bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1160: CtBP1 is the molecular link that associates breast cancer and metabolic syndrome
Authors: De Luca Paola , Dalton Nicolás , Moiola Cristian Pablo , Flumian Carolina , Scalise Georgina , Porretti Juliana , Massillo Cintia , Kordon Edith , Todaro Laura , Vazquez Elba , Meiss Roberto , De Siervi Adriana 
Published: August 2015

Abstract
Breast cancer is still one of the most important public health problems in the entire world. Obesity and metabolic syndrome (MS) increases the incidence and aggressiveness of breast cancer. C-Terminal Binding Protein (CtBP1) is a transcriptional corepressor of tumor suppressor genes and is considered a molecular sensor of cell metabolic state due to is activated in high energy conditions (high NADH). In this work we studied the effects of the activation of CtBP1 pathway by metabolic syndrome on breast tumor development and progression. We generated a murine model of MS by chronic high fat diet (HFD) administration. By histological and whole mount methods, we found that breast tissue of animals receiving HFD presented higher levels of immature adipose tissue and an increased glandular area with more generation of lateral branches and terminal end buds of mammary ducts. Breast tissue of HFD animals also showed higher expression of the proliferation markers (cyclin D1) and epithelial markers (E-cadherin). Interestingly, HFD induced CtBP1 expression in the mammary ducts. Furthermore, the number and size of mamospheres generated with LM38-LP breast cancer cells were significantly increased when cells were incubated with serum from HFD fed mice compared to the serum of animals under control diet (CD). In addition, to investigate CtBP1 role in tumor progression we performed xenografts in nude mice fed with CD or HFD by subcutaneous injecton of breast tumor cells MDA MB 231 with depleted CtBP1 expression (shRNA CtBP1) or control cells (shRNA scramble). We found that CtBP1 depletion dramatically decreased tumor growth and KI67 expression relative to control tumors. Furthermore, xenografts developed in HFD fed mice were less differentiated compared to CD. Finally, CtBP1 diminished expression tumors showed lower mesenchymal markers expression, progenitor cells markers and markers involved in mammary development. Our studies demonstrated for the first time that gene transcription regulation by CtBP1 provides an important molecular link among MS, CtBP1 function and tumor growth. Hence, these results suggest an association to understand metabolism and breast cancer.
Citation Format: Paola De Luca, Nicolás Dalton, Cristian Pablo Moiola, Carolina Flumian, Georgina Scalise, Juliana Porretti, Cintia Massillo, Edith Kordon, Laura Todaro, Elba Vazquez, Roberto Meiss, Adriana De Siervi. CtBP1 is the molecular link that associates breast cancer and metabolic syndrome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1160. doi:10.1158/1538-7445.AM2015-1160
Abstract 1161: Metformin has an inhibitory effect on cell proliferation but does not induce death in colorectal cancer
Authors: Mogavero Angela , Maiorana Maria Valeria , Bertan Claudia , Bozzi Fabio , Pierotti Marco A. , Gariboldi Manuela 
Published: August 2015

Abstract
Metformin, a widely used and well-tolerated antidiabetic drug, may reduce cancer risk and improve prognosis of certain malignancies. In vitro and in vivo studies on several cancer models have evaluated the potential antitumorigenic effects of metformin and many clinical trials are looking to its use for suppressing tumor growth. However, the mechanism for its anti-cancer effect remains uncertain and needs to be clarified. Here we investigated the anti-cancer activity of metformin on colorectal cancer growth by treating three colorectal cancer cell lines, HT29, HCT116, HCT116p53-/-, with the drug. We found that, at a dose of 5mM, metformin reduced cell proliferation in all the colorectal cancer cells analyzed, as shown by BrdU incorporation assays. Metformin induced cell cycle arrest in G0/G1 phase that was accompanied by a strong decrease of cyclin D1, c-Myc expression, and inhibition of pRB phosphorylation. The antiproliferative activity of the drug resulted mediated by suppression of mTOR and IGF-1/AKT pathways. In particular, we observed inactivation of mTOR and of its downstream targets S6 and 4EBP1, both in an AMPK dependent and independent way, and also downregulation of the activity of IGF1R. We analysed the biological mechanisms by which metformin inhibited cell proliferation by evaluating its ability to induce apoptosis, autophagy or senescence, as observed in other cancer cell lines. Unexpectedly, we found that metformin did not stimulate any of these mechanisms in colorectal cancer cells. In support of these results, a colony formation assay showed that metformin did not arrest growth of cells, but only slowed down cell ability of forming colonies. Our findings highlight that metformin inhibits the proliferation of colorectal cancer cell lines as a consequence of promoting cell cycle arrest in the G0/G1 phase, but does not induce cell death. Further investigations are needed to better elucidate the mechanisms altered by the drug in colorectal cancer and caution should be used when treating cancer patients with metformin.
