bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1880: Role of fatty acid synthase and do novo lipogenesis in liver cancer development in mice.
Authors: Chen Xin , Li Lei , Wang Chunmei , Evert Matthias , Calvisi Diego F. , Semenkovich Clay F. 
Published: August 2014

Abstract
Aberrant metabolism, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty Acid Synthase (Fasn) catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA. Increased Fasn expression has been reported in multiple tumor types, and inhibition of Fasn expression has been shown to have tumor-suppressing activity. However, how increased de novo lipogenesis contributes to tumor initiation and progression, especially in vivo, remains unknown.
In our previous studies, we showed that overexpression of the activated form of AKT (myr-AKT) induced de novo lipogenesis, hepatocyte proliferation and, eventually, liver cancer formation in mice. The tumorigenesis process could be significantly accelerated via co-expression of activated form of Ras. In the AKTRas tumor model, tumors were predominantly (&gt;80%) hepatocellular carcinoma (HCC), and the remaining (&lt;20%) were intrahepatic cholangiocarcinoma (ICC). The ICCs were induced via hepatocyte-biliary epithelial cell metaplasia in a Notch dependent manner. Intriguingly, fat droplet formation, increased expression of Fasn and other lipogenesis pathway genes were identified in HCC lesions, but not ICC lesions. To define whether Fasn-mediated de novo lipogenesis is a key metabolic event downstream of mTORC1 during AKTRas-induced hepatocarcinogenesis, we utilized Fasn flox/flox mice, and co-expressed AKTRas in the Fasn KO hepatocytes. Of note, we found that ablation of Fasn completely inhibited AKT induced lipogenesis and hepatocyte proliferation in mice. However, loss of Fasn modestly delayed AKTRas-induced liver tumor development. Histological analysis revealed that these tumor lesions were predominantly ICCs. The ICC cells were highly proliferative, and did not express Fasn or any other lipogenic pathway gene. The results suggest that Fasn-mediated de novo lipogenesis is required for AKTRas-induced HCC formation, but this process is dispensable for ICC formation.
In summary, our experiments support a critical role for Fasn as a downstream effector of mTORC1 in HCC pathogenesis. However, Fasn-mediated do novo fatty acid synthesis is not required in all tumor types. It is likely that other sources of fatty acids, presumably including those derived from the diet, can be utilized by cancer cells for membrane synthesis during cell proliferation.
Citation Format: Xin Chen, Lei Li, Chunmei Wang, Matthias Evert, Diego F. Calvisi, Clay F. Semenkovich. Role of fatty acid synthase and do novo lipogenesis in liver cancer development in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1880. doi:10.1158/1538-7445.AM2013-1880
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1883: 2-Hydroxyglutarate: A candidate oncometabolite in breast cancer.
Authors: Mishra Prachi 
Published: August 2014

Abstract
Recent work in our laboratory identified a poor outcome tumor subtype with a high tissue 2HG concentration, distinct genome-wide DNA methylation, and a stem cell-like transcriptional signature. Currently, we do not know the origin of 2HG in these tumors but ruled out that it is caused by acquired isocitrate dehydrogenase mutations. Tumors with high 2HG tended to be estrogen receptor (ER)-negative and were over-represented among the African-American patients. Additional investigations revealed that 2HG can accumulate in a subset of human breast cancer cell lines to 50- to 100-fold above the baseline in non-cancerous cells, reminiscent of the difference between 2HG-high tumors and their adjacent non-cancerous tissue. The majority of the 2HG-high cell lines showed basal-like characteristics. While some cancer cells had these highly increased 2HG levels, other cell lines did not accumulate 2HG, providing a model to study 2HG treatment effects in cell lines with low endogenous 2HG and to identify the origin of increased 2HG production in those cell lines with high endogenous 2HG. Thus, we tested the hypothesis that 2HG influences breast cancer phenotypes. These experiments showed that 2HG induced phenotypic alterations, DNA methylation pattern alterations, proliferation, increased invasion and migration, and EGFR pathway activation in breast epithelial cells consistent with its oncogenic function in breast cancer. However, the observed phenotypes were partly cell line- and dose-dependent in our short term assays. Our results also indicated that different subtypes of breast cancer cells may respond differentially to 2HG, which suggests that possibly different cellular pathways are activated by 2HG in the various subtypes.
