bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A84: Regulation of 6-phosphofructo-2-kinase (PFKFB3) by estradiol and implications for the treatment of ER+ metastatic breast cancer
Authors: Clem Brian , Tapolsky Gilles , Chesney Jason 
Published: May 2016

Abstract
Estradiol (E2) administered to estrogen receptor positive (ER+) breast cancer patients stimulates glucose uptake by tumors. This E2-induced metabolic flare is predictive of the clinical effectiveness of anti-estrogens and downstream metabolic regulators of E2 are expected to have utility as targets for the development of anti-breast cancer agents. While the stimulation of glucose metabolism by E2 has been demonstrated, relatively little is known about the precise downstream effectors required for E2 to stimulate glucose metabolism in breast cancer. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) control glycolytic flux via their product, fructose-2,6-bisphosphate (F26BP), which activates 6-phosphofructo-1-kinase (PFK-1). We recently demonstrated that PFKFB3 expression is elevated in breast cancer lymph node metastases and that exposure of human MCF-7 and T-47D breast cancer cells to E2 causes a rapid increase in 14C-glucose uptake and glycolysis that is coincident with an induction of PFKFB3 mRNA (via ER binding to its promoter), protein expression and the intracellular concentration of its product, F26BP. Importantly, we also found that selective inhibition of PFKFB3 expression and activity using siRNA or a PFKFB3 inhibitor, PFK158, markedly reduces the E2-mediated increase in F26BP, 14C-glucose uptake and glycolysis. In the current study, we sought to determine if co-administration of PFK158, with ICI 182,780 (fulvestrant), would offer a greater anti-tumor effect. In unpublished results, we demonstrated that the combination of the anti-estrogen, fulvestrant, with PFK158 results in greater regressions of MCF-7 xenografts than either drug alone in athymic BALB/C mice. In addition to regulating glucose metabolism, PFKFB3 has been found to be a regulator of the cell cycle via cyclin dependent kinases. We postulated that the combination of PFK158 with the newly FDA-approved CDK4/6 inhibitor palbociclib may result in a synergistic increase in apoptosis. We found that PFK158 markedly increased apoptosis caused by palbociclib in MCF-7 breast cancer cells but not in normal human mammary epithelial cells. Taken together, these data indicate that PFKFB3 inhibitors such as PFK158 may have clinical utility for the treatment of ER+ breast cancers when combined with anti-estrogen agents and/or CDK4/6 inhibitors.
Citation Format: Yoannis Imbert-Fernandez, Brian Clem, Gilles Tapolsky, Jason Chesney. Regulation of 6-phosphofructo-2-kinase (PFKFB3) by estradiol and implications for the treatment of ER+ metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A84.
Abstract A86: LRP16, interacting with PKR, prolongs NF-kappaB activation and drives colorectal cancer tumorigenesis
Authors: Li Xiaolei , Wu Zhiqiang , Han Weidong 
Published: May 2016

Abstract
NF-kappaB frequently activated in colorectal cancer (CRC) is linked to rapid malignant progression of CRC and is also crucial for the maintenance of homeostasis and therapy resistance. However, the underlying mechanisms how NF-kappaB activation and the crosstalk of NF-kappaB with other transcription factors are controlled in CRC remain incompletely understood. Here, we show that LRP16 physically interacts with double-stranded RNA-dependent protein kinase (PKR) functions as a signal transducer in signaling pathways activated by different stimuli by a variety of effectors, including NF-kappaB. Overexpression of LRP16 confers PKR autophosphorylation leading to the phosphorylation and activation of the NF-kappaB complex. Modulation of NF-kappaB mediated gene expression in response to diverse signals is coordinated by PKR through the phosphorylation and activation of IKK complex and this process does not require PKR kinase activity. We identified PKR, an essential regulatory subunit of the IKK complex. Silencing PKR expression by RNA interference blocked LRP16 induced expression of NF-kappaB target genes. These cells were also not protected from apoptosis in response to chemotherapy. In vivo, overexpression of LRP16 promotes CRC tumorigenesis, in turn, inhibition of LRP16 or PKR blunts CRC tumorigenesis. These results demonstrated that LRP16 likely functions by recruiting PKR to the IKK complex and thus serves a regulatory function for NF-kappaB activation, suggesting that a novel role for LRP16 as mediator of chemotherapy resistance modulated in part through the protective effects of NF-kappaB activation and may be a novel strategy in the future to overcome chemotherapy resistance in CRC.
Citation Format: Xiaolei Li, Zhiqiang Wu, Weidong Han. LRP16, interacting with PKR, prolongs NF-kappaB activation and drives colorectal cancer tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A86.
Abstract A90: Dichloroacetate can overcome drug resistance via decreased ABC drug transporter expression and PDK2 inhibition
Authors: Achuthan Santhi , Callaghan Richard , Blackburn Anneke C. 
Published: May 2016