Citation Format: Angela Mogavero, Maria Valeria Maiorana, Claudia Bertan, Fabio Bozzi, Marco A. Pierotti, Manuela Gariboldi. Metformin has an inhibitory effect on cell proliferation but does not induce death in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1161. doi:10.1158/1538-7445.AM2015-1161
Abstract 1162: Investigating the NAD metabolome in Ewing Sarcoma
Authors: Mutz Cornelia N. , Schwentner Raphaela , Kauer Maximilian O. , Ban Jozef , Aryee Dave N. T. , Erhardt Sophie , Fuchs Dietmar , Heitger Andreas , Kovar Heinrich 
Published: August 2015

Abstract
Ewing Sarcoma (ES) is the second most common bone cancer in children and adolescents with a high metastatic potential. Tumor development is driven by the specific t(11;22)(q24;q12) chromosomal translocation resulting in generation of the chimeric transcription factor EWS-FLI1.
Recently, ES has been reported to be exquisitely sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1). This enzyme uses NAD as substrate and was demonstrated to regulate EWS-FLI1 in a feed-back mechanism. NAD is a key metabolite essential for sustaining cellular energy metabolism. It plays a central role in cellular redox reactions, DNA repair, and in the maintenance of genomic stability serving as a donor of ADP-ribose. The other major mammalian NAD consumer is the deacetylase SIRT1 which we observed to be specifically highly expressed in ES metastases. PARP1 and SIRT1 are crucial for coupling cellular metabolism to transcriptional gene regulation as well as to stress response. Usually, NAD is regenerated from nicotinamide in the NAMPT-dependent salvage pathway or from the reduction of pyruvate via LDHA (Warburg effect), but can also be synthesized de novo from tryptophan. Interestingly, the knockdown of EWS-FLI1 in ES cells comes along with alterations in the expression of multiple enzymes involved in NAD biosynthesis and regeneration, including TDO2, KMO, NMNAT1, NAPRT, NAMPT, and LDHA. We are interrogating the role of EWS-FLI1 mediated modulation of these enzymes and of specific small molecule inhibitors on cellular tryptophan consumption, kynurenine production and intracellular NAD levels of Ewing sarcoma cells. Additionally, we are investigating the functional consequences thereof on constitutive and stress-induced protein poly(ADP)-ribosylation and acetylation.
Preliminary results suggest that NAMPT inhibition diminishes PARP1 activity due to low NAD, implying a pivotal role for the regenerative salvage pathway in ES cells. TDO2-dependent tryptophan consumption increases in the absence of the oncogene.
These studies aim at a better understanding of factors influencing Ewing sarcoma sensitivity to therapies targeting PARP1 and the NAD metabolome.
