bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1011: Endostatin regulates androgen receptor-mediated metabolic and oxido-reductive pathways in prostate cancer cells
Authors: Lee Joo Hyoung , Kang Minsung , Mobley James A. , Sonpavde Guru , Garvey W. Timothy , Darley-Usmar Victor M. , Ponnazhagan Selvarangan 
Published: July 2016

Abstract
Endostatin (ES) has been recognized for decades as an endogenous protein with antiangiogenic function. Recent findings, however, indicate the pleiotropic effects of ES in different tissue and cell types, ensuing further investigation on unidentified molecular mechanisms of action. Previously, we have shown that ES exerts a direct role in suppressing prostate cancer cell proliferation by inhibiting androgen receptor (AR) activity, signifying therapeutic potential of ES for targeting both tumor epithelia and endothelia. Subsequent to this finding, we identified robust glucose influx and significant reduction of intracellular ROS levels in LNCaP cells upon ES treatment. The ES mutants with low AR binding did not promote glucose uptake through GLUT1 augmentation, suggesting that AR-targeted effects of ES include modulation of downstream metabolic pathways. Surprisingly, global proteome analysis showed that the levels of major metabolic enzymes either in glycolytic pathway or TCA cycle were not changed upon ES treatment. Instead, ES markedly increased the levels of G6PD (5-fold), NAMPT (2.5-fold), and NAPRT (5-fold), indicating upregulation of the late-limiting steps in NAD biosynthesis and pentose phosphate pathway (PPP). Further proteome analysis of ES-treated LNCaP cells strongly indicated upregulation of ROS scavenging machinery, including SOD2 (3- fold), CAT (2-folds), GSS (2-fold), GSR (1.8-fold), and POR (4.6-fold). Overall, these data suggest that ES can modulate intracellular ROS levels by augmenting glucose uptake, NAD biosynthesis, and the NADPH levels by shunting metabolic pathways to PPP. Given that basal ROS levels are known to increase upon disease progression to higher grade prostate tumors, ES effect of promoting ROS scavenging machinery can be employed as an adjuvant to re-sensitize prostate cancer cells to ROS-inducing chemo- and radiation therapies.
Abbreviations: CAT: catalase, GLUT1: glucose transporter isoform 1, G6PD: glucose-6-phosphate dehydrogenase, GSS: glutathione synthase, GSR: glutathione reductase, NAMPT: nicotinamide phosphoribosyltransferase, NAPRT: nicotinate phosphoribosyltransferase, POR: NADPH-cytochrome P450 reductase, ROS: reactive oxygen species, SOD2: manganese superoxide dismutase, TCA: tricarboxylic acid
Citation Format: Joo Hyoung Lee, Minsung Kang, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan. Endostatin regulates androgen receptor-mediated metabolic and oxido-reductive pathways in prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1011.
Abstract 1016: Variants in autophagy related genes and clinical characteristics in melanoma: a population-based study
Authors: White Kirsten A. m. , Luo Li , Thompson Todd A. , Torres Salina , Hu Chien-An A. , Thomas Nancy E. , Anton-Culver Hoda , Gruber Stephen B. , From Lynn , Busam Klaus J. , Orlow Irene , Kanetsky Peter A. , Marrett Lorraine D. , Gallagher Richard P. , Zanetti Roberto , Rosso Stefano , Dwyer Terry , Cust Anne E. , Venn Allison , Begg Colin B. , Berwick Marianne , Lillyquist Jenna 
Published: July 2016

