bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A22: An LKB1-CRTC1 circuit regulates glycosylated COX-2 and predicts drug response in lung cancer
Authors: Cao Chunxia , Gao Ruli , Zhang Min , Amelio Antonio L. , Fallahi Mohammad , Chen Zirong , Gu Yumei , Hu Chengbin , Welsh Eric A. , Engel Brienne E. , Haura Eric , Cress W. Douglas , Wu Lizi , Zajac-Kaye Maria , Kaye Frederic J. 
Published: May 2016

Abstract
Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins important for mitogenic signaling. Here we report that COX-2 is a transcriptional target of the CREB co-activator CRTC1. In addition, we detected a correlation between the LKB1-null status and presence of 72/74 kDa glycosylated COX-2, but not inactive hypoglycosylated COX-2 in fresh lung adenocarcinoma samples. Since CRTC1 is suppressed by cytoplasmic shuttling following LKB1/AMPK/SIK phosphorylation, we developed an LKB1 signature in lung cancer to search the Connectivity-MAP drug response database. Remarkably, all high-ranking drugs positively associated with the LKB1-null signature were known CRTC1 activators. Somatic LKB1 mutations are present in 20% of lung adenocarcinomas and we observed growth and cell motility inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1, but negligible inhibition in LKB1-wildtype cells. In summary, the CREB co-activator CRTC family directly links LKB1 with COX-2 activation and provides a new framework for selecting patients for COX-2 inhibition.
Citation Format: Chunxia Cao, Ruli Gao, Min Zhang, Antonio L. Amelio, Mohammad Fallahi, Zirong Chen, Yumei Gu, Chengbin Hu, Eric A. Welsh, Brienne E. Engel, Eric Haura, W. Douglas Cress, Lizi Wu, Maria Zajac-Kaye, Frederic J. Kaye. An LKB1-CRTC1 circuit regulates glycosylated COX-2 and predicts drug response in lung 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 A22.
Abstract A36: Amino acids rather than glucose accounts for the majority of cell mass in rapidly proliferating mammalian cells
Authors: Hosios Aaron M. , Hecht Vivian C. , Johnson Marc , Rathmell Jeffrey C. , Manalis Scott R. , Heiden Matthew G. Vander 
Published: May 2016

Abstract
To facilitate growth and division, proliferating cells must duplicate their mass over the cell cycle. Glucose and glutamine are the most consumed nutrients by proliferating mammalian cells, but the extent to which these and other nutrients contribute directly to cell mass has not been investigated. Using isotope labeled nutrients, we quantified the fraction of cell mass derived from different fuels and find that surprisingly neither glucose nor glutamine provide the majority of carbon present in cells. Instead, amino acids, which are consumed at substantially lower rates, together account for the majority of cell mass. While glucose carbon has diverse fates, glutamine is overwhelmingly diverted into protein and its incorporation into cell mass greatly exceeds that of other amino acids, suggesting that glutamine-driven anapleurosis is primarily used for amino acid biosynthesis. Our findings demonstrate that the most heavily consumed nutrients do not make a proportionately large contribution of carbon to macromolecule biosynthesis.
Citation Format: Aaron M. Hosios, Vivian C. Hecht, Marc Johnson, Jeffrey C. Rathmell, Scott R. Manalis, Matthew G. Vander Heiden. Amino acids rather than glucose accounts for the majority of cell mass in rapidly proliferating mammalian cells. [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 A36.
Abstract A43: BRAF-mutated melanomas exhibit distinct metabolic programs that may determine therapeutic response
Authors: Hardeman Keisha N. , Peng Chengwei , Paudel Bishal , Tyson Darren , Young Jamey D. , Quaranta Vito , Fessel Joshua P. 
Published: May 2016