Citation Format: Cornelia N. Mutz, Raphaela Schwentner, Maximilian O. Kauer, Jozef Ban, Dave N. T. Aryee, Sophie Erhardt, Dietmar Fuchs, Andreas Heitger, Heinrich Kovar. Investigating the NAD metabolome in Ewing Sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1162. doi:10.1158/1538-7445.AM2015-1162
Abstract 117: DOT1L is a human chromosome stability gene
Authors: Guppy Brent , McManus Kirk 
Published: August 2015

Abstract
The loss of genome stability is an early event that drives the development and progression of virtually all tumor types. Recent studies have revealed that certain histone post-translational modifications exhibit dynamic and global increases in abundance that coincide with mitosis and exhibit essential roles in maintaining genomic stability. Histone H2B ubiquitination at lysine 120 (H2Bub1) is regulated by RNF20, an E3 ubiquitin ligase that is mutated/altered in numerous tumor types. Through an evolutionarily conserved trans-histone pathway, H2Bub1 is an essential pre-requisite for subsequent downstream di-methylation events at lysines 4 (H3K4me2) and 79 (H3K79me2) of histone H3. Although the role that RNF20 plays in tumorigenesis has garnered much attention, the downstream components of the trans-histone pathway, H3K4me2 and H3K79me2, and their potential contributions to genome stability remain largely overlooked. In this study, we employ single-cell imaging, and biochemical approaches to investigate the spatial and temporal patterning of RNF20, H2Bub1, H3K4me2 and H3K79me2 throughout the cell cycle. Using two independent human cell lines, we show that H2Bub1, H3K4me2 and H3K79me2 exhibit distinct temporal progression patterns throughout the cell cycle. Most notably, we demonstrate that H3K79me2 is a highly dynamic histone PTM that reaches maximal abundance during mitosis in an H2Bub1-independent manner. Using RNAi and chemical genetic approaches, we identify DOT1L as the histone methyltransferase responsible for mitotic-associated increases in H3K79me2. We also demonstrate that the loss of mitotic H3K79me2 levels correlates with increases in chromosome numbers and increases in mitotic defects. Collectively, these data suggest that H3K79me2 dynamics during mitosis are normally required to maintain genome stability and further implicate the loss of H3K79me2 during mitosis as a pathogenic event that contributes to the development and progression of tumors.
Citation Format: Brent Guppy, Kirk McManus. DOT1L is a human chromosome stability gene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 117. doi:10.1158/1538-7445.AM2015-117
Abstract 118: EGFL6, a potential novel ligand of EGFR, play roles in Nasopharyngeal cacinoma metastasis through establishing invasive and long-distant metastatic niche by paracrine and autocrine
Authors: Chen Jinna , Jiang Chen , Yang Jing , Yu Ya-hui , Li Lei , Xiang Yang-qun , Guan Xinyuan 
Published: August 2015

Abstract
Distant metastasis is the leading cause of treatment failure in Nasopharyngeal carcinoma (NPC). Our study focused on the searching of potential targets for NPC metastasis treatment. cDNA microarray was applied in this screening. We compared gene expression level in metastatic NPC, non-metastatic NPC and inflammatory cases with different bioinformatic methods. EGFL6 was chosen for further study. The over-expression of EGFL6 was confirmed in NPC cell lines and 63% of the metastatic cases(n = 7/11, 3 years follow-up) by Q-PCR. EGFL6 was identified as an independent prognostic index for NPC distant metastasis survival prognostic, P = 0.023 (n = 96, QPCR). As a follicle stem cell specifically expressed secretion protein, EGFL6 showed its powerful strength in promoting cell migration and especially the formation of aggressive morphology in the matrix-gel based three-dimensional culture. With the overexpression of secreting EGFL6, CNE2 cells formed the follicle-like structure but with more aggressive leading edge, which invaded deep into the matrix-gel instead of forming single layer epithelial structure. EGFL6 overexpressed SUNE1 cells breakthrough the restriction of its regular sphere structure, and migrated for more spaces. In vivo study also showed that EGFL6 dramatically increased the tumorigenisis in subcutaneous injection assay and the growth of metastatic tumor in the mice tail vein injection experiment. Mechanism study showed that EGFL6 was a potential novel ligand of EGFR. Our resulted demonstrated that EGFL6 could bind to EGFR and caused its phosphorylation, which activated EGFR and leaded to its internalization. c-Src was subsequently phosphorylated, and the MAPK/ERK signalling cascade was activated. The EGFL6 bound cells down-regulated their expression of E-cadherin and loosed the connection with the adjacent cells, strength their F-actin and vimentin towards the direction they migrated, which indicated a transition from epithelial to mesenchymal characteristic. Further study is on going to investigate the potential of EGFL6 as a therapeutic target for NPC metastatic treatment. In conclusion, we found that EGFL6 was a potential novel ligand of EGFR, which played roles in NPC metastasis through establishing invasive and long-distant metastatic cancer niche by paracrine and autocrine.
