of the apoptotic cell death pathways activated upon ζ1 depletion with siRNAs. We have identified a small molecule which disrupts the formation of COPI vesicles in biochemical and immunofluorescence studies, and also kills cells in a ζ1-specific manner. In addition we have shown that the unfolded protein response (UPR) is activated by ζ1 depletion but that it is not the primary activator of apoptotic cell death in cancer cells. The identification of small molecules which can inhibit ζ1-containing COPI will be a valuable tool for cancer therapy as well as the study of COPI biology. In addition, elucidation of the mechanism of activation and execution of apoptosis upon COPI depletion will provide insight into methods for combination therapy.
Citation Format: David J. Oliver, Anusha Chaparala, Emeka Okafor, Carlos J. Camacho, Alexander S. Doemling, Felix T. Wieland, Igor B. Roninson, Michael Shtutman. Identification of cancer-specific COPI inhibitors and their associated apoptotic cell death pathways. [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 5104. doi:10.1158/1538-7445.AM2014-5104
Abstract 5107: The role of PERIOD2 for radioprotection against ionizing radiation in mice bone marrow
Authors: Alexandrou Aris , Menaa Cheikh , Liu Chris , Pai Steven , Xiao Kai , Fan Ming , Juma Shuaib , Fu Loning , Murphy William J. , Li Jian Jian 
Published: May 2015

Abstract
Background: Circadian deregulation is associated with the development of numerous diseases, including cancer, diabetes, and several neurological disorders. A recent study shows that the onset of carcinogenicity is specifically linked to the time of exposures (day or night) to ultraviolet light and ionizing radiation in mice. This effect is believed to be mediated through radiation-induced DNA damage and deregulation of the WNT/β-Catenin signaling pathway, hence affecting cell survival and proliferation.
Results: The current studies aim to elucidate the contribution of a core circadian gene, Period2 (Per2), in the radioprotective response of mice bone marrow. Epithelial cells and mice bone marrow express PER2 in contrast to cancer cells. Bone marrow isolated from Per2 knockout mice exhibit radioresistence to high doses of ionizing radiation (HDIR; 2Gy) compared to wild-type mice controls suggesting that Per2 expression was responsible for radiation-induced cell death. This finding was translated by increased granulocyte-macrophage (GM-CFUs) clonogenic survival and reduced cell apoptosis. Mechanistic analysis showed that Per2 knockout mice bone marrow expressed higher levels of procaspase3 and less expression of active caspase3 after HDIR treatment compared to wild-type mice bone marrow and sham irradiated controls. Furthermore, Per2 knockout mice treated with 12Gy total body radiation (TBIR) showed an 80% survival verses 30% survival in wild-type mice. Whole genome-wide sequencing detected signal transduction pathways reflecting enhanced DNA damage repair capacity in knockout mice bone marrow, hence defining the role of PER2 in the radioresistant phenotype in vivo.
Conclusions: This data is the first evidence supporting the critical role of PER2 in protecting mice hematopoietic stem cells (HSCs) from HDIR via enhancement of genes involved in DNA repair signaling networks.
Citation Format: Aris Alexandrou, Cheikh Menaa, Chris Liu, Steven Pai, Kai Xiao, Ming Fan, Shuaib Juma, Loning Fu, William J. Murphy, Jian Jian Li. The role of PERIOD2 for radioprotection against ionizing radiation in mice bone marrow. [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 5107. doi:10.1158/1538-7445.AM2014-5107
Abstract 5114: The chemomodulatory effects of resveratrol and didox on herceptin cytotoxicity in breast cancer cell lines
Authors: Ellatif Ghada A. Abd , Tadros Marianne Georges , Naim Ashraf Bahey Eldin Abd El , Khalifa Amany Ibrahim , Alabd Ahmad M. 
