bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1187: Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma
Authors: Hettmer Simone , Schinzel Anna C. , Tchessalova Daria , Richards Nigel GJ , Hahn William C. , Wagers Amy J. 
Published: August 2015

Abstract
Background. Currently available therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets in sarcomas by selective targeting of the molecular networks that support sarcoma cell proliferation. Experimental approach. Mouse sarcomas driven by expression of oncogenic Kras(G12v) and disruption of CDKN2A (p16p19) were induced by ex-vivo transduction and intramuscular injection of mouse satellite cells. Kras; p16p19null sarcomas identified a cluster of genes upregulated in mouse sarcomas and human rhabdomyosarcoma compared to normal skeletal muscle. A customized shRNA proliferation screen was used to identify transcripts within this cluster that reduced sarcoma cell proliferation. Target gene effects on sarcoma growth were evaluated in mouse and human sarcoma cell lines and xenografts.
Results. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Conclusions. The generation of new protein mass by rapidly proliferating sarcoma cells requires adequate Asparagine availability. Asparagine reliance of sarcoma cells may represent an actionable, metabolic vulnerability with potential anti-rhabdomyosarcoma therapeutic value.
Citation Format: Simone Hettmer, Anna C. Schinzel, Daria Tchessalova, Nigel GJ Richards, William C. Hahn, Amy J. Wagers. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1187. doi:10.1158/1538-7445.AM2015-1187
Abstract 1190: Prognostic significance of serine synthesis pathway-related protein expression in patients with resected colon cancer
Authors: Kang Byung Woog , Kim Jong Gwang , Chae Yee Soo , Lee Soo Jung , Yoon Shinkyo , Yoon Ghil Suk 
Published: August 2015

Abstract
Background
We analyzed the prognostic impact of serine synthesis pathway-related protein expression in a large number of patients with colon cancer.
Methods
PDK1, PDK2, PKM2, PHGDH, PSAT, and ER betta expression were investigated on the basis of the immunohistochemistry of tissue microarray specimens from 486 colon cancer patients who underwent curative surgery between 2006 and 2010. We scored the staining intensity (0 through 3) and percentage of positive cells (0 through 4), and the staining score was defined as sum of these scores used to categorize the each expression as low (0 through 3) or high (4 or more).
Results
For the 486 patients, the median age was 66 (30-90) years at the time of surgery. The pathologic stages after the surgical resection were as follows: stage I (n = 98), stage II (n = 213), and stage III (n = 175). A total of 201 (41.4%) was identified as high PDK2 (staining score ≥4). The survival analysis showed that the expression of serine synthesis pathway-related protein had no effect on the overall survival and disease-free survival (DFS) except that the grade of PDK2 expression was significantly associated with the DFS (p = 0.028). On the multivariate analysis that included age, histology, TNM stage, and CEA level, no significant association between the grade of the PDK2 expression and DFS was observed.
Conclusion
The current study suggests that the tissue expression of serine synthesis pathway-related protein is not an independent prognostic marker for patients with surgically resected colon cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Byung Woog Kang, Jong Gwang Kim, Yee Soo Chae, Soo Jung Lee, Shinkyo Yoon, Ghil Suk Yoon. Prognostic significance of serine synthesis pathway-related protein expression in patients with resected colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1190. doi:10.1158/1538-7445.AM2015-1190
Abstract 1203: Metastasis-associated oncogene RhoC as a regulator of glutamine metabolism in the inflammatory breast cancer cell line SUM149
Authors: Yates Joel A. , Wynn Michelle L. , Wu ZhiFen , Evans Charles R. , Burant Charles , Schnell Santiago D. , Merajver Sofia D. 
Published: August 2015