Abstract
Introduction: The primary hurdle for effective chemotherapy is the inherent or acquired drug resistance of cancer cells. The glycolytic phenotype (or Warburg effect) is a major metabolic signature of cancer cells. Dichloroacetic acid (DCA) is a non-toxic drug, which can reverse the glycolytic phenotype by inhibiting pyruvate dehydrogenase kinases (PDKs). Recent studies have linked changes in cancer cell metabolism to multi-drug resistance (MDR) phenotypes. We have examined whether reversal of the glycolytic phenotype with DCA can restore sensitivity in drug resistant cancer cells.
Methodology: We examined DCA's effects in doxorubicin (DOX)-resistant MDA-MB-231 and MCF7 cells (made by continuous exposure to increasing DOX concentrations for one month) and their DOX-sensitive counterparts by neutral red cell viability assay. Intracellular drug uptake was measured by flow cytometry and expression of PDKs and drug transporters was measured by western blotting.
Results: DCA treatment (1mM for 48hrs) significantly (p&lt;0.05) enhanced DOX toxicity in DOX-resistant cells restoring sensitivity to a level similar to parental cells. This is despite DCA having no effect on DOX toxicity in parental cells. PDK2 expression was higher in the drug-selected cells compared to parental cells suggesting the sensitising effect of DCA on drug resistant cells could be an on-target effect. DCA pre-treatment increased the intracellular retention of DOX and mitoxantrone. DCA effectively reduced the expression of ATP-binding cassette (ABC) drug transporters such as P-glycoprotein and ABCG2 in DOX-resistant MDA-MB-231 and MCF7 cells and in vivo in 4T1 mouse mammary tumors. DCA pre-treatment also sensitised the MDR cell line MCF7-FLV1000 towards mitoxantrone induced apoptosis.
Conclusion: DCA may be an effective chemo-sensitizing agent in a wide range of MDR cancers, acting by reducing drug transporter expression and inhibiting PDKs.
Citation Format: Santhi Achuthan, Richard Callaghan, Anneke C. Blackburn. Dichloroacetate can overcome drug resistance via decreased ABC drug transporter expression and PDK2 inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A90.
Abstract B13: Akt-independent PDK1 signaling in regulation of purine biosynthesis
Authors: An Songon 
Published: May 2016

Abstract
Molecular association of cancer cell metastasis with signaling pathways has been explicated so as to aid in the development of new prognostic models for better cancer therapies. However, those metastatic signaling pathways are barely explored to take account of the functions of enzymes involved in cellular metabolism. Particularly, the metabolic enzymes in de novo purine biosynthesis have been overlooked for their potential roles in cancer cell metastasis even though they have been successfully validated anti-cancer drug targets. Meanwhile, several lines of recent discoveries on de novo purine biosynthesis suggest that the spatiotemporal assembly of purine biosynthetic enzymes, the purinosome, is under controls of signaling pathways in cancer cells. The results of the inquiry reveal an unanticipated mechanism of action of 3-phosphoinositide-dependent protein kinase 1 (PDK1) signaling pathways in regulation of purine biosynthesis in an Akt-independent manner. Considering the biological action of the Akt-independent PDK1 signaling in anchorage-independent growth of breast cancer cells, we hypothesize that purinosome assembly and disassembly are regulated by Akt-independent PDK1 signaling pathways during breast cancer cell migration and invasion. Collectively, the research coupling two druggable anti-cancer targets will reveal the importance of the heretofore unrecognized molecular interaction between the Akt-independent PDK1 signaling and the purinosome, leading to therapeutic intervention in the management of breast cancer metastasis.
Citation Format: Songon An. Akt-independent PDK1 signaling in regulation of purine biosynthesis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B13.
Abstract B15: Metastatic breast tumors regulate gene expression at distal mammary sites that predicts patient outcome
Authors: Lee Jiyoung , Bainer Russell , Frankenberger Casey , Rabe Daniel , Saleh sadiq , Park Morag , An Gary , Gilad Yoav , Rosner Marsha Rich 
Published: May 2016