Citation Format: Jinna Chen, Chen Jiang, Jing Yang, Ya-hui Yu, Lei Li, Yang-qun Xiang, Xinyuan Guan. EGFL6, a potential novel ligand of EGFR, play roles in Nasopharyngeal cacinoma metastasis through establishing invasive and long-distant metastatic niche by paracrine and autocrine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 118. doi:10.1158/1538-7445.AM2015-118
Abstract 1180: Hexokinase II plays a pivotal role in colorectal cancer cell proliferation and survival
Authors: Ho Nelson , Coomber Brenda L. 
Published: August 2015

Abstract
The Warburg Effect describes the widely observed metabolic phenotype of cancer cells and their heavy reliance on the glycolytic pathway for energy production regardless of oxygen tension. This is a result of alterations to metabolic signaling pathways leading to an upregulation in key glycolytic enzymes. Hexokinase II (HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumors. 3-bromopyruvate (3BP) has been shown to primarily target HKII, and is a promising anti-cancer compound capable of targeting critical metabolic pathways in cancer cells. Here we examine the importance of HKII to cell proliferation and survival and also whether its inhibition could provide a therapeutic strategy in human colorectal cancer (CRC). Initially, established human CRC cell lines (HCT116, Caco2, SW480, DLD-1) were screened for HKII mRNA and protein expression. Cell proliferation and survival following HKII inhibition via both siRNA and 3BP treatment was determined using crystal violet staining, flow cytometry and western blotting. Sensitivity to 3BP was correlated with HKII expression amongst the cell lines screened. We next examined the pro-survival AKT signaling pathway via western blotting and found that AKT phosphorylation was dependent on 3BP dose and was residue-specific. Immunofluorescence was then used to examine subcellular HKII localization. Following 3BP treatment, mitochondrial localization of HKII was lost. As a result of tumor vascular abnormalities, regions within a tumor are exposed to transient and/or chronic ischemia, resulting in altered oxygen and nutrient availablity. To examine the effects of glucose availability on 3BP sensitivity, media glucose was gradually reduced in a step-wise manner and HKII expression, cell proliferation and cell survival were evaluated in CRC cell lines. Cells grown under reduced or normal glucose conditions were less sensitive to 3BP exposure than cells grown under high glucose conditions, and responses correlated with changes in HKII expression. Using immunostaining, we examined the expression of HKII in both normoxic and ischemic regions in FFPE samples of human CRC. These results were correlated to tumor stage and grade, along with patient outcome. Results from this study further define the role of HKII in colorectal cancer progression and show that 3-bromopyruvate could be useful as an anti-cancer therapy against CRC tumors with high expression of HKII.
Citation Format: Nelson Ho, Brenda L. Coomber. Hexokinase II plays a pivotal role in colorectal cancer cell proliferation and survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1180. doi:10.1158/1538-7445.AM2015-1180
Abstract 1183: Metabolic characterization of follicular lymphoma transformation
Authors: Poore Brad , Ortega-Molina Ana , Nguyen Christopher , Zhao Liang , Blackwell Anne , Hartung Thomas , Wendel Hans-Guido , Le Anne 
Published: August 2015

Abstract
Follicular lymphoma (FL), a form of non-Hodgkin lymphoma, is the second most common form of B-cell lymphoma and remains incurable in the majority of cases despite recent advances in therapy. Following an indolent phase, 50% of patients suffer disease transformation to an aggressive form of lymphoma (transformed FL; tFL). This dramatic switch in disease behavior typically culminates in rapid deterioration and patient demise. Accordingly, much effort has been focused on understanding the genetics of transformation and has resulted in the identification of key genetic lesions (e.g. MYC activation, loss of p53, cell cycle controls, activation of NFKB (TNFAIp3/A20)). However, exactly how tumor metabolism, which is altered by these genetic lesions, contributes to disease aggressiveness is not known and therefore the metabolic changes that occur upon FL transformation are poorly understood. We have developed a murine model of FL transformation that recapitulates key genetic and pathological aspects of human FL (Oricchio et al, 2011). This model allows us to study the genetics and metabolism of FL transformation. Specifically, we will systematically define the metabolic profiles of genetically defined murine lymphomas that represent different stages of transformation and cross-compare metabolic changes to primary patient samples. This ensures focus on clinically relevant changes and provides metabolic annotation of distinct tumor genotypes. This study builds on the complementary strengths of the Le lab (Johns Hopkins) in cancer metabolism and the Wendel lab (MSKCC) in modeling FL genetics. Our study shows that MYC transformed FL exhibits a distinct metabolic profile as compared to indolent follicular lymphoma or normal spleen. The most altered pathways examined thus far are glycolysis and amino acid metabolism. We believe that the transformed lymphoma is more reliant upon glycolysis and may be exhibiting aerobic glycolysis, also known as the Warburg Effect. This is substantiated from previous experiments in which a Burkitt lymphoma line, also overexpressing MYC, was found to have altered glycolytic intermediates levels. We next plan to examine the metabolic profile of other transformed follicular lymphoma models of known genetic backgrounds. We will also cross validate the transformed mouse models with follicular lymphoma patient samples of known genetic backgrounds to identify potential metabolic markers.
Citation Format: Brad Poore, Ana Ortega-Molina, Christopher Nguyen, Liang Zhao, Anne Blackwell, Thomas Hartung, Hans-Guido Wendel, Anne Le. Metabolic characterization of follicular lymphoma transformation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1183. doi:10.1158/1538-7445.AM2015-1183
Abstract 1194: O-GlcNAcylation regulates breast cancer lipid metabolism via sterol regulatory element binding protein 1
Authors: Sodi Valerie L. , Bacigalupa Zachary , Ferrer Christina , Reginato Mauricio 
Published: August 2015

Abstract
The Warburg hypothesis states that cancer cells display altered metabolic features to support their rapid growth and biosynthetic demands including increased glycolytic flux to synthesize necessary building blocks required by growing cells. Increased glucose uptake feeds not only glycolysis but other glucose dependent pathways as well, such as the Hexosamine Biosynthetic Pathway (HBP). HBP diverts fructose-6-phosphate from glycolysis to produce UDP-GlcNAc, the amino sugar donor to O-GlcNAc Transferase (OGT). Analagous to phosphorylation, O-GlcNAcylation can alter protein function and stability and itself is altered in several disease states. Our lab has demonstrated that OGT and O-GlcNAcylation are elevated in breast cancer and that expression of this enzyme is critical for various cancer phenotypes such as avoidance of ER stress and apoptosis, supporting invasion and metastasis and more recently promotion of Warburg effect. Here we demonstrate that OGT and O-GlcNAc are important for lipid metabolism in cancer cells through regulation of transcription factor SREBP-1 and its targets. Metabolic profiling revealed that OGT depletion in MDA-MB-231 cells decreased various lipids metabolites measured, including long-chain fatty acids, lysolipids and essential fatty acids. OGT suppression results in a decrease in SREBP-1 protein and mRNA and reduction of its transcriptional targets, enzymes involved in lipid synthesis, in both breast cancer cells and highly lipogenic normal tissue, the mammary fat pad. Over-expression of SREBP-1 blocks apoptosis induced by OGT suppression in 2D and 3D culture. Overall, we show that OGT and O-GlcNAc play a role in yet another process critical to cancer cell survival, lipid metabolism.
Citation Format: Valerie L. Sodi, Zachary Bacigalupa, Christina Ferrer, Mauricio Reginato. O-GlcNAcylation regulates breast cancer lipid metabolism via sterol regulatory element binding protein 1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1194. doi:10.1158/1538-7445.AM2015-1194