Published: May 2015

Abstract
Herceptin is considered an essential treatment option for double negative breast cancer. Resveratrol and didox are known chemopreventive agents with potential anticancer properties. The aim of the current study is to investigate the influence of resveratrol and didox on the cytotoxicity profile of herceptin in her-2 receptor positive and her-2 receptor negative breast cancer cell lines. The IC50's of herceptin in T47D and MCF-7 were 0.126±0.01 ng/ml and 26.71±1.85 ng/ml respectively. Equitoxic combination of herceptin with resveratrol or didox in T47D significantly reduced the IC50 to 0.05±0.01 and 0.029±0.006 ng/ml, respectively and similar results were obtained in MCF-7. The gene expression of Bcl-xl was markedly decreased in T47D cells following treatment with herceptin/resveratrol compared to herceptin alone. Immunocytochemical staining of her-2 receptor in T47D cells showed a significant reduction after treatment with herceptin/resveratrol combination compared to herceptin alone. On the other hand, combination of herceptin and didox had no significant effect on her-2 receptor expression. Cell cycle analysis showed an arrest at G2/M phase for both cell lines following treatment with herceptin alone and in either combinations regimen. In conclusion the combination of herceptin with resveratrol and didox improved the cytotoxic profile of herceptin in T47D (her-2 receptor positive cell line) and to a lesser extent in MCF-7 (her-2 receptor negative cell line).
Citation Format: Ghada A. Abd Ellatif, Marianne Georges Tadros, Ashraf Bahey Eldin Abd El Naim, Amany Ibrahim Khalifa, Ahmad M. Alabd. The chemomodulatory effects of resveratrol and didox on herceptin cytotoxicity in breast 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 5114. doi:10.1158/1538-7445.AM2014-5114
Abstract 5115: The Bcl-2 Homology Domain-3 Mimetic, Obatoclax, chemosensitizes muscle invasive bladder cancer cell lines to cisplatin treatment
Authors: Steele Thomas , Pham Dan , Phan Kathy , Ghosh Paramita , White Ralph deVere , Vinall Ruth L. 
Published: May 2015

Abstract
The primary objective of this study was to determine whether inhibition of anti-apoptotic Bcl-2 family protein activity causes decreased clonogenicity and/or increased apoptosis of muscle invasive bladder cancer (MI-BC) cell lines when used in combination with cisplatin, the standard of care treatment for MI-BC, and/or pre-miR-34a, a miRNA that targets several components of pathways know to promote tumor progression and chemoresistance. Obatoclax, a Bcl-2 homology domain-3 mimetic that has been demonstrated to prevent Bcl-2, Bcl-xL, and Mcl-1 from interacting with and inhibiting Bax and Bak, was used for this study. The impact of Obatoclax, in combination with cisplatin and/or pre-miR-34a, on clonogenic potential and apoptosis was assessed in three MI-BC cell lines (T24, TCCSuP, 5637) using clonogenic assay and annexin V flow cytometry respectively. The ability of Obatoclax to prevent interaction between Bcl-2, Bcl-xL, and Mcl-1, with Bax and Bak was assessed via immunoprecipitation and western blot. The impact of treatments on apoptosis/survival pathways was assessed via western blot. Obatoclax mediated a dose-dependent increase in apoptosis in all three MI-BC cell lines. Obatoclax was able to decrease binding of Bak to Bcl-xL, and cause decreased expression of Bcl-2 and Bcl-xL. Unexpectedly, Obatoclax also mediated a dose-dependent decrease in cdk4, cdk6, and cyclin D1. Combining Obatoclax with cisplatin or/and pre-miR-34a caused further inhibition of clonogenic potential of all three cell lines compared to treatment with single agents. Of the combination treatments, Obatoclax combined with cisplatin mediated the biggest increase in apoptosis levels. Treatment with Obatoclax, cisplatin, and pre-miR-34a actually decreased apoptosis levels. Western blot revealed that treatment with Obatoclax was unable to overcome the effect of pre-miR-34a on causing increased Bcl-2 and Bcl-xL expression. Our data demonstrate that Obatoclax chemosensitizes MI-BC cell lines to cisplatin and indicate that in vivo testing of this combination treatment is warranted. The data do not support further testing of pre-miR-34a in this setting. With the current 5-year survival rate for MI-BC being only 35%, clearly new and improved treatment options are needed for this disease.