Abstract
Nearly 60% of melanomas have an activating mutation in the BRAF kinase. Targeted inhibition of mutant BRAF has prolonged overall survival, but responses are highly variable. To investigate the response variability, we utilized a panel of eight BRAF V600E or D mutated melanoma cell lines and treated them with the targeted mutant BRAF inhibitor, PLX4720. Under PLX4720 treatment, the cell lines exhibited a spectrum of concentration-dependent sensitivities based on measured proliferative rates over 96 hours of treatment. Since dysregulated metabolism has been shown to influence therapy resistance, we hypothesized that this spectrum of sensitivity would vary concordantly along a single metabolic phenotype. To test this hypothesis we measured glucose and amino acid uptake, lactate production, extracellular acidification upon mitochondrial inhibition, and proliferative rates under lactogenic glycolysis (oxamic acid) and ATP-synthase (oligomycin) inhibition in the cell lines. Interestingly, we did not find a single metabolic spectrum but rather unique clusters of metabolic phenotypes ranging from glycolysis-, amino-acid-, and oxidative phosphorylation-dependent to high metabolically flexible cell lines. Particularly, some cell lines were extremely sensitive to even low concentrations of oligomycin, whereas the majority of cell lines exhibited concentration-independent decreases of approximately ½ their proliferative rate under vehicle control. Metabolism and cell growth are intimately linked to cell cycle status, so we asked whether sensitivity to PLX4720 is abrogated when cells are selected under PLX4720 treatment. Using a fluorescence ubiquitination cell cycle indicator (FUCCI) to label dividing cells (G2/S/M phases), we pre-treated melanomas with PLX4720 or vehicle, flow-sorted FUCCI+ and FUCCI-cells, then re-treated with PLX4720. This revealed there was no positive selection for PLX4720-resistant subclones, as the PLX4720 treated FUCCI+/- cells pheno-copied the proliferative rates of the vehicle treated FUCCI+/- cells. Taken together, our results suggest that BRAF-mutated melanomas exist in a metabolically rich landscape that may be an important factor in response to targeted BRAF inhibition. The long-term goal is to translate these metabolic differences clinically, possibly by coupling metabolic and oncogene targeted therapies.
Citation Format: Keisha N. Hardeman, Chengwei Peng, Bishal Paudel, Darren Tyson, Jamey D. Young, Vito Quaranta, Joshua P. Fessel. BRAF-mutated melanomas exhibit distinct metabolic programs that may determine therapeutic response. [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 A43.
Abstract A47: The regulation of TIGAR
Authors: Lee Pearl , Cheung Eric C. , Vousden Karen H. 
Published: May 2016

Abstract
The p53 tumor suppressor protein inhibits the development of cancer by initiating various cellular responses including apoptosis, senescence and cell cycle arrest. In addition to this, recent studies have found that p53 is also able to influence cell metabolism. TP53-induced glycolysis and apoptosis regulator (TIGAR) was discovered as a p53 target functioning as a fructose-2,6-bisphosphatase. In this way, TIGAR can modulate glucose metabolism, resulting in enhanced NADPH production and antioxidant defence.
While discovered as a p53 target, basal expression of TIGAR is not affected by loss of p53 or its family member TAp73 in mice and increased expression of TIGAR in the small intestines is still observed following irradiation in these animals. Moreover, this induction is retained in mice deleted of both p53 and TAp73, demonstrating that TIGAR expression is not dependent on either of these transcription factors.
In mouse intestines, TIGAR is important in repair following tissue injury and mice that are TIGAR-deficient show elevated levels of oxidative stress following damage. As the Wnt/Myc signalling pathway is important in cellular proliferation and tissue regeneration, its potential role in regulating TIGAR was investigated. Deletion of APC in mouse intestines, leading to high Wnt pathway activation, results in an increased expression of TIGAR, suggesting that the Wnt/Myc signalling pathway may influence the regulation of TIGAR.
Together, the results suggest that TIGAR can be regulated through p53-dependent and independent mechanisms to contribute to the control of tissue regeneration and tumorigenesis.
Funded by Cancer Research UK, PL is a recipient of an MRC studentship.
Citation Format: Pearl Lee, Eric C. Cheung, Karen H. Vousden. The regulation of TIGAR. [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 A47.
Abstract A51: Targeting mTOR metabolism for glioblastoma cancer therapy
Authors: Tandle Anita , Kramp Tamalee , Tofilon Philip , Camphausen Kevin 
Published: May 2016