Citation Format: Prachi Mishra. 2-Hydroxyglutarate: A candidate oncometabolite in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1883. doi:10.1158/1538-7445.AM2013-1883
Abstract 1886: Metabolic alterations associated with pancreatic cancer-induced cachexia.
Authors: Shukla Surendra K. , Singh Pankaj K. 
Published: August 2014

Abstract
Cachexia, a metabolic syndrome, leads to loss of muscle weight and fat tissues. Cancer-induced cachexia accounts for nearly 20% of all cancer-related deaths and is most prevalent in patients with gastric, pancreatic, colon and lung cancer. Although association of cachexia with various types of cancers has been known for a long time, the molecular mechanism of cancer-induced cachexia is still not well understood. Better understanding of the cancer-related cachexia syndrome may provide novel therapeutic targets and improved health care for cancer patients. By culturing differentiated C2C12 and 3T3-L1 cells in the presence of pancreatic adenocarcinoma cell or immortalized epithelial cell supernatants, we established cell culture-based cachexia model systems to investigate the depletion of muscle mass and fatty acid storage. Progressive physiological and biochemical alterations during muscle fibre breakdown and adipocyte fat depletion were assayed by utilizing western blotting, real-time PCR and cell imaging. We then investigated metabolomic alterations in C2C12 and 3T3-L1 cell lines in response to the cachectic factors secreted by the tumor cells. We performed differential metabolomic analyses on tumor cell supernatant-treated or control treated differentiated C2C12 muscle fibers and 3T3-L1-derived adipocytes by utilizing 2D 1H-13C HSQC NMR technique. Alterations in metabolic pathways were also investigated by evaluating the expression of metabolic genes in the corresponding pathways by performing quantitative real-time PCR. To obtain further insights into the metabolic alterations that trigger cachexia, we extended our studies to in vivo mouse orthotopic xenograft models and investigated alterations in metabolic gene expression and metabolite flux in muscle and fat tissues of tumor-bearing mice. Our results identify crucial nodes in metabolite flux that can be targeted to regulate cell growth, proliferation, and turnover in muscle and fat tissues during cancer-induced cachexia.
Citation Format: Surendra K. Shukla, Pankaj K. Singh. Metabolic alterations associated with pancreatic cancer-induced cachexia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1886. doi:10.1158/1538-7445.AM2013-1886
Abstract 1889: Can the moonlighting glycolytic enzyme α-enolase be a therapeutic target in pancreatic cancer.
Authors: Capello Michela , Principe Moitza , Chattaragada Michelle Samuel , Riganti Chiara , Zhou Weidong , Ferri-Borgogno Sammy , Rolla Simona , Liotta Lance , Petricoin Emanuel , Cappello Paola , Novelli Francesco 
Published: August 2014

Abstract
Aberrant metabolism together with invasion and metastasis are hallmarks of cancer. This is particularly true for pancreatic ductal adenocarcinoma (PDAC), characterized by rapid progression, invasiveness and resistance to treatments. We have previously described α-enolase (ENOA) as a PDAC-associated antigen. It is a moonlighting protein that works both as a key metabolic enzyme and as a membrane plasminogen receptor. In order to clarify its multifunctional role in pancreatic tumorigenesis we investigated the effect of ENOA knockdown in PDAC cells. Protein expression alterations following ENOA knockdown in the human PDAC cell line CFPAC-1 were revealed by LC-MS/MS analysis. On the basis of a spectra count label-free quantitation approach a large number of proteins mainly involved in cell adhesion, metabolism and proliferation were found to be differentially expressed in ENOA silenced cells compared to the control. After ENOA silencing, PDAC cells displayed a delay in proliferation and decreased survival and colony formation capabilities, even if the pyruvate production was not affected. The growth inhibition was partially due to an increased concentration of intracellular reactive oxygen species (ROS) mainly generated through the sorbitol and NADPH oxidase pathways. Moreover in ENOA silenced cells, the in vitro plasminogen-driven invasion was abolished and the number of lung tumor masses was significantly reduced in SCID-beige mice injected with ENOA silenced cells compared to mice injected with control cells. These effects are under further confirmation in other PDAC cell lines. All together, these findings propose ENOA as a promising target for developing new therapies in pancreatic cancer management.