Abstract
Metabolic reprogramming is increasingly recognized as a fundamental hallmark of cancer. While the Warburg effect and normal proliferative metabolism are similar, they are not equivalent. We hypothesize that there are key drivers of malignant metabolism that can be modulated to impede cancer proliferation without substantial effects on normal tissue growth. Using 13C-labeled glucose and glutamine tracers in combination with mass spectrometry and measurements of extracellular glucose, lactate, and glutamine flux, we have characterized system level differences in a series of breast cancer cell lines as well as normal-like breast epithelial cells. We observed an increase in the reductive carboxylation of glutamine-derived citrate and alpha-ketoglutarate in the triple-negative inflammatory breast cancer cell line SUM149. We also observed that the SUM149 exhibit high levels of HIF-1α and low levels of oxygen consumption under normoxia, suggesting that the cell line is highly adapted to hypoxia. Surprisingly, the stable depletion of HIF-1α via shRNA had no significant effect on the metabolic profile of these cells. Previous work by our lab and others has demonstrated that the GTPase RhoC is a driver of the metastatic phenotype exhibited by inflammatory breast cancer. Activation of RhoC is known to induce cytoskeletal rearrangements and increase invasive potential. The Rho GTPase family of proteins has also recently been linked to metabolism, specifically regulation of glutaminase activity. Here we show that stable knockdown of RhoC in SUM149 cells results in a marked decrease in the rate of both glutamine uptake and intracellular reductive carboxylation. This work reinforces the role of RhoC as an important driver of inflammatory breast cancer metastatic potential. We conclude that RhoC remains an important clinical target with the potential to alter patient outcomes.
Citation Format: Joel A. Yates, Michelle L. Wynn, ZhiFen Wu, Charles R. Evans, Charles Burant, Santiago D. Schnell, Sofia D. Merajver. Metastasis-associated oncogene RhoC as a regulator of glutamine metabolism in the inflammatory breast cancer cell line SUM149. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1203. doi:10.1158/1538-7445.AM2015-1203
Abstract 1209: Dissecting by 13C tracers the utilization of glucose and glutamine for the synthesis of fatty acids in triple negative breast cancer cells
Authors: Strigun Alexander , Reszka Regina , Schiewe Hans-Joerg , Laine Jean-Philippe , Rennefahrt Ulrike 
Published: August 2015

Abstract
Triple negative breast cancer (TNBC) is an aggressive cancer, which is resistant to the majority of available chemotherapies. We have recently identified significant differences in the levels of membrane lipids and fatty acids between two distinct TNCB metabolic subtypes (MST2 and MST3) (Beatty et al., 2014, manuscript submitted). Fatty acid synthesis has recently been discussed as potential pharmaceutical target.
In order to evaluate whether glucose or glutamine is the preferred carbon source for palmitic acid synthesis, TNBC cell lines (BT549 and HCC1806) were fed with fully labelled glucose and fully labelled glutamine ([U-13C6]glucose and [U-13C5]glutamine) in independent experiments. Fully labelled glutamine allows conclusions on total usage of glutamine via the reductive and the oxidative part of the TCA-cycle. In order to assess the contribution of glutamine to palmitic acid synthesis via the reductive pathway we fed the subtypes with single labelled glutamine [5-13C1]glutamine. Enrichment of 13C in palmitic acid from all labelling experiments was measured via GC-MS (gas chromatography coupled mass spectrometry).
Feeding the TNBC subtypes with [U-13C6]glucose and [U-13C5]glutamine resulted in a higher enrichment of 13C in palmitic acid derived from glucose as compared to glutamine in both subtypes, indicating that glucose is the main carbon source at the tested conditions. Feeding the cells with [5-13C1]glutamine also resulted in an enrichment of 13C in palmitic acid in both subtypes, which indicates that reductive glutamine metabolism contributes to palmitic acid synthesis in both subtypes. Based on the 13C-palmitic acid data from both glutamine isotopes we found that palmitic acid synthesis preferably occurs via the reductive path in MST3 (61% of total glutamine use) while the oxidative path seems the preferred route (34% of total glutamine use) in MST2.
The presented data indicate that glucose is the main carbon source for fatty acid synthesis in both MSTs, suggesting a higher sensitivity towards pharmacological targeting of glucose metabolism. Despite of the lower dependency on glutamine, TNCBs of the MST3 subtype seem more sensitive towards targeting the reductive glutamine metabolism.
Citation Format: Alexander Strigun, Regina Reszka, Hans-Joerg Schiewe, Jean-Philippe Laine, Ulrike Rennefahrt. Dissecting by 13C tracers the utilization of glucose and glutamine for the synthesis of fatty acids in triple negative breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1209. doi:10.1158/1538-7445.AM2015-1209
Abstract 1228: Identification of a novel p53 target regulating p53-induced apoptotic pathway
Authors: Mori Jinichi , Lo Paulysally , Tanikawa Chizu , Nakamura Yusuke , Matsuda Koichi 
Published: August 2015