Abstract
The molecular interactions between cancer and stromal cells within the tumor microenvironment enable tumor invasion, intravasation, and metastasis at distant sites. However, the degree to which metastatic breast tumors reprogram stromal cells both locally and at distant mammary tissues is not well understood. To address this question, we used species-specific RNA sequencing in a mouse xenograft model to determine how the metastasis suppressor RKIP influences transcription in tumor and stroma tissues. Here we show that metastatic tumors prime mammary tissue at a distant site in a manner that reflects local stromal responses. In addition, gene expression in metastatic breast tumors is pervasively correlated with gene expression in local stroma of both mouse xenografts and human patients. Changes in local and distant stromal gene expression elicited by metastatic tumors are better predictors of subtype and patient survival than tumor gene expression, supporting the use of stromal-based strategies for the diagnosis and prognosis of breast cancer. One mechanism by which changes at contralateral distal mammary breast occur is through exosomes secreted by tumor cells. These results indicate that tumors prime contralateral mammary tissue in a manner that reflects local stromal changes and predicts metastatic disease. This study has future application to our understanding of contralateral breast cancer.
Citation Format: Jiyoung Lee, Russell Bainer, Casey Frankenberger, Daniel Rabe, sadiq Saleh, Morag Park, Gary An, Yoav Gilad, Marsha Rich Rosner. Metastatic breast tumors regulate gene expression at distal mammary sites that predicts patient outcome. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B15.
Abstract B21: An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation
Authors: Ye Peiying , Liu Yu , Chen Chong , Tang Fei , Wu Qi , Wang Xiang , Liu Chang-Gong , Liu Xiuping , Liu Runhua , Liu Yang , Zheng Pan 
Published: May 2016

Abstract
mTOR senses nutrient and energy status to regulate cell survival and metabolism in response to environmental changes. Surprisingly, targeted mutation of Tsc1, a negative regulator of mTORC1, caused a broad reduction in miRNAs due to Drosha degradation. Conversely, targeted mutation of Raptor, an essential component of mTORC1, increased miRNA biogenesis. mTOR activation increased expression of Mdm2, which is hereby identified as the necessary and sufficient ubiquitin E3 ligase for Drosha. Drosha was induced by nutrient and energy deprivation and conferred resistance to glucose deprivation. Using a high-throughput screen of a miRNA library, we identified four miRNAs that were necessary and sufficient to protect cells against glucose-deprivation-induced apoptosis. These miRNA was regulated by glucose through the mTORC1-MDM2-DROSHA axis. Taken together, our data reveal an mTOR-Mdm2-Drosha pathway in mammalian cells that broadly regulates miRNA biogenesis as a response to alteration in cellular environment.
Citation Format: Peiying Ye, Yu Liu, Chong Chen, Fei Tang, Qi Wu, Xiang Wang, Chang-Gong Liu, Xiuping Liu, Runhua Liu, Yang Liu, Pan Zheng. An mTORC1-Mdm2-Drosha axis for miRNA biogenesis in response to glucose- and amino acid-deprivation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B21.
Abstract B46: The use of quantitative proteomics to increase the knowledge about metabolic symbiosis in a tumor microenvironment
Authors: Maes Evelyne , Wenes Mathias , Valkenborg Dirk , Mertens Inge , Prenen Hans , Mazzone Massimiliano , Baggerman Geert 
Published: May 2016