Citation Format: Michela Capello, Moitza Principe, Michelle Samuel Chattaragada, Chiara Riganti, Weidong Zhou, Sammy Ferri-Borgogno, Simona Rolla, Lance Liotta, Emanuel Petricoin, Paola Cappello, Francesco Novelli. Can the moonlighting glycolytic enzyme α-enolase be a therapeutic target in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1889. doi:10.1158/1538-7445.AM2013-1889
Abstract 1892: Integrated energetics and flux analysis reveals differential metabolic reprogramming in highly and less invasive cancer cells.
Authors: Achreja Abhinav , Yang Lifeng , Zhao Hongyun , Marini Juan C. , Nagrath Deepak 
Published: August 2014

Abstract
Cancer cell metabolism was investigated using systems biology tools such as metabolic flux analysis (MFA) to reveal intracellular cancer cell metabolic flux distribution. To obtain a complete role of nutrient-induced deprivation in metabolic reprogramming of cancer cells, we need to use metabolic flux analysis to determine unknown intracellular fluxes. MFA provides a framework for the estimation of intracellular fluxes and energy balance analysis (EBA) ensures the thermodynamic feasibility of the computed optimal metabolic fluxes. MFA uses stoichiometric and mass balance constraints to compute the intracellular fluxes. Here, we have developed an integrated energy balance and flux balance analysis framework. Our framework allows estimation of intracellular fluxes and reveals specific adaptations and dysregulation of metabolic pathways in ovarian cancer cells as a result of the nutrient (glucose and glutamine) deprivation conditions.
Glutamine and glucose are known to be important for cancer cell survival, growth and progression. Thus, there is a strong motivation to study metabolic alternations caused by glucose and glutamine deprivation and uncover links between various fuel sources for highly and less invasive cancer cells. Our findings indicate that NAD+/NADH ratio regulates glutamine's direct effect on lactate production irrespective of the bioenergetic substrate requirement for different kinds of cancer cells. Our findings, using quantification of metabolites pertaining to central carbon and nitrogen metabolism provided clues as to which pathways relevant to glycolysis, the pentose phosphate pathway, the TCA, urea cycles and lipid cycles, amino acid and nucleotide metabolisms may be altered by glucose and glutamine in cancer cells. This resulted in identification of dominant factors which control cancer metabolism. We believe that development of our oncosecretomics based metabolic strategy provides an unprecedented opportunity for the development of nutritional supplementation that can deregulate the adaptations and alterations induced by various nutrients in cancer metabolism.
Citation Format: Abhinav Achreja, Lifeng Yang, Hongyun Zhao, Juan C. Marini, Deepak Nagrath. Integrated energetics and flux analysis reveals differential metabolic reprogramming in highly and less invasive cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1892. doi:10.1158/1538-7445.AM2013-1892
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1893: Spectroscopic imaging unveils altered cholesterol metabolism in prostate cancer .