Citation Format: Thomas Steele, Dan Pham, Kathy Phan, Paramita Ghosh, Ralph deVere White, Ruth L. Vinall. The Bcl-2 Homology Domain-3 Mimetic, Obatoclax, chemosensitizes muscle invasive bladder cancer cell lines to cisplatin treatment. [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 5115. doi:10.1158/1538-7445.AM2014-5115
Abstract 5130: Functional role of the crosstalk between arginine methylation and phosphorylation of hnRNPK during DNA damage
Authors: Yang Jen-Hao 
Published: May 2015

Abstract
HnRNPK is an RNA/DNA binding protein participating in chromatin remolding, RNA processing and DNA damage response. In addition, elevation of hnRNPK has been associated with tumor development and progression. Moreover, hnRNPK is known as co-transcription factor of p53 to regulate cell cycle arrest and apoptosis upon DNA damage. A variety of post-translational modifications of hnRNPK has been identified and shown to regulate its function, including phosphorylation, ubiquitination, sumoylation and methylation. However, the functional significance of hnRNPK arginine methylation remains unclear. In this study, we characterize the function of two essential arginine methylation of hnRNPK and demonstrate that they are able to inhibit the nearby PKCδ phosphorylation. Since PKCδ is a pro-apoptotic kinase upon DNA damage, we further investigate whether these essential arginine methylations of hnRNPK participate in the regulation of cell apoptosis.
Citation Format: Jen-Hao Yang. Functional role of the crosstalk between arginine methylation and phosphorylation of hnRNPK during DNA damage. [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 5130. doi:10.1158/1538-7445.AM2014-5130
Abstract 5141: Inhibition of HDAC1 leads to subtype switching in the SW13 adrenal adenocarcinoma line
Authors: Lam Jessica M. , Daggett Juliane , Leyva Kathryn J. , Hull Elizabeth E. 
Published: May 2015

Abstract
HDAC (histone deacetylase) enzymes are highly expressed in cancer cells and HDAC inhibitors have shown promise in clinical trials for certain patients in multiple types of cancer. In this context, the ability of the SW13 human adrenal adenocarcinoma line to switch between two well-established subtypes in response to HDAC inhibition is of interest. However, the previously characterized inhibitor (trichostatin A) is a toxic, broad-spectrum inhibitor affecting both class I and class II HDACs which have roles in the nucleus and cytosol, respectively. Multiple HDAC inhibitors are screened for their ability induce switching between the SW13 subtypes to identify which HDAC enzyme is necessary for controlling SW13 subtype switching. Results suggest that inhibition of class I HDAC1 increases the rate of conversion between SW13- to SW13+ cells. The effect of HDAC1 inhibition may be enhanced by HDAC3 inhibition as MS-275, an inhibitor specific for HDAC1 but with some specificity for HDAC3, is most effective, particularly when compared to the efficacy of depudecin, an HDAC1 specific inhibitor. After conversion to SW13+, there is increased acetylation on histone H3 but not histone H4 when compared to levels in SW13-, suggesting that the role of acetylation on the H3 tail plays an essential role in the subtype switch. SW13- cells do not express Brg1 or Brm, the mutually exclusive ATPase subunits of the SWI/SNF complex, and do not have an active SWI/SNF complex. Altered activity of this complex and the increased histone H3 acetylation may contribute to the extensive changes in gene expression observed between SW13+ and SW13- subtypes.