Abstract
In response to various cellular stresses, p53 induces its target genes and suppresses tumor development. However, the anti-tumor function of p53 has not been fully elucidated. The purpose of our study is the identification and functional analysis of novel p53 downstream targets. We conducted cDNA microarray analysis by using Hct116p53+/+ and p53-/- cells treated with adriamycin and identified p53 inducible protein (p53IP) as a novel p53 downstream target. Induction of p53IP mRNA was confirmed by qRT-PCR. We also found that p53IP protein was increased only in Hct116p53+/+ cells by adriamycin treatment. The result of reporter assay and ChIP assay revealed the direct binding of p53 to p53-binding sequence within p53IP promoter. Colony formation assay by using HCT116 cells indicated that ectopic expression of p53IP significantly inhibited tumor cell growth. Furthermore, knockdown of p53IP with siRNA inhibited apoptosis of tumor cells induced by DNA damage. Our findings indicated that p53IP as a important mediator of p53-dependent apoptotic pathway.
Citation Format: Jinichi Mori, Paulysally Lo, Chizu Tanikawa, Yusuke Nakamura, Koichi Matsuda. Identification of a novel p53 target regulating p53-induced apoptotic pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2015-1228
Abstract 1245: Peroxiredoxin induction in breast cancer
Authors: Buurma Valerie , Freeman Brendan , Adzenyah Akosua , Pettit Gregory , Heinen Felicitas , Muhlbauer Jillian , Phelan Shelley A. 
Published: August 2015

Abstract
Cancer cells possess elevated levels of reactive oxygen species (ROS) that can enhance genomic instability and alter redox signaling. Aberrant antioxidant expression has also been recognized in many cancers, suggesting an adaptive response to the cancerous state. Breast cancers express significantly elevated levels of Peroxiredoxins (Prdxs), a family of thiol-specific antioxidant proteins involved in regulating cell growth and proliferation in many cell types. We previously reported overexpression of many Prdx proteins in the MCF-7 breast cancer line, as well as their importance in doxorubicin-resistance in this line. In the present study, we analyzed Prdx levels in several human breast tumor samples, and further investigated possible mechanisms of Prdx regulation in MCF-7 cells. Comparison of breast tumor and adjacent normal breast tissue from almost 20 patients showed that most patients exhibited elevated levels of several Prdx proteins in the tumor tissue. To begin to understand possible regulators of Prdxs in breast cancer, we focused on transcriptional regulators known to be aberrantly expressed in breast cancer, and also implicated in antioxidant regulation. Sequence analysis revealed potential binding sites for NF-κB, Nrf2, and AP-1 in several peroxiredoxin promoters. We found high levels of NF-κB in MCF-7 cells, as compared to normal breast epithelial cells. We further showed that a chemo-resistant MCF-7 culture generated from 14 days of doxorubicin treatment exhibited markedly decreased NF-κB expression. We then used both siRNA and chemical inhibition of NF-κB to examine the effect on Prdx regulation in these cells and found gene-specific effects. Similar studies are currently underway for Nrf2 and AP-1. This investigation will help to elucidate the role of peroxiredoxins in breast cancer cell survival, and the mechanism by which these cells alter Prdx levels to avoid death and achieve chemoresistance.
Citation Format: Valerie Buurma, Brendan Freeman, Akosua Adzenyah, Gregory Pettit, Felicitas Heinen, Jillian Muhlbauer, Shelley A. Phelan. Peroxiredoxin induction in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1245. doi:10.1158/1538-7445.AM2015-1245
Abstract 125: Protein kinase C loss-of-function mutations in cancer reveal role as tumor suppressor
Authors: Antal Corina E. , Hudson Andrew M. , Kang Emily , Zanca Ciro , Wirth Christopher , Stephenson Natalie L. , Trotter Eleanor W. , Gallegos Lisa L. , Miller Crispin , Furnari Frank , Hunter Tony , Brognard John , Newton Alexandra C. 
Published: August 2015