Abstract
Aerobic glycolysis (the Warburg effect), first recognized almost a century ago, by Otto Warburg is a core hallmark of cancer. The Warburg effect describes a switch in glucose metabolism from oxidative phosphorylation to glycolysis. Recently links have been established between the oncogenic pathways that drive tumorigenesis and the mechanistic basis of tumor cell metabolism. The kinase mTOR is a major driver of tumor metabolism and proliferation of cancer cells, acts downstream of numerous oncogenic pathways. Several drugs targeting the mTOR pathway are being developed, however the most common drug rapamycin does not inhibit mTOR complex-2. Therefore in the current study, we examined the potential benefit of MLN0128, a novel potent mTOR ATP competitive inhibitor, as a therapeutic strategy for glioblastoma (GBM), one of the deadliest brain tumors.
We studied the action of MLN0128 in human GBM tumor cells and patient derived stem cells. We show the inhibitory effect of MLN0128 in nanomolar concentrations on tumor proliferation in multiple GBM cell lines via the blockage of phospho-AKT, -ribosomal protein, -4EBP1 inhibiting both mTORC1 and mTORC2 signaling in GBM. Reduction of invasive potential and disruption of paxillin localization to focal adhesions was observed in vitro. MLN0128 treatment decreased glucose consumption and lactate production. It inhibited rate of glycolysis, glycolytic capacity and glycolytic reserve. It also inhibited ATP production, mitochondrial respiration and spare respiratory capacity. MLN0128 was superior in inhibiting metabolism compared to rapamycin. On clonogenic survival assay MLN0128 decreased GBM cell survival and increased radiosensitivity. In vivo treatment of mouse xenografts with MLN0128 downregulated mTOR targets and significantly inhibited tumor volume compared to drug and irradiation alone. Combination treatment of GBM cells with MLN0128 and other chemotherapeutic agents like carboplatin, irinotecan and TMZ showed synergistic effects when combination index was calculated in GBM tumor cells and stem cells. However, the therapeutic efficacy of TMZ combination was greater than MLN0128 combination with either carboplatin or irinotecan. Moreover, similar TMZ chemosensitivity was observed in MGMT non-methylated, TMZ in-sensitive GBM stem cells and MGMT methylated GBM cells. These findings support the rationale for clinical testing of MLN0128 in patients with GBM to provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors with standard care.
Citation Format: Anita Tandle, Tamalee Kramp, Philip Tofilon, Kevin Camphausen. Targeting mTOR metabolism for glioblastoma cancer therapy. [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 A51.
Abstract A60: Inhibition of growth of bladder cancer cells by compounds that affect glucose metabolism
Authors: Lea Michael A. , Altayyar Mansour , desBordes Charles 
Published: May 2016