Abstract
Autophagy has been linked with melanoma, but no polymorphisms in autophagy related (ATG) genes have been investigated for association with melanoma prognostic indicators and survival. We examined 5 ATG gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped for five SNPs with a known or suspected impact on autophagic flux. While we did not identify an association with survival, a significant association was identified between the minor allele for an ATG16L polymorphism (rs2241880) and a decrease in Breslow thickness (p = 0.03), earlier tumor stage at diagnosis (OR 0.47, 95% CI 0.27-0.81, p = 0.02) and younger age at diagnosis (p = 0.02). In addition, two SNPs in ATG5 (rs2245214 and rs510432) were found to be significantly associated with increased tumor stage of melanoma (OR 1.84 95% CI 1.12-3.02, p = 0.05; OR 1.47 95% CI 1.11-1.94, p = 0.03). Finally, we identified inverse associations between the minor allele of rs2245214 and melanomas on the scalp or neck (OR 0.20, 95% CI 0.05-0.86, p = 0.03); rs1864182 (OR 0.42, 95% CI 0.21-0.88, p = 0.02) and brisk TILs, and rs510432 (OR 0.55 95% CI 0.34-0.87, p = 0.01) with non-brisk TILs, although they were not globally significant. In summary, our data suggests that ATG SNPs, while not associated with survival, may be associated with Breslow thickness, tumor stage, age at diagnosis, and aggressive histopathological factors. These associations could contribute to our current understanding of the significant role of autophagy in melanoma progression.
Citation Format: Kirsten A. m. White, Li Luo, Todd A. Thompson, Salina Torres, Chien-An A. Hu, Nancy E. Thomas, Hoda Anton-Culver, Stephen B. Gruber, Lynn From, Klaus J. Busam, Irene Orlow, Peter A. Kanetsky, Lorraine D. Marrett, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Terry Dwyer, Anne E. Cust, Allison Venn, Colin B. Begg, Marianne Berwick, Jenna Lillyquist. Variants in autophagy related genes and clinical characteristics in melanoma: a population-based study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1016.
Abstract 1021: Lipidomic analysis: a powerful tool for evaluating lipid metabolism in cultured cancer cells
Authors: Eiríksson Finnur F. , Magnusdottir Manuela , Halldorsson Skarphedinn , Thorsteinsdottir Margret , Ögmundsdottir Helga M. 
Published: July 2016

Abstract
Lipids have numerous functions in biological processes, structural as well as regulatory. Cancer cells show differences from healthy normal cells in their metabolism, including lipid metabolism, which contribute to their survival and growth. Overexpression of fatty acid synthase (FASN) is commonly observed in cancer cells and there is also evidence of other lipid pathways being changed in tumor cells. The general aim of this project is to establish a lipidomic based UPLC-QToF method for evaluation of lipid composition in cultured cells of normal and cancerous origin using electrospray quadrupole traveling wave ion mobility Q-ToF mass spectrometry. Cell lines were selected based on their lipid metabolism, including three breast cancer cell lines: SK-Br-3 (overexpresses FASN), T47D (TP53-mutated), MCF7 (estrogen receptor-positive); and one pancreatic cancer cell line, ASPC-1(overexpresses 5-and 12-lipoxygenases). Furthermore, we analyzed the immortalized breast epithelial stem cell line D492 along with its subline, D492M, that has undergone epithelial to mesenchymal transition (EMT). Principal component analysis (PCA) revealed distinct differences in lipid composition between all the cell lines tested, each cell line showed a clear cluster of lipid components and patterns that were reproducible between experiments. The Sk-Br-3 was most clearly separated from the other two breast cancer cell lines. Further analysis revealed significant differences in levels of phosphocholins (PC) that are elevated in Sk-Br-3compared to other cell lines. Further investigations of the data have led to identification of certain PC that are different between cell lines. Significant differences were detected in the lipid composition of D492 and D492M. In conclusion, different levels of lipid-synthesizing enzymes are reflected in distinct lipid profiles in breast cancer cells. The observed differences in lipid profiles of the breast epithelial cell line and its mesenchymal-like subline may provide an insight into membrane changes associated with EMT and help evaluate lipidomes of tumor samples from patients in terms of invasive potential.
Citation Format: Finnur F. Eiríksson, Manuela Magnusdottir, Skarphedinn Halldorsson, Margret Thorsteinsdottir, Helga M. Ögmundsdottir. Lipidomic analysis: a powerful tool for evaluating lipid metabolism in cultured cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1021.
Abstract 1022: The ketone body β-hydroxybutyrate down regulates c-Myc signaling in a malignant glioma model
Authors: Rossi Alex P. , Silva-Nichols Helena B. , Woolf Eric C. , Scheck Adrienne C. 
Published: July 2016