Abstract
Protein kinase C (PKC) remains an elusive chemotherapeutic target despite decades of research. To determine whether PKC isozymes function as oncogenes or tumor suppressors, we analyzed 8% of PKC mutations identified in human cancers. Surprisingly, the majority were loss-of-function and none were activating. Loss-of-function mutations were found in all PKC subgroups and acted by impeding 2nd messenger binding or preventing processing phosphorylations. Bioinformatic analysis revealed that PKC mutations might cooperate with co-occurring mutations in cancer drivers. Correction of a patient-identified, loss-of-function PKCβ mutation by CRISPR-mediated genome editing, in a colon cancer cell line, suppressed anchorage-independent growth and reduced tumor growth in xenograft models. Hemizygous deletion provided an anchorage-independent growth advantage, revealing PKC is haploinsufficient for tumor suppression. Several mutations were dominant-negative, suppressing global PKC signaling output. These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapeutic strategies should focus on restoring PKC activity, not inhibiting it.
Citation Format: Corina E. Antal, Andrew M. Hudson, Emily Kang, Ciro Zanca, Christopher Wirth, Natalie L. Stephenson, Eleanor W. Trotter, Lisa L. Gallegos, Crispin Miller, Frank Furnari, Tony Hunter, John Brognard, Alexandra C. Newton. Protein kinase C loss-of-function mutations in cancer reveal role as tumor suppressor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 125. doi:10.1158/1538-7445.AM2015-125
Abstract 1252: Arginylation as a new link between oxidative stress response and prostate cancer progression
Authors: Zhang Fangliang , Birnbaum Michael D. , Kumar Akhilesh , Morgan William M. 
Published: August 2015

Abstract
In this study, we evaluate the role of post-translational arginylation in prostate cancer, and introduce its potential as a biomarker of prostate cancer progression. Arginylation has not yet been studied in cancer. Our lab has observed Aringyltransferase (Ate1) is required for oxidative stress-mediated apoptosis. Our preliminary data in multiple eukaryotic cell models demonstrate that a downregulation of Ate1 increases resistance to oxidative stress, and elevated Ate1 is sufficient to induce cell death. Preliminary data mining shows that a downregulation of Ate1 correlates with a poorer prognosis in prostate cancer. Because prostate cancer cells produce a high amount of oxidative stress, the decrease of Ate1 likely increases their survival. We hypothesize that Ate1 is essential for the normal cellular response to insurmountable oxidative stress leading to apoptosis, and that a downregulation of Ate1 will promote cancer cell progression. We found that a loss of Ate1 in a nontumorigenic fibroblast cell line promotes spontaneous tumorigenicity within immunocompromised mice, a disruption of normal cell-cell interactions, and loss of contact inhibition. Also consistent with our hypothesis, prostate cancer cell line PC-3 with stably knocked down Ate1 exhibit higher invasiveness in the Boyden Chamber invasion assay, and higher resistance to H2O2-induced cell death during a 12-hour variable dose treatment. Similarly, the highly metastatic subpopulation of PC-3, PC3-ML, has naturally reduced Ate1 and exhibits higher invasiveness and resistance to H2O2. Finally, histological analysis of primary patient prostate cancer samples show a dramatic reduction of Ate1 compared to normal prostate tissue. These findings warrant further study of Ate1 as a metastasis suppressor, as well as a potential biomarker for prostate cancer progression.
Citation Format: Fangliang Zhang, Michael D. Birnbaum, Akhilesh Kumar, William M. Morgan. Arginylation as a new link between oxidative stress response and prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1252. doi:10.1158/1538-7445.AM2015-1252
Abstract 126: PI3 kinase plays important role in c-Kit/V560D mediated oncogenic signaling
Authors: Sun Jianmin 
Published: August 2015