Authors: Yue Shuhua , Li Junjie , Lee Seung Young , Shao Tian , Song Bing , Cheng Liang , Hu Chang-Deng , Liu Xiaoqi , Ratliff Timothy L. , Cheng Ji-Xin 
Published: August 2014

Abstract
Metabolic reprogramming allows cancer cells to sustain high proliferative rates and resist cell death. Whereas alterations to glucose and amino acid metabolism have been extensively studied, altered lipid metabolism in cancer is increasingly recognized based on the findings of imbalanced lipid signaling network and dysregulated lipogenic enzymes. Storage of neutral lipids in lipid droplets (LDs), an essential aspect of lipid metabolism, is however long underappreciated until recent advances in LD biology. In human prostate cancer cell lines, neutral lipid accumulation was commonly seen and partially attributed to the up-regulation of fatty acid synthase, a key lipogenic enzyme catalyzing fatty acid biosynthesis and implicated in many human malignancies including prostate cancer. However, because the composition of LDs is not accessible with fluorescence microscopy, the exact role of lipid accumulation in prostate cancer progression remains elusive. By vibration-based spectroscopic imaging of 65 specimens collected from 61 prostate cancer patients and healthy donors, we found for the first time a marked shift from lipofuscin-like autofluorescent granules in normal, benign, and prostatic intraepithelial neoplasia lesions to cholesteryl ester (CE)-rich LDs in high-grade and metastatic prostate cancers. Quantitatively, CE amount was found ∼5 folds higher in high-grade relative to low-grade prostate cancers. Cellular studies demonstrate that the activated PI3K/Akt/mTOR/SREBP pathway accounts for accumulation of CEs via elevated LDL uptake and cholesterol esterification. Blockage of cholesterol esterification with an acetyl-coA cholesterol acyltransferase (ACAT) inhibitor significantly slows the growth and induces apoptosis of prostate cancer both in vitro and in vivo. These findings suggest that CE can be a quantifiable molecular marker for diagnosis of prostate cancer, especially for differentiation between low-grade and high-grade prostate cancers which currently has up to 40% inter-observer discordance. Moreover, targeting the altered cholesterol metabolism opens new opportunities for treating advanced prostate cancer in human patients.
Citation Format: Shuhua Yue, Junjie Li, Seung Young Lee, Tian Shao, Bing Song, Liang Cheng, Chang-Deng Hu, Xiaoqi Liu, Timothy L. Ratliff, Ji-Xin Cheng. Spectroscopic imaging unveils altered cholesterol metabolism in prostate cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1893. doi:10.1158/1538-7445.AM2013-1893
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1897: Metformin treatment leads to the accumulation of lipid in breast cancer cell lines - a potential new biomarker of response and mechanism of action.
Authors: Lord Simon , Collins Jennifer , Fielding Barbara , Patel Neel , Gleeson Fergus , Harris Adrian , Karpe Fredrik 
Published: August 2014

Abstract
There is growing interest in the anticancer effect of the diabetes drug, metformin, and several clinical studies are underway worldwide. Metformin's anticancer effects are thought to be mediated by its activation of AMPK and subsequent downstream catabolic effects on protein and lipid metabolism pathways that are commonly dysregulated in cancer cells.
We have used mass spectrometry techniques and stable isotopes to investigate the effects of metformin on breast cancer cell lipid metabolism.
There was great variability in lipid metabolism response to 2mM metformin treatment in a panel breast cancer cell lines (MCF7, BT474, ZR-75-1, T47D MDA-MB-157, MDA-MB-468 and MDA-MB-231). Levels of stearic acid (p=0.019), palmitoleic acid (p=0.01), oleic acid (p=0.002), cis-vaccenic acid (p=0.003) increased 3-4 fold with metformin treatment in MCF7 cells but there was no significant change for MDA-MB-231 cells. 2mM Metformin decreased fatty acid β-oxidation of oleate 4-fold (p=0.03). Accumulation of de novo lipogenesis derived (p=0.004) and exogenous fatty acid (p=0.02) occurred in MCF7 cells but siRNA knockdown of AMPK did not abrogate these effects. A 3-fold decrease in the diglyceride to triglyceride ratio (p=0.02) suggested reduced lipolysis and inhibited adipose triglyceride lipase activity. Reduced incorporation of exogenous fatty acid into phospholipid was evident (p=0.002). Heterogeneity of lipid metabolism response correlated with effects on proliferation, oxygen consumption and mitochondrial morphology.