Abstract
For more than a century, it is known that in a solid tumor, malignant cancer cells co-reside with stromal cells including fibroblasts and immune cells. In addition, changes in metabolic requirements of malignant cells are necessary to cover their high proliferative rate. Although it has been demonstrated that complementary metabolic functions of tumor cells and their supporting local stroma (e.g. cancer-associated fibroblasts, adipocytes) contribute to the progression of cancer, less is known about the metabolic needs of immune cells in this local tumor microenvironment. However, in the context of cancer, immune cells, including tumor-associated macrophages (TAMs) are of high interest since it is known that these cells are able to influence tumor progression by allowing the establishment of an attractive environment for tumor growth and metastasis. Studying the expression profiles of proteins involved in metabolic processes of these cells might be a good strategy to elucidate this question.
In this study, we applied quantitative proteomics to study the differences in protein expression of TAMs vs. control macrophages (both bone marrow-derived and peritoneal macrophages) isolated from an in vivo murine model for non-small cell lung adenocarcinoma. In our peptide-centric two dimensional liquid chromatography (LC)- tandem mass spectrometry (MS/MS) setup where Tandem Mass Tag (TMT) labeling is applied, we were able to identify 1250 unique proteins, of which 1178 proteins were quantified with all six TMT reporter ions. Interestingly, analysis of the differentially expressed proteins indicate that several Gene Ontology terms regarding metabolic pathways including glutathione metabolic processes (p= 3.47 e-14) and pentose phosphate shunt (p= 2.29 e-8) were enriched. These data suggest that TAMs can reprogram their metabolism in order to survive to the oxidative stress existing in this kind of microenvironment.
In conclusion, our results illustrate that proteome analysis is a good strategy to obtain insights in the biology of tumor-associated macrophages.
Citation Format: Evelyne Maes, Mathias Wenes, Dirk Valkenborg, Inge Mertens, Hans Prenen, Massimiliano Mazzone, Geert Baggerman. The use of quantitative proteomics to increase the knowledge about metabolic symbiosis in a tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B46.
Abstract B61: Effects of metformin on papillary thyroid cancer apoptosis and autophagy
Authors: Song Young Shin , Kim Eun Young , Sun Hyun Jin , Park Young Joo , Park Do Joon , Cho Sun Wook 
Published: May 2016

Abstract
Metformin, an anti-diabetic drug used in type 2 diabetes treatment, is reported to have therapeutic roles in several human cancers. The present study investigated the Effects of metformin on papillary thyroid cancer (PTC) cell apoptosis and autophagy. Metformin inhibited PTC cell viability and increased cell apoptosis in various doses (0.5-20mM) in two different PTC cell lines (BCPAP and BHP10-3SC). Additionally, metformin-treated PTC cells showed increased LC3B-II with ATG5-ATG12 complex suggesting the induction of autophagy. Interestingly, treatment of autophagy inhibitor, BafA1, enhenced metformin-mediated PTC cell apoptosis. In conclusion, the inhibition of autophagy might enhance the anticancer effects of metformin on PTC cells.
Citation Format: Young Shin Song, Eun Young Kim, Hyun Jin Sun, Young Joo Park, Do Joon Park, Sun Wook Cho. Effects of metformin on papillary thyroid cancer apoptosis and autophagy. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B61.
Abstract IA26: Identifying metabolic liabilities in obesity-associated pancreatic cancer
Authors: Zaytouni Tamara , Dubois Cory , Hitchcock Daniel , Stylopoulos Nicholas , Clish Clary , Kalaany Nada 
Published: May 2016