Abstract
Oncogenic mutations of c-Kit are often identified in mastocytosis, gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML). The activation mechanism of the most often occurring mutation, D816V in exon 17 of c-Kit, has been well studied while other mutations remain fairly uncharacterized in this respect. In this study, we show that the constitutive activity of the exon 11 mutant V560D is weaker than the D816V mutant except that the phosphorylation of the Src family kinase binding site, Tyr568, is similar in both c-Kit mutants. The ligand for c-Kit, stem cell factor (SCF), induced phosphorylation of downstream signaling proteins, such as Akt and Erk, in c-Kit/V560D expressing cells was stronger than that in c-Kit/D816V expressing cells. Although cells expressing c-Kit/V560D showed increased ligand-independent proliferation and survival compared to wild-type c-Kit expressing cells, these biological effects were less than c-Kit/D816V expressing cells. In contrast to cells expressing wild-type c-Kit, cells expressing c-Kit/V560D are independent of Src family kinases for downstream signaling. However, this independence of Src family kinases is not due to a Src-like kinase activity of the mutant receptor that c-Kit-D816V holds. Blockage of the association of PI3 kinase with c-Kit/V560D by point mutation, but not inhibition of PI3-kinase with pharmacological inhibitors, totally blocked ligand-independent activation of the receptor, suggesting a key role of the non-lipid kinase activity of PI3 kinase in c-Kit/V560D mediated oncogenic signal transduction. Thus, PI3 kinase is an attractive treatment target in c-Kit mutations induced malignancies independent of its lipid kinase activity.
Citation Format: Jianmin Sun. PI3 kinase plays important role in c-Kit/V560D mediated oncogenic signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 126. doi:10.1158/1538-7445.AM2015-126
Abstract 1270: Ribosome biogenesis is reduced by oncogenic stress in normal cells and is sufficient to trigger cellular senescence
Authors: Lessard Frédéric , Bourdeau Véronique , Igelmann Sebastian , Deschênes-Simard Xavier , Montero Marinieve , Ferbeyre Gerardo 
Published: August 2015

Abstract
Senescence is a stable arrest of cell proliferation in which the cells remain viable and metabolically active but display a constitutive activation of the DNA damage response and of the tumor suppressors p53 and RB. The senescent phenotype can be induced by multiple stresses including short telomeres and oncogenes. We have shown that senescence involves the ERK-dependent degradation of selective proteins involved in cell cycle progression and tumorigenesis. We called this process senescence associated protein degradation (SAPD) and it involves many nucleolar proteins that play a role in ribosome biogenesis. Using tritium pulse labelling we found a strong decrease of rRNA synthesis in senescent cells. In addition, qPCR with primers flanking known rRNA processing sites demonstrated defects in the processing of rRNA in senescent cells. Knocking down some of the nucleolar proteins degraded in senescence was sufficient to trigger the process indicating that a decrease in ribosome biogenesis is causal to cellular senescence. Senescence induced by depletion of ribosome biogenesis factors was characterized by accumulation of p53 and in some cases rescued by inhibition of p53 using shRNAs or the viral oncoprotein E6. We will discuss how reduced ribosome biogenesis impact protein biosynthesis in senescent cells.
Citation Format: Frédéric Lessard, Véronique Bourdeau, Sebastian Igelmann, Xavier Deschênes-Simard, Marinieve Montero, Gerardo Ferbeyre. Ribosome biogenesis is reduced by oncogenic stress in normal cells and is sufficient to trigger cellular senescence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1270. doi:10.1158/1538-7445.AM2015-1270