Abstract
Glioblastoma (GB) is the most common primary malignant brain tumor with a dismal median survival of 1.5 years. To address the need for novel therapeutics for the treatment of GB, investigations into high fat, low carbohydrate ketogenic diets (KD) have been explored as potential adjuvant therapeutic modalities. Preclinical studies of the KD in a mouse model of malignant glioma demonstrated that the KD extended median survival when used alone and substantially potentiated both radiotherapy and chemotherapy. However, the underlying mechanisms by which the KD exerts its therapeutic benefits remain poorly understood. A key result of the KD is the production of the ketone bodies β-hydroxybutyrate (βHB), acetoacetate, and acetone. Of these, BHB is the most prevalent ketone body produced. In order to elucidate the underlying molecular mechanisms of the KD, we have examined the interactions between BHB and the mouse glioma cell line GL261-Luc2. Previously, we demonstrated the ability of βHB to recapitulate the in vivo effects of the KD in tumor cells in an in vitro model. In the present study, we demonstrate that the ketone βHB is able to significantly down regulate the master transcription factor c-Myc, which is intimately involved in cell cycle progression, apoptosis, proliferation, DNA damage and repair, and metabolism. Overexpression of c-Myc is tied to a variety of human malignancies. In GB, upregulation of c-Myc signaling has been connected to an increase in tumor glucose metabolism. Furthermore, downregulating c-Myc expression has been demonstrated to confer sensitivity to tumors. We show that doses of both 5mM and 10mM βHB significantly reduced the expression of c-Myc in the GL261-Luc2 cell line when evaluated by both immunocytochemistry and western blot. Downregulation of c-Myc may, in part, be a mechanism by which βHB and thus the KD exert their radiosensitizing and antiproliferative effects on tumors. We intend to further investigate the role of c-Myc in the KD by investigating downstream targets of c-Myc as well as potential regulators of c-Myc transcription that are affected by BHB.
Citation Format: Alex P. Rossi, Helena B. Silva-Nichols, Eric C. Woolf, Adrienne C. Scheck. The ketone body β-hydroxybutyrate down regulates c-Myc signaling in a malignant glioma model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1022.
Abstract 1028: A mouse model of allelic loss of the core autophagy gene BECN1 in ovarian cancer
Authors: Delaney Joe R. , Patel Chandni , Stupack Dwayne G. 
Published: July 2016

Abstract
Autophagy, a process of protein and organelle recycling, can both suppress and promote tumors. Gliomas, KRAS mutant, and BRAF driven tumor models require functional autophagy for maximal tumorigenicity and/or tumor progression. Inhibition of autophagy is able to eliminate many human cancer cell lines. However, allelic loss of the autophagy gene BECN1 is present in the majority of ovarian cancers, and BECN1 loss incurs early tumorigenesis in mouse models free of other oncogenic stimuli. Recent sequencing efforts and analyses, depending on the study, have both supported and refuted the relevance of BECN1 allelic loss in ovarian and breast cancers. To directly address the role of BECN1 allelic loss in ovarian cancer, we crossed BECN1 heterozygous knockout dams with MISIIR-TAg sires. In this model, the MISIIR promoter induces expression of large T antigen specifically in the ovarian and fallopian epithelium, inhibiting p53 activity and driving ovarian cancers in a manner befitting its human analogue. Here we present our pre-publication findings relating to the oncogenesis and progression of this murine BECN1 allelic loss model of ovarian cancer. We compare the in vivo murine results to those of in vitro human cell line models of beclin depletion, which exhibit higher basal dsDNA break repair signaling, mitochondrial stress, and reactive oxygen species generation.
Citation Format: Joe R. Delaney, Chandni Patel, Dwayne G. Stupack. A mouse model of allelic loss of the core autophagy gene BECN1 in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1028.
Abstract 1041: Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A549 and H460 lung cancer cell lines
Authors: Sappington Daniel , Penney Rosalind , Siegel Eric , Boysen Gunnar 
Published: July 2016

Abstract
Increased glutamine uptake is known to drive cancer cell proliferation, making tumor cells glutamine-dependent. Glutamine provides additional carbon and nitrogen sources for cell growth. The first step in glutamine utilization is its conversion to glutamate by glutaminase (GLS). Glutamate is a precursor for glutathione synthesis, and we investigated the hypothesis that glutamine drives glutathione synthesis and thereby contributes to cellular defense systems. The importance of glutamine for glutathione synthesis was studied in H460 and A549 lung cancer cell lines using glutamine-free medium and BPTES a GLS inhibitor. Metabolic activities were determined by targeted mass spectrometry. A significant correlation between glutamine consumption and glutathione excretion was demonstrated in H460 and A549 tumor cells. Culturing in the presence of [13C5]glutamine demonstrated that by 12 hrs &gt;50% of excreted glutathione is derived from glutamine. Culturing in glutamine-free medium or treatment with Bis-2-(5-phenyl-acetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a glutaminase (GLS)-specific inhibitor, reduced cell proliferation and viability, and abolished glutathione excretion. Treatment with glutathione-ester prevented BPTES induced cytotoxicity. Inhibition of GLS markedly radiosensitized the lung tumor cell lines, suggesting an important role of glutamine-derived glutathione in determining radiation sensitivity. We demonstrate here for the first time that a significant amount of extracellular glutathione is directly derived from glutamine. This finding adds yet another important function to the already known glutamine dependence of tumor cells and probably tumors as well.
Citation Format: Daniel Sappington, Rosalind Penney, Eric Siegel, Gunnar Boysen. Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A549 and H460 lung cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1041.
Abstract 1048: Modulation of lipid metabolism through inhibition of acetyl-CoA carboxylase with ND-646 leads to potent inhibition of breast cancer cell growth in vitro and in vivo
Authors: Rocnik Jennifer L. , Miao Wenyan , Harriman Geraldine , Greenwood Jeremy , Bhat Sathesh , Harwood H. James , Kapeller Rosana , Westlin William F. 
Published: July 2016

Abstract
Metabolic attenuation is a promising approach to cancer therapy and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. Many cancer types are dependent on fatty acid synthesis as a primary source of energy and for providing lipids for expansion of cell and nuclear membranes in rapidly proliferating cells. The rate-limiting enzyme in fatty acid synthesis, acetyl-CoA carboxylase (ACC), has been shown to be highly expressed in human breast cancer. ACC is thought to be critical for the growth and survival of cancer cells, especially within a tumor microenvironment where exogenous fatty acids might be limited. Effective therapeutic options for triple negative breast cancer are limited and identification of robust targeted agents without overt toxicity for this indication are especially needed. Dual inhibition of the ACC isozymes, ACC1 and ACC2, results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. We have identified ND-646, a potent, selective, allosteric inhibitor of ACC with broad tissue distribution that binds to the ACC biotin carboxylase domain and potently inhibits the dimerization and enzymatic activity of both ACC1 (IC50 = 3.5nM) and ACC2 (IC50 = 4.1nM). Profiling the potency of ND-646 in vitro in a panel of breast cancer cell lines including triple negative and BRCA1 mutant cell lines demonstrated potent inhibition of cell proliferation with IC50s&lt;100nM. The anti-proliferative effects were more pronounced when cells were cultured in media containing delipidated serum. Daily oral dosing of ND-646 at 25 mg/kg BID, 50 mg/kg QD, and 50 mg/kg BID in mice bearing orthotopic triple negative MDA-MB-468 breast cancer xenografts led to tumor growth inhibition of 60-70% that correlated with compound exposure and target engagement in the tumor. Analysis of ND-646 treated tumors demonstrated disruption of tumor tissue architecture and induction of apoptosis and necrosis suggesting a direct effect on cell survival. These results provide further evidence that de novo lipogenesis is an important mediator of breast cancer cell growth and survival, and that selective inhibition of ACC is a viable therapeutic strategy for treatment of breast cancer.
Citation Format: Jennifer L. Rocnik, Wenyan Miao, Geraldine Harriman, Jeremy Greenwood, Sathesh Bhat, H. James Harwood, Rosana Kapeller, William F. Westlin. Modulation of lipid metabolism through inhibition of acetyl-CoA carboxylase with ND-646 leads to potent inhibition of breast cancer cell growth in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1048.
Abstract 1050: Inhibition of the polyamine synthesis pathway is synthetically lethal with loss of argininosuccinate synthase 1 in cancer
Authors: Szlosarek Peter W. , Locke Matthew , Ghazaly Essam , Lattanzio Laura , Lo Nigro Cristiana , Martin Sarah A. 
Published: July 2016

Abstract
Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme for arginine biosynthesis. ASS1 expression is lost in a range of different tumour types, including 50% of malignant pleural mesotheliomas. Starving ASS1-deficient cells of arginine with arginine blockers such as ADI-PEG20 can induce selective lethality and has shown great promise in the clinic. However, recent data has shown that ASS1-deficient tumours can become resistant to this therapy although the mechanisms behind this resistance remain unclear. We have generated the first model of ADI-PEG20 resistance in mesothelioma cells whereby we observe re-expression of ASS1, via demethylation of the ASS1 promoter. Through coordinated transcriptomic and metabolomic profiling, we have shown that ASS1-deficient cells have decreased levels of acetylated polyamines, resulting in an increased activation of the polyamine synthesis pathway. Upon arginine deprivation, we observe a decrease in polyamine metabolites in the ASS1-deficient cells only, suggesting that exogenous arginine is required to maintain polyamine biosynthesis in the absence of ASS1. We identify for the first time a compensatory increase in polyamine synthesis gene expression upon ASS1 loss and highlight a synthetic lethal dependence between ASS1-deficiency and polyamine metabolism, which could potentially be exploited for the treatment of ASS1-negative cancers.
Citation Format: Peter W. Szlosarek, Matthew Locke, Essam Ghazaly, Laura Lattanzio, Cristiana Lo Nigro, Sarah A. Martin. Inhibition of the polyamine synthesis pathway is synthetically lethal with loss of argininosuccinate synthase 1 in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1050.
Abstract 1051: Activation of PI3K pathway in breast cancer associates with tumor phospholipid fatty acid composition
Authors: Hajjaji Nawale , Arbion Flavie , Fautrel Alain , Villalva Claire , Karayan-Tapon Lucie , Jourdan Marie-Lise 
Published: July 2016

Abstract
Background
Ever since the discovery of the PI3K/Akt/mTOR pathway key role in breast cancer resistance, several molecules have been developed to target this pathway. However, mechanisms of resistance restrain their efficacy. An in-depth understanding of the interactions of PI3K pathway is essential to improve its blockade and avoid resistance. Preclinical studies reported that lipid composition of cancer cells altered the activation of PI3K pathway, thus suggesting another possible molecular interaction with lipid metabolism. The aim of this study was to analyze the relationship between the activation of PI3K pathway and tumor lipid composition in breast cancer patients.
Methods
Frozen and formalin-fixed paraffin-embedded tumor specimens were retrieved for 50 French patients with stage I to III primary breast cancer treated uniformly with surgery, adjuvant chemotherapy, radiation therapy and endocrine therapy. The tumor specimens were analyzed for PIK3CA gene mutation, PTEN protein expression by immunohistochemistry, and pAktS473, pAktT308, mTOR, pS6K, and S6RP by protein array. Tumor total fatty acid (FA) and phospholipid FA compositions were analysed using mass spectroscopy. Pearson test was used for correlation analyses.
Results
Mean age was 53 years. All tumors were ER or PR positive and HER-2 negative, and 76% were node positive. PI3K mutation was observed in 14% of cases, and 34% were PTEN negative or had low PTEN expression. Mean tumor satured fatty acid (SFA) level was 33.78 mol%, monounsaturated FA (MUFA) level was 46.46 mol%, n-6 polyunsaturated FA (PUFA) level was 18.08 mol%, and n-3 PUFA level was 1.68 mol%. Large and high grade tumors had a higher SFA content. MUFA rich tumors were frequently low grade. There was a positive correlation between d18:1/C20:0 ceramide level and Akt, mTOR and p70S6K expression. mTOR expression also correlated with 18:0 lysophosphatidylserine (lysoPS), 36:1 PS, 38:3 PS, 38:5 PS, 40:5 PS, 40:6 PS, 34:0 phosphatidylcholine (PC), 34:1 PC, and 38:3 PC.
Conclusions
Our results show that SFA associated with a more aggressive tumor phenotype and that PI3K pathway activation significantly correlated with fatty acid composition of specific tumor phospholipids. These results suggest a potential role of tumor lipid metabolism in PI3K pathway activation.
Citation Format: Nawale Hajjaji, Flavie Arbion, Alain Fautrel, Claire Villalva, Lucie Karayan-Tapon, Marie-Lise Jourdan. Activation of PI3K pathway in breast cancer associates with tumor phospholipid fatty acid composition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1051.