Abstract
The tendency of cancer cells to have enhanced rates of glycolysis presents a target for combination therapy with agents that affect glucose metabolism. We have explored the action of three compounds on a panel of eight human bladder cancer cell lines showing a spectrum of growth rates. The compounds were an inhibitor of PFKFB3, namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), an inhibitor of pyruvate dehydrogenase kinase, dichloroacetate, and, paradoxically, phenformin. The biguanide phenformin increases glucose metabolism in some cancer cell lines but it can also be growth inhibitory. Effects on glucose metabolism and lactic acid production were monitored respectively by an enzyme-linked colorimetric assay for glucose in the medium and changes in the pH of the medium reflected by the absorbance of phenol red at 560 nm. Changes in these parameters were most marked for the rapidly growing T24 and UM-UC-3 bladder cancer cells and generally showed parallel changes with control and treated cells. We had previously established growth inhibitory effects of 10µM 3PO on the eight bladder cancer cell lines monitored by staining with sulforhodamine B. Inhibitory effects of 2.5 mM dichloracetate have been observed with additive inhibitory effects when cells were treated with combinations of 3PO and dichloracetate. Effects of phenformin as a single agent were studied at 10, 25 and 50µM. Concentration-related increases in medium acidification and glucose uptake were most consistently seen with T24 cells. The effects with 50µM phenformin could be blocked by coincubation with 2.5 mM dichloracetate. On the other hand, additive inhibitory effects on growth may be observed with combinations of phenformin and dichloroacetate. Sensitivity to the actions of phenformin could not be simply related to growth rate. The T24 and UM-UC-3 cells have similar growth rates and had similar inhibitory effects on growth when treated with phenformin. However, medium acidification and glucose uptake were less affected in the UM-UC-3 cells. Although there are conditions in which phenformin appears to increase the Warburg effect as it relates to glucose metabolism, there can be additive growth inhibitory effects when bladder cancer cells are treated with phenformin in combination with agents that inhibit glucose metabolism.
Citation Format: Michael A. Lea, Mansour Altayyar, Charles desBordes. Inhibition of growth of bladder cancer cells by compounds that affect glucose metabolism. [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 A60.
Abstract A85: Concurrent targeting of glutamine and asparagine metabolism produces synergistic inhibition of tumor cell proliferation
Authors: Schramm Cicely L. , Xie Zhi , Kindt Erick , Li Wenlin , Wang Fang , Fantin Valeria R. 
Published: May 2016

Abstract
One of the best characterized examples of metabolic changes occurring in a wide range of cancer cells is dependence on the non-essential amino acid glutamine. We identified requirements for several other non-essential amino acids, including asparagine, across a panel of glutamine-dependent and –independent breast and lung cancer cell lines. Glutamine and asparagine metabolism are tightly linked. Therefore, we hypothesized that concurrent targeting of the metabolism of these two non-essential amino acids could cooperatively interfere with tumor cell growth. Treatment with a glutaminase inhibitor, BPTES, and concurrent enzymatic depletion of asparagine produced a synergistic antiproliferative effect in many, but not all, cancer cell lines. Mechanistic data suggest that metabolic circuitry gets co-opted to maintain amino acid pools following combined targeting of glutamine and asparagine metabolism, resulting in mitochondrial dysfunction and redox imbalance. Following combination treatment, alterations in mitochondrial metabolism and cystine influx were observed, but overall amino acid levels remained surprisingly stable. These metabolic changes were reflected in cellular functional readouts as measured by Seahorse analysis and measurement of ROS levels. Importantly, they were also linked to the synergistic antiproliferative phenotype. Our results provide new mechanistic insight into the interplay between glutamine and asparagine metabolism in cancer cells and suggest that dual targeting of metabolically linked non-essential amino acids may be promising as a therapeutic strategy.
Citation Format: Cicely L. Schramm, Zhi Xie, Erick Kindt, Wenlin Li, Fang Wang, Valeria R. Fantin. Concurrent targeting of glutamine and asparagine metabolism produces synergistic inhibition of tumor cell 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 A85.
Abstract A87: Targeting the mitochondrial quality control machinery in acute myeloid leukemia
Authors: Jeyaraju Danny V. , Voisin Veronique , Ramakrishnan Ashwin , Hurren Rose , Maclean Neil , Gronda Marcela , Minden Mark , Bader Gary , Schimmer Aaron D. 
Published: May 2016