Citation Format: Jessica M. Lam, Juliane Daggett, Kathryn J. Leyva, Elizabeth E. Hull. Inhibition of HDAC1 leads to subtype switching in the SW13 adrenal adenocarcinoma line. [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 5141. doi:10.1158/1538-7445.AM2014-5141
Abstract 5145: KDM2B expression regulates ribosome biogenesis and cancer cell growth in a p53-dependent manner
Authors: Penzo Marianna , Casoli Lucia , Sicuro Laura , Galibiati Alice , Pollutri Daniela , Govoni Marzia , Ceccarelli Claudio , Santini Donatella , Taffurelli Mario , Treré Davide , Montanaro Lorenzo 
Published: May 2015

Abstract
Ribosome biogenesis is a cellular process requiring a fine-tuned control, as its deregulation is linked to cancer progression. Indeed, tumors characterized by an intense ribosome biogenesis often display a more aggressive biological and clinical behavior. Ribosomal RNA (rRNA) synthesis is controlled at several levels, the higher one being the epigenetic regulation of chromatin portions containing rRNA genes. KDM2B (Lysine (K)-specific demethylase 2B) is a histone demethylase modulating the accessibility of rRNA genes, thereby repressing their transcription. In particular KDM2B is known to specifically act on trimethylated K4 of histone H3 (H3K4) associated with rDNA. In this study we aimed to define the contribution of KDM2B expression to the biological features of breast cancer, a tumor type whose clinical behavior is known to be related to the rate of ribosome biogenesis. We show that, in primary breast carcinomas, lower KDM2B expression correlates with an increased size of specifically stained nucleolar organizer regions, a morphological parameter directly related to the rate of ribosome biogenesis, and with a poorer prognosis. In vitro, in breast cancer-derived cell lines, siRNA mediated KDM2B knock-down (KD) induced an increase in H3K4 trimethylation and in rRNA transcription. However, this is mirrored by an augmented cell proliferation only in p53 compromised cells, while p53 competent cells undergo cellular senescence and death. The latter effect, appears to be mediated by a p38-mediated phosphorylation of p53, inducing the expression of p15Ink4b and p21Waf1, and is not linked to p53 stabilization. In the long term, stable KDM2B KD in p53-compromised breast cancer cells induced a series of additional biological features including their augmented cellular clonogenic potential and invasive capability. Altogether our data indicate that abnormal JHDM1B-mediated epigenetic activation of rDNA genes elicits a p53-mediated growth arrest, but may promote cancer cell growth when p53 is lacking.
Citation Format: Marianna Penzo, Lucia Casoli, Laura Sicuro, Alice Galibiati, Daniela Pollutri, Marzia Govoni, Claudio Ceccarelli, Donatella Santini, Mario Taffurelli, Davide Treré, Lorenzo Montanaro. KDM2B expression regulates ribosome biogenesis and cancer cell growth in a p53-dependent manner. [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 5145. doi:10.1158/1538-7445.AM2014-5145
Abstract 5147: Deregulation of G9a and its functional roles in liver cancer
Authors: Wei Lai , Tsang Felice Ho-Ching , Lau Jeffery Chi-Fai , Au Sandy Leung-Kuen , Lee Joyce Man-Fong , Wong Carmen Chak-Lui , Ng Irene Oi-Lin , Wong Chun-Ming 
Published: May 2015

Abstract
Liver cancer, primarily hepatocellular carcinoma (HCC), is the fifth most common cancers and the third leading cause of cancer mortality worldwide. In recent years, deregulated epigenetic mechanisms were found important in a wide range of human carcinogenesis, including HCC. The epigenetic changes elicited by various environmental factors and lifestyles (such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, chronic alcohol intake) were suspected to promote HCC development. However, the underlying mechanism and specific gene targets are still unknown. Our previous study suggested that deregulation of epigenetic regulators was a common event in human HCC. Among 90 epigenetic modifiers analyzed in human HCC, Euchromatic histone-lysine N-methyltransferase 2 (EHMT2/G9a) was the most significantly up-regulated one. G9a is a SET domain containing histone methyltransferase specific for histone H3 lysine 9 mono- and di-methylation. Previous work had revealed that G9a is important for embryonic development and adipocyte differentiation. However, little is known about functional roles of G9a in human HCC. We hypothesize that deregulation of G9a may led to aberrant epigenetic changes and contribute to initiation and progression of human HCC. In this study, we found that G9a mRNA expression in primary HCC was 3 folder than their corresponding non-tumor liver and 10 fold higher than normal livers. The up-regulation of G9a was detected in 63% (24/38) of primary HCC samples and was significantly associated with the presence of venous invasion (P = 0.006). The frequent G9a up-regulation in HCC was attributed to gene amplification and microRNA deregulation. We showed that 53% of HCC samples have 3 or more copies of G9a gene. In addition, we identified that miR-1 was a post-transcriptional regulator of G9a. Ectopic expression of miR-1 suppressed G9a 3′-untranslated-region-coupled luciferase activity. Functionally, knockdown of G9a significantly suppressed HCC cell proliferation, migration and colony formation. We also demonstrated that UNC0638, as a G9a specific inhibitor, could effectively inhibit HCC cell growth and cause cell morphology changes. By utilizing nude mice model, we showed that depletion of G9a drastically inhibited in vivo tumorigenicity. Our finding suggested that up-regulation of G9a contributed to the liver carcinogenesis and could be a therapeutic target for HCC treatment.