Abstract
Obesity is a rising pandemic that is increasingly being recognized for its striking correlation with the incidence of/mortality from cancers of different tissues, particularly that of the pancreas. Ranking as the fourth leading cause of cancer death in the United States, pancreatic ductal adenocarcinoma (PDAC) is a highly lethal, insidious malignancy whose poor prognosis is reflected in a 5-year survival rate of only 5%. In an obese state characterized by elevated circulating levels of insulin and insulin-like growth factor-1 (IGF-1), metabolic signaling pathways, including PI3K/Akt might be aberrantly regulated, altering tumor cell metabolism and driving the maintenance of PDAC. Recognized as a hallmark of cancer formation, altered cellular metabolism is evident in Kras-driven PDAC tumors. However, the specific metabolic impact of obesity and increased insulin and IGF-1 levels on PDAC tumors has not been thoroughly investigated. We performed a large orthotopic xenograft experiment involving the injection of human pancreatic cancer cells modified to either express constitutively active, myristoylated Akt, or a control fluorescent protein (CFP) into the pancreata of lean or diet-induced obese immunodeficient mice. We find that control CFP-tumors grown in obese mice and all Akt-tumors, independent of obesity, are significantly larger than CFP-tumors grown in lean mice. Gene expression and metabolomics analyses demonstrate a striking representation of distinct metabolic pathways, including the nitrogen/arginine or urea cycle pathway in pancreatic tumors grown in obese versus lean mice. This pathway enrichment partially overlaps with that observed in the Akt-driven tumors, independent of obesity. Here we describe the validation of these results by altering urea cycle gene expression in the human PDAC cells and assessing their effect on PDAC cell proliferation, survival, metabolism, and response to arginine deprivation both in tissue culture in vitro and as orthotopic xenografts in the pancreata of lean or diet-induced obese mice in vivo. These studies will help identify metabolic dependencies in Akt-driven or non-Akt-driven pancreatic tumors grown under either obese/hyperinsulinemic or lean states, that could be targeted therapeutically in PDAC patients.
Citation Format: Tamara Zaytouni, Cory Dubois, Daniel Hitchcock, Nicholas Stylopoulos, Clary Clish, Nada Kalaany. Identifying metabolic liabilities in obesity-associated pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA26.
Abstract PR05: Aspartate metabolism links the urea cycle with nucleic acid synthesis in cancerous proliferation
Authors: Rabinovich Shiran , Yizhak Keren , Sun Qin , Brandis Alexander , Helbling Daniel , Dimmock David , Nagamani Sandesh , Ruppin Eytan , Erez Ayelet 
Published: May 2016

Abstract
Argininosuccinate synthase (ASS1) is a urea cycle cytosolic enzyme that conjugates aspartate transported across the mitochondria and citrulline. In the liver, this is a critical step in conversion of nitrogenous waste to urea, whereas in most other tissues, it is the penultimate step in arginine synthesis. Citrullinemia is a urea cycle disorder caused by germline mutations that lead to decreased flux through ASS1. Citrullinemia type I (CTLN I) is caused by ASS1 deficiency and citrullinemia type II (CTLN II) is caused by deficiency in mitochondrial aspartate transporter Citrin. In contrast to the established role of ASS1 in ureagenesis, it was found to be somatically silenced in multiple cancers for which the purpose is unknown. Whereas ASS1 silencing renders the tumors auxotrophic for arginine, we hypothesized that down-regulation of ASS1 has an arginine-independent survival effect by redirecting of aspartate towards pyrimidine synthesis.
Supported by computational modeling and using multiple methodologies including studies of fibroblasts from patients with CTLN I and CTLN II, cancer cells, clinical data, robust informatics analysis of multiple tumors, we show that ASS1 is a key regulator of the mitochondria-derived aspartate flux. Silencing of ASS1, leads to preferential diversion of aspartate away from the synthesis of arginine and urea to pyrimidine synthesis. Decreasing aspartate flux to pyrimidine synthesis by either expressing ASS1 in cancer cells that have endogenous silencing, or by blocking the transport of aspartate through the mitochondrial membrane by inhibiting Citrin, decreases cell proliferation due to decreased nucleic acid synthesis.
Our results demonstrate that ASS1 silencing is a novel mechanism to support nucleic acid synthesis in cancers and provides the first metabolic link between the urea cycle enzymes and pyrimidine synthesis.
Citation Format: Shiran Rabinovich, Keren Yizhak, Qin Sun, Alexander Brandis, Daniel Helbling, David Dimmock, Sandesh Nagamani, Eytan Ruppin, Ayelet Erez. Aspartate metabolism links the urea cycle with nucleic acid synthesis in cancerous proliferation. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR05.