Abstract
Recently, we demonstrated that a subset of AML cells and stem cells have metabolic vulnerabilities in the mitochondria and oxidative phosphorylation (OXPHOS) chain that could impact on the ability of AML and AML stem cells to handle increased electron flux in the respiratory chain (Sriskanthadevan et al., Blood, 2015). To identify additional vulnerabilities in the mitochondria of AML cells and AML stem cells, we analyzed RNA expression levels of a panel of mitochondrial quality control proteins using the nCounter Analysis System (Nanostring technologies) in bulk as well as the progenitor enriched fraction of AML patients and normal donors. Among the top hits was the mitochondrial processing peptidase (MPP) that was upregulated in AML cells and progenitors compared to normal hematopoietic cells. MPP is a metallopeptidase composed of a regulatoryα subunit and a proteolytic β subunit that cleaves presequences from several nuclear encoded and mitochondrially imported proteins. To further analyze the expression of MPP in AML, we analyzed publicly available datasets (Eppert et al., (GSE30377), Laurenti et al., (GSE42414) and Norversthen et al., (GSE24759)). GSEA (Gene Set Enrichment Analysis) on stem enriched as well as bulk AML cells demonstrated upregulation of MPPα and β as well as increased expression of the mitochondrial protein import pathway in a subset of AML cells and stem cells compared to normal hematopoietic cells and stem cells.
To understand the importance of MPP in AML cells, we knocked down MPPα and β using shRNA in lentiviral vectors and confirmed target knockdown by immunoblotting. Knockdown of MPPα or β reduced the growth and viability of OCI-AML2 cells. Mechanistically, knockdown of MPP β increased mitochondrial ROS generation.
Thus, the mitochondrial protein import pathway is upregulated in a subset of AML cells and stem cells. Moreover inhibition of this pathway at the level of MPPα and β is cytotoxic to AML cells and disrupts mitochondrial function.
Citation Format: Danny V. Jeyaraju, Veronique Voisin, Ashwin Ramakrishnan, Rose Hurren, Neil Maclean, Marcela Gronda, Mark Minden, Gary Bader, Aaron D. Schimmer. Targeting the mitochondrial quality control machinery in acute myeloid leukemia. [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 A87.
Abstract A89: Glycolytic cancer cell metabolism suppressed by transplantation of exogenous normal mitochondria into human breast cancer cells
Authors: Elliott Robert L. , Jiang Xian-Peng , Head Jonathan F. 
Published: May 2016

Abstract
Most cancer cells switch metabolism from mitochondria-based glucose oxidation to cytoplasmic glycolysis even under normoxia (the Warburg effect). The effect promotes tumorigenesis, cancer growth, invasion and drug resistance. We hypothesize that introduction of normal mitochondria into cancer cells might suppress the Warburg effect. Normal human (MCF-12A) and mouse (EpH4-Ev) mammary epithelia, and human breast cancer (MCF-7) and mouse mammary adenocarcinoma (4T1) cell lines were used in this study. We found that isolated fluorescent probe-stained mitochondria of MCF-12A or EpH4-Ev could enter into cancer cells when co-cultured with MCF-7 or 4T1 cells respectively, confirmed by fluorescent and confocal microscopy. The mitochondria from MCF-12A cells inhibited the proliferation of breast cancer MCF-7 cells in a dose dependent pattern and increased drug sensitivity of MCF-7 cells to doxorubicin, paclitaxel and carboplatin. Real time qPCR showed that exogenous normal mitochondria suppressed the gene expression of 11 glycolytic enzymes, and glucose transporter 1 and 3 of MCF-7 cells. These results suggest that normal mitochondria suppress cancer proliferation and increase drug sensitivity by the mechanism of inhibition of cancer cell glycolysis and glucose consumption. Isolated mitochondria have remained viable in culture for over three weeks and still actively entered cancer cells and inhibited cancer proliferation. In mouse model bearing the 4T1 mammary adenocarcinoma, isolated MitoTracker orange dye-stained mitochondria of EpH4-Ev, when directly injected into tumor mass, entered into 4T1 cancer cells in 24 hours. Therefore, normal mitochondrial transfer could be a cell-based therapy for cancer and other mitochondrial disorders.
Citation Format: Robert L. Elliott, Xian-Peng Jiang, Jonathan F. Head. Glycolytic cancer cell metabolism suppressed by transplantation of exogenous normal mitochondria into human breast cancer cells. [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 A89.