Citation Format: Lai Wei, Felice Ho-Ching Tsang, Jeffery Chi-Fai Lau, Sandy Leung-Kuen Au, Joyce Man-Fong Lee, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Chun-Ming Wong. Deregulation of G9a and its functional roles in liver 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 5147. doi:10.1158/1538-7445.AM2014-5147
Abstract 5150: JMJD3 suppresses progression of colorectal carcinoma by regulating cell cycle and anti-apoptosis
Authors: Tokunaga Ryuma , Nakagawa Shigeki , Sakamoto Yasuo , Karashima Ryuichi , Ida Satoshi , Imamura Yu , Ishimoto Takatsugu , Iwagami Shiro , Baba Yoshifumi , Miyamoto Yuji , Yoshida Naoya , Baba Hideo 
Published: May 2015

Abstract
Background: JMJD3 has been known to play important roles in transcriptional regulation and cell proliferation by demethylating histone3 lysin27 (H3K27) in various cancers. However, the mechanism underlying JMJD3-mediated transcriptional regulation and the relation with prognosis were unclear in colorectal carcinoma. Here, we investigated the expression of JMJD3 in clinical samples and the function of JMJD3 in colorectal carcinoma cell lines.
Methods: Quantitative real-time PCR were performed to check the expression of JMJD3 mRNA using the carcinoma and normal colorectal tissue in 14 colorectal carcinoma patients who underwent a curative surgery.
In vitro analysis, we investigated the expression of JMJD3 in colorectal carcinoma cell lines by Western Blotting, and we knocked down the expression of JMJD3 by using small interfering RNA in Colo201 and colo320. The influence of JMJD3 on cell growth, apoptosis and cell cycle was assessed by growth assay, apoptosis assay and cell cycle analysis. We checked the changes of cell cycle related genes by real time PCR.
Results: In clinical samples, the expression of JMJD3 in carcinoma tissue was significantly lower than in normal tissue (P=0.02). In vitro analysis, we knocked down the expression of JMJD3 by siRNA targeting JMJD3 and checked the reduction on mRNA and protein level. Knockdown of JMJD3 significantly increased cell proliferation (P=0.02), reduced apoptosis (P=0.003), and increased G2/M phase population (P = 0.05) which was detected by FACS. Moreover, knockdown of JMJD3 significantly decreased the expression of p15INK4B in quantitative real-time PCR.
Conclusion: We showed the expression of JMJD3 in carcinoma tissue was lower than in normal tissue and demonstrated that the down-regulation of JMJD3 resulted in the increase of cell proliferation, acceleration of cell cycle and anti-apoptosis in vitro analysis. These results suggest that JMJD3 is a tumor suppressor gene for colorectal carcinoma.
Note: This abstract was not presented at the meeting.
Citation Format: Ryuma Tokunaga, Shigeki Nakagawa, Yasuo Sakamoto, Ryuichi Karashima, Satoshi Ida, Yu Imamura, Takatsugu Ishimoto, Shiro Iwagami, Yoshifumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. JMJD3 suppresses progression of colorectal carcinoma by regulating cell cycle and anti-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 5150. doi:10.1158/1538-7445.AM2014-5150