bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2379: PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function
Authors: Zhao Yiqing , Wang Zhenghe 
Published: August 2018

Abstract
Department of Genetics & Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
In addition to phosphorylation, tyrosine residues in proteins can have nitration at the 3-carbon position on the phenol ring (Y-NO2). Protein tyrosine nitration occurs under both physiological and pathologic conditions. However, enzymes that add or remove this protein modification remain to be identified. Protein tyrosine phosphatase receptor T (PTPRT) is one of the twelve receptor protein tyrosine phosphatases (RPTPs) that have two catalytic PTP domains in their intracellular parts. While the membrane proximal PTP domains (D1) are protein tyrosine phosphatases, it has been thought that the C-terminal PTP domains (D2) are pseudo-phosphatase that lack enzymatic activity. Here we report that the pseudo-phosphatase domain (D2) of PTPRT is a denitrase that removes nitro-groups from tyrosine residues in paxillin. PTPRT normally functions as a tumor suppressor and is frequently mutated in a variety of human cancers including colorectal cancer. Interestingly, a fifth of tumor-derived mutations of PTPRT are located in the D2 pseudo-PTP domain. We demonstrate that some of the tumor-derived mutations located in the pseudo-phosphatase domain impair the denitrase activity. Moreover, PTPRT mutant mice that inactivate the denitrase activity are susceptible to carcinogen-induced colon tumor formation. Our study uncovers a novel enzyme that functions as a tumor suppressor.
Citation Format: Yiqing Zhao, Zhenghe Wang. PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2379.
Abstract 2385: Evaluation of GCN2 chemical probes: Activity in leukemia
Authors: Lough Lea , Sherman Dan , Ni Eric , Thandapani Palaniraja , Aifantis Ioannis , Cardozo Timothy 
Published: August 2018

Abstract
Cellular stress signals activate adaptive signaling pathways of the mammalian integrated stress response (ISR), which converge at the phosporylation of eIF2α. Drug-like chemical inhibitors targeting major ISR kinases have been identified, with the exception of GCN2. We synthesized and evaluated a series of GCN2 inhibitors based on a triazolo[4,5-d]pyrimidine scaffold. Several compounds potently inhibited GCN2 in vitro in orthogonal assays and displayed good selectivity over the related kinases PERK, HRI, and IRE1. The compounds had low solubility at pH 7.4, but sufficient permeability to inhibit phosporylation of eIF2α in HEK293T cells with an IC50 &lt; 150 nM. In a screen of the NCI-60 cancer cell line panel, the leukemia cells were the only group of cancer cell lines to uniformly exhibit growth inhibition. Given the previously reported genetic association of Gcn2 with resistance to asparaginase, which is a first line clinical leukemia therapy, pharmacologic inhibition of Gcn2 may overcome resistance to asparaginase treatment in leukemia.
Citation Format: Lea Lough, Dan Sherman, Eric Ni, Palaniraja Thandapani, Ioannis Aifantis, Timothy Cardozo. Evaluation of GCN2 chemical probes: Activity in leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2385.
Abstract 2390: When MLK3 meets PAK1: Its implication in breast cancer tumorigenesis
Authors: Das Subhasis , Nair Rakesh Sathish , Mishra Rajakishore , Bhowmik Tanmoy , Rana Basabi , Rana Ajay 
Published: August 2018

Abstract
Mixed Lineage Kinase-3, also known as MAP3K11 is a member of a larger family of MAP3Ks, called MLKs. MLK3 has been reported to play an important role in pro-apoptotic signaling, however its role in tumorigenesis is still not fully elucidated. Previously, we reported that MLK3 is down regulated by estrogen and HER2 amplification and this down regulation provided a survival advantage to ER+ and HER2+ breast cancer cells. To further understand the role of MLK3 signaling in breast cancer pathogenesis, we aimed to identify the upstream kinase(s) that might regulate MLK3 activity and perhaps tumorigenesis.
Based on available information from yeast, where Ste20 members are upstream of Ste11 (i.e. MAP3K), we hypothesized that mammalian homologue of Ste20, PAK1 could be upstream of MLK3. PAK1 kinase has been reported to be a major oncogene in many cancers, including breast cancer. Our results were however, counterintuitive to our hypothesis. We observed that instead, MLK3 was able to associate, and activate PAK1 Kinase activity. These results suggested that perhaps MLK3 is either upstream or parallel to PAK1 in the mammalian signaling network. We also observed that PAK1 was phosphorylated by MLK3 on Ser133 and Ser204 sites. Interestingly, Alanine substitution of S133 site constitutively activated PAK1 kinase activity, whereas Alanine substitution of the S204 site completely blocked MLK3-induced PAK1 activation. Constitutive active MLK3 was not able to phosphorylate and activate double mutant PAK1 S133A, S204A in vitro or in HEK293 cells, clearly indicated that PAK1 S204 site is important for MLK3-induced PAK1 activation. Since PAK1 is an oncogene in breast cancer, we determined the biological effect of S204 phosphorylation on breast cancer progression. Stable breast cancer cell line, MDA-MB-468, expressing PAK1 S204A, inhibited migration, invasion and showed significantly smaller tumors, compared to WT PAK1-expressing cells. Taken together, our results suggest that MLK3-induced modulation of PAