bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3216: Cytosolic leucine metabolism regulates the expression of prometastatic proteins: The genesis of a new druggable target
Authors: Papathanassiu Adonia E. , Vu Hong A. 
Published: August 2012

Abstract
Branched chain amino acid metabolism begins with the reversible transamination of the amino acids to the corresponding α-keto acids. The reaction is catalyzed by the enzyme Bcat. The cytosolic form of this enzyme, also known as Bcat1, is thought to be expressed only in embryonic tissues, in select adult organs (brain, ovary), and in c-myc induced brain tumors. In the current study, Bcat1 is shown to be expressed by a variety of tumor cell lines including MCF-7, MDA-MB-231, MDA-MB-435, and HT-29. Its expression appears to be associated with the ability of the cells to uptake glucose since treatment of MDA-MB-231 with 2-deoxyglucose leads to the suppression of the cellular Bcat1 levels in vitro and in vivo. In the cytosol, Bcat1 appears to complex with CD147, a protein known to promote cancer growth and metastasis through multiple pathways. Silencing of Bcat1 in MDA-MB-231 and MDA-MB-435 cells results in the downregulation of CD147, while inhibition of Bcat1 by ERG-240, a small molecule structurally related to leucine, leads to downregulation of the cell surface expressed CD147 and its transmembrane partner monocarboxylate transporter-4 (MCT-4) in MDA-MB-231 breast cancer cells. MCT-4 is known to mediate the expedient removal of lactate, a cytotoxic by-product of cancer glycolysis, from the cytosol. Furthermore, treatment of MDA-MB-435 cells with 10 mM ERG-240 results in downregulation of matrix metalloproteinase 9 (MMP-9) production, while treatment of normal adult fibroblasts with either ERG-240 or conditioned media of MDA-MB-435 cells previously exposed to ERG-240 results in downregulation of MMP-2 production. The later is attributed to the ability of ERG240 to suppress the presence of soluble CD147 in the conditioned media. Exocytosis of CD147 has been implicated in the formation of the pre-metastatic niche through inductions of MMPs and VEGF. Inhibition of Bcat1 by ERG-240 suppresses cell proliferation in various tumor cell lines with an IC50 value of 5 to 10 mM. ERG240-induced inhibition of MDA-MB-231 cell migration is also observed. The results from an on-going in vivo study are presented. In summary, our experiments suggest that: a) metabolism of branched chain amino acids is intimately linked with the expression of proteins controlling metastatic activities of tumor cells and b) Bcat1, which is not expressed by normal adult tissues, is an attractive target for the development of new, non-toxic anticancer therapies.
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 3216. doi:1538-7445.AM2012-3216
Abstract 3223: Magnetic resonance spectroscopic imaging of lactate in LDH-A silenced metastatic breast tumors
Authors: Rizwan Asif , Serganova Inna , Ni Xiaohui , Thakur Sunitha , Zakian Kristen L. , Blasberg Ronald , Koutcher Jason 
Published: August 2012

Abstract
Glucose and glutamine are the major carbon sources for rapidly proliferating tumors. They provide the precursors for proteins, lipids, and nucleic acids, and as well as metabolic-reducing capability (NADPH). Pyruvate is mainly derived from glucose and glutamine metabolism and can be converted to lactate by the lactate dehydrogenase (LDH) complex or enter the TCA cycle for conversion to CO2 and ATP. Recently, a link between tumor lactate levels (monitored by MRSI), LDH-A expression and tumor phenotype has been demonstrated (Serganova I. et al., 2011). We hypothesize that tumor lactate levels monitored by MRSI will reflect LDH-A enzymatic activity, tumor “aggressiveness” and the propensity for developing metastases. The current study employs 4T1 cells bearing the stable produced LDH-A shRNA to down regulate the level of LDH-A expression. LDH-A silenced and control 4T1 breast cancer cells were injected into the mammary fat pad of athymic nu/nu female mice (5 mice for each group). The in vivo growth rate of the LDH-A silenced tumors was significantly slower than that of control tumors; the average doubling time of the LDH-A silenced tumors was 1.5 fold higher than control tumors (p&lt;0.01). The lactate signal was acquired using a selective multiple-quantum coherence transfer (SelMQC) editing sequence in combination with chemical shift imaging (CSI) (He Q. et al., 1995). The tumors were scanned at small (∼100 mm3) and larger (∼300 mm3) volumes and in vivo lactate concentration was measured. The LDH-A silenced tumors produce less lactate, ∼ 6 mM at small volumes and ∼ 3 mM at larger volumes, whereas the control tumors produce ∼ 11 mM at small, and ∼7 mM at larger volumes. Preliminary results suggest that high tumor lactate concentrations are linked with a greater propensity to develop metastases. Studies evaluating metastatic burden are ongoing. We suggest that LDH-A expression and tumor lactate levels may be potential markers of elevated metastatic potential. In addition, MRSI might offer a noninvasive approach for assessing tumor progression and metastatic potential.
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 3223. doi:1538-7445.AM2012-3223
Abstract 3230: Fenofibrate-mediated energy crisis and apoptotic cell death of glioblastoma
Authors: Wilk Anna M. , Urbanska Katarzyna , Impastato David , Reiss Krzysztof 
Published: August 2012

Abstract
Glioblastomas are one of the most aggressive brain tumors which are characterized by rapid cell growth, infiltration of the Central Nervous System (CNS), and resistance to all known anticancer regiments. Therefore, the development of new more effective therapies against Glioblastoma is the major challenge for modern medicine. Fenofibrate, a drug widely utilized to lower lipid concentration in the blood, is one of the very promising anti-cancer treatments with low systemic toxicity. This potent agonist of PPARδ is thought to shift energy metabolism from glycolysis to fatty acid α-oxidation and, therefore, it may be toxic to glycolysis -dependent brain tumor cells (Warburg effect). While the toxicity to cancer cells appears to be clear, the precise mechanism/s of fenofibrate action against brain tumors seems to be much more complex and remains to be elucidated. To understand metabolic basis of the anti-cancer action of fenofibrate, we have analyzed extracellular acidification (ECAR) and oxygen consumption (OCR) using XF 24 Extracellular Flux Analyzer (Seahorse Bioscience), mitochondrial membrane potential as well as ATP level in different glioblastoma cell lines (LN229, U87MG, T98G). Surprisingly, we found that basal oxygen consumption (OCR) decreased significantly in Glioblastoma cells pretreated with fenofibrate, and the addition of metabolic toxins did not change their metabolic profile. Decreased oxygen consumption was due to the direct interaction of fenofibrate with complex I, a protein involved in the mitochondrial electron transport chain. We additionally found that, in parallel to the metabolic changes, fenofibrate triggers cell cycle arrest followed by apoptosis. The mechanisms involve a PPARδ-mediated effect, which leads to the energy crisis and apoptosis, as well as a PPARδ-independent pathway which results in FOXO3a nuclear translocation and activation of the proapoptotic protein Bim. Overall our data strongly support an anticancer action of fenofibrate by shifting the glycolitic-dependent cell metabolism to fatty acids α-oxidation with subsequent energy crisis and apoptotic cell death.
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 3230. doi:1538-7445.AM2012-3230
Abstract 3232: CZ48 activation by human tumor cytosol inhibited in the presence of NADPH
Authors: Markides Constantine S.A. , Battershell Lauren E. , Vardeman Dana M. , Giovanella Beppino C. 
Published: August 2012

Abstract
CZ48, the 20-O-propionate ester of Camptothecin (CPT), is a non-toxic prodrug of CPT first described by Cao et al. (1998). The propionate side-chain is enzymatically cleaved in target tissues. This gives rise to CPT, an inhibitor of Topoisomerase I, which then blocks cell division causing selective tumor toxicity. We have previously established the preferential activation of CZ48 in tumor tissues compared to normal tissues and an ultra-sensitive assay to detect it (2009). The present studies explore the specifics of that activation in vitro using both cells in culture and surgically removed xenografted tumors from nude mice. DOY lung adenocarcinoma was grown subcutaneously in nude mice and then surgically excised, homogenized and serially centrifuged to produce specific subcellular fractions. The bulk of esterase activity was found to be concentrated in the cytosol, while the microsomal fraction showed minimal activity. All other fractions tested were below the limit of detection. Microsomes showed only a fraction of the esterase activity of the cytosol (99.78 ± 14.89 ng/ml versus 487.48 ± 16.69 ng/ml CPT produced overnight), but even that little activity was eradicated in the presence of an NADPH redux regeneration system (10.0 ± 7.26 ng/ml). This inhibition was also observed in the cytosolic fractions. Deconstructing the redux system led to the conclusion that NADPH was inhibiting the activation of CZ48: when incubating cytosol with CZ48 in the presence of 26.1 mM NADPH, 66mM MgCl2, or 66mM Glucose-6-phosphate, only NADPH exhibited any effect on the esterase activity of CZ48, resulting in only 106.00 ± 15.49 ng/ml CPT produced overnight. These data reinforce the notion that CZ48 is metabolized to CPT by a non-microsomal, non CYP450 enzymatic process in tumor tissues.
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 3232. doi:1538-7445.AM2012-3232
Abstract 3237: XRay structure of human glutaminase in complex with BPTES and analysis of BPTES-resistant mutants
Authors: Delabarre Byron , Hurov Jonathan , Gross Stefan 
Published: August 2012

Abstract
Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. A splice variant of GLS1 (GAC) is elevated in certain cancers and is specifically inhibited by bis-2-(5-phenylacetimido-1,2,4, thiadiazol-2-yl)ethyl sulfide (BPTES). We describe here the first full length crystal structure of GAC both in the presence and absence of BPTES molecules. Two BPTES molecules bind at a interface region of the GAC tetramer in a manner which appears to lock the GAC tetramer into a non-productive conformation. The importance of these loops with regards to overall enzymatic activity of the tetramer was revealed by a series of GAC point mutants designed to create a BPTES resistant GAC. An unintended but nonetheless interesting transfer of phosphate activation activity was observed upon inserting key residues from GLS-2 into GLS-1.
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 3237. doi:1538-7445.AM2012-3237
Abstract 3242: Wnt secretion is required for colon cancer cell survival
Authors: Voloshanenko Oksana , Erdmann Gerrit , Iris Augustin , Boutros Michael 
Published: August 2012

Abstract
Aberrant activation of Wnt signalling has an important function in the onset and progression of colorectal cancer. Sporadic colorectal carcinomas are associated with mutations in APC or β-catenin, leading to a constitutive activation by preventing the degradation of β-catenin, allowing its accumulation in the nucleus and drive the expression of transcriptional target for growth and proliferation. While mutations in APC or β-catenin are found in almost all cases of sporadic colon cancer, the molecular circuits that control Wnt signalling pathways in colon cancer cells have not been fully resolved. Here we show that colon cancer cells require Wnt secretion for survival. We combined RNAi-mediated depletion of signalling factors and transcriptional profiling to map the topology of Wnt pathways. We demonstrate that Evi/Wls, a protein required for the secretion of Wnt proteins, impairs the expression of β-catenin dependent transcriptional targets. Blocking Wnt secretion is sufficient to inhibit Wnt signalling and cell survival of colon cancer cell lines ex vivo and in vivo, independent of their APC and β-catenin mutational status. We conclude that mutations in APC and β-catenin in colon cancer do not render colon cancers independent of autocrine activation through Wnt ligands. These results may open new avenues for therapeutic interventions in colon cancer by antagonists of Wnt signalling that act at or upstream of the receptor level.
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 3242. doi:1538-7445.AM2012-3242
Abstract 3246: TMS1 / ASC is critical for primary ciliogenesis and participates in cell migration
Authors: Abreu Eladio , Patel Pritty , Kline Erik , Marcus Adam , Vertino Paula 
Published: August 2012

Abstract
TMS1/ ASC encodes a bipartite signaling protein that functions in programmed cell death and proinflammatory response. Loss of function of TMS1/ASC through epigenetic silencing has been implicated in the pathogenesis of several malignancies, including breast and prostate cancer, although the precise mechanism by which TMS1 loss promotes tumorigenesis remains unclear. Recently, we showed that, in breast epithelial cells, TMS1/ASC silencing promotes resistance to detachment induced apoptosis or ‘anoikis’ through a mechanism that involves the inhibition of procaspase-8 cleavage and Bim upregulation. Here, we further characterized the role of TMS1 in breast epithelial cell adhesion and motility. We found that while TMS1 was dispensable for adhesion to fibronectin, it was necessary for efficient migration across a transwell chamber towards a chemoattractant and in wound-closure. siRNA mediated silencing of TMS1 inhibited breast cell invasion through a Matrigel matrix. Subcellular localization studies showed that adhesion of breast epithelial cells to a fibronectin substratum induced the aggregation of TMS1 into barrel-like structures that formed at the apical cell surface. Primary cilia are solitary, sensory organelles that serve as platforms for multiple signaling pathways. Signalling from these organelles plays an important role in linking environmental cues to cell growth control. Interestingly, primary cilia are observed at much lower frequencies on cancer cells. Physical and temporal similarities between the observed TMS1 barrel-like structures and the basal structures of primary cilia suggest that TMS1 may be linked to adhesion and migration activities by regulating the function and/or biogenesis of primary cilia. To test this hypothesis, we used HEK293 kidney epithelial cells expressing an inducible myc-tagged TMS1 and TMS1-/- MEFs to explore the role of TMS1 in primary ciliogenesis. We found that in the absence of TMS1, HEK293 cells were unable to produce primary cilia, but cilia formation could be induced upon TMS1 induction. Taken together, our studies provide evidence of a novel non-apoptotic, inflammasome-independent role for TMS1 in epithelial cell biology. Furthermore, TMS1 silencing may contribute to carcinogenesis by conferring a tumor suppression disadvantage resulting from primary ciliogenesis deficiencies. Supported by Department of Defense/CDMRP Breast cancer grant W81XWH-08-1-0390 and NIH Institutional Research and Academic Career Development Award (IRACDA) K12GM000680.
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 3246. doi:1538-7445.AM2012-3246
Abstract 3383: Expression and role of BORIS/CTCFL in human cancer stem cells
Authors: Benhattar Jean , Alberti Loredana 
Published: August 2012

Abstract
The existence of CSCs, a small population that drives the tumors development, progression, metastasis and drug resistance, could explain the failure of several anti-cancer therapy. The discovery of the genes responsible for the CSCs phenotype would point out to the development of new target for the cancer therapy. To date, many tumor markers have been identified but almost none of them are specific to target the CSCs population. The cancer testis gene BORIS/CTCFL was shown to be exclusively expressed in germ cells in normal tissues and was involved in epigenetic reprogramming. BORIS is slightly activated in a wide variety of tumors. It is not clear if this expression is due to basal expression in almost all tumor cells or rather to the expression in a restricted population of cells, as in the CSC. To date, there is no validated antibody against BORIS. Therefore, to analyze BORIS expression in vivo, we developed a molecular beacon (MB) imaging technology to detect BORIS mRNA gene expression. BORIS MB binds to its specific target and produced fluorescence signal at 37°C in vitro, as well as in vivo in the cells expressing high level of BORIS mRNA. BORIS was found to be expressed only in Side Population cells (Hoechst negative cells) in different tumor cell lines (HeLa, HT29, Raji, MB-MDA-231). Our data indicates that BORIS-positive cells are present at low frequency (0.01% is the estimated frequency) in tumor cell lines. Quantitative RT-PCR analysis revealed a significantly higher expression level of BORIS in SP sorted cells (10-20 fold) compared to that from non-SP cells, similar resultswere obtained in colon spheres (40 fold) compared to adherent cells. This result indicates that BORIS is overexpressed in CSCs enriched population of tumor cells. To define the potential role of BORIS in CSCs, we performed shRNA knockdown experiments in several tumor cell lines. We found that BORIS mRNA inhibition could allow decreasing cancer cell survival in studied tumor cell lines, supporting the hypothesis that BORIS could be critical for the survival and self-renewal of tumors. In conclusion, our study provides evidence that BORIS/CTCFL is a promising marker of CSCs that could also play a critical role in the maintenance of self-renewal capacity of the tumor initiating cells and as a consequence, of tumor survival. Therefore, due to its restricted expression in normal tissues and its reexpression in a wide variety of tumors, BORIS/CTCFL could become a good target for cancer therapy.
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 3383. doi:1538-7445.AM2012-3383
Abstract 3391: Interaction of microRNAs and target genes in bladder cancer metastasis
Authors: Ru Yuanbin , Kechris Katerina J. , Smith Steven C. , Calin George A. , Theodorescu Dan 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through base pairing with other mRNA transcripts. MiRNA expression signatures have characterized many phenotypes in bladder cancer, including grade, stage, and metastasis. However, simultaneous mRNA changes accompanying the miRNA profile, along with the miRNA:mRNA interaction, were not systematically studied in these phenotypes. To gain insights into the miRNA regulatory network in bladder cancer metastasis, we profiled miRNA and mRNA expressions in two pairs of metastatic and non-metastatic cell lines. Interactions between differentially expressed miRNAs and mRNAs were predicted using six software. We identified 194 miRNA:mRNA pairs between 18 up-regulated miRNAs and 66 down-regulated genes in metastatic cells; while the down-regulation of miRNAs and the increased expression of target genes were rare. The overexpression of one of the miRNAs, hsa-miR-146a, is confirmed by quantitative RT-PCR in metastatic cell lines. The 66 potential target genes are enriched in cytoskeleton organization and actin binding, underlining the importance of cell motility in cancer metastasis. Analysis of microarray data from two patient cohorts indicated lower expression of the 66 miRNA target genes in tumors than in normal bladder tissues. Our results suggest the significance of miRNA regulatory network in cancer metastasis and provide a list of potential miRNA:mRNA pairs for further investigation.
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 3391. doi:1538-7445.AM2012-3391