Our data shows that metformin has marked effects on accumulation of fatty acid in breast cancer cells most likely due to reduced lipolysis and β-oxidation and these effects cannot be explained as a result of AMPK activation. This work will contribute to developing biomarkers for metformin's metabolic anticancer effect and our understanding of how to combine it with other therapies to exploit synthetic lethality. We have initiated a multicenter, phase II, single arm clinical study, to further characterise metformin influenced, cancer relevant metabolic pathways. We will look to assess the correlation between metabolic biomarkers, including the use of mass spectrometry and gas chromatography analysis of tissue samples, and metabolic response using 18F-FDG PET-CT scans.
Citation Format: Simon Lord, Jennifer Collins, Barbara Fielding, Neel Patel, Fergus Gleeson, Adrian Harris, Fredrik Karpe. Metformin treatment leads to the accumulation of lipid in breast cancer cell lines - a potential new biomarker of response and mechanism of action. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1897. doi:10.1158/1538-7445.AM2013-1897
Abstract 190: Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice by suppressing aldo-keto reductase family 1B10 (AKR1B10).
Authors: Liao Jie , Chung Yeon Tae , Li Haonan , Zhang Wanying , Yang Guang-Yu 
Published: August 2014

Abstract
Sulindac inhibits carcinogenesis via the mechanism that appears beyond cyclooxygenase inhibition. Recently sulindac has been identified as competitive inhibitors of aldo-keto reductase family 1B10 (AKR1B10). AKR1B10 is involved in the process of carbonyls, farnesyl and geranylgeranyl as well as retinal metabolisms, and these metabolic activities are important to carcinogenesis. However, there is no evidence on if inhibition of pancreatic carcinogenesis by sulindac is via inhibition of AKR1B10 and protein prenylation (i.e., Kras protein). To determine the effect of sulindac on pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice, five-week-old mice were fed with either AIN-93M diet or AIN-93M diet contained 200ppm sulindac (n=20 mice/group). Kaplan-Meier survival analysis with Log-Rank test was performed to analyze the effect of sulindac on animal survival from the development of pancreatic carcinoma. The results showed that average animal survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice was 143.7 ± 8.8 days; and with the sulindac 200ppm treatment, animal survival significantly increased to 168.0 ± 8.8 days (p&lt;0.005). Extensively histopathological analyses revealed that 90% of mice developed malignant pancreatic carcinomas, of which 10% invasive pancreatic adenocarcinoma had metastasis to liver and lymph nodes. With 200ppm sulindac treatment, incidence of pancreatic cancer and its metastasis were significantly reduced to 56% and 0%, respectively (P&lt;0.01). Immunchemical analysis showed that sulindac treatment significantly decreased Ki-67-labeled cell proliferation, increased caspase-3-labeled cell apoptosis, and suppressed phosphorylated ERK1/2. In vitro mouse pancreatic carcinoma cells derived from the LSL-KrasG12D/+-LSL-Trp53R172/+-Pdx-1-Cre mice were further treated with sulindac and revealed that sulindac inhibited AKR1B10 enzyme activity, suppressed Kras and HDJ2 protein prenylation, and further inhibited phosphylation of C-raf, ERK1/2 and MEK1/2. Similar to sulindac treatment, siRNA-silencing AKR1B10 expression resulted in a significant reduction of Kras protein prenylation and its downstream signals. Our results demonstrate that sulindac inhibits pancreatic carcinogenesis, mainly via inhibition of kras protein prenylation and its activated signals by targeting AKR1B10. (supported NCI R01 CA164041)
Citation Format: Jie Liao, Yeon Tae Chung, Haonan Li, Wanying Zhang, Guang-Yu Yang. Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1-Cre mice by suppressing aldo-keto reductase family 1B10 (AKR1B10). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 190. doi:10.1158/1538-7445.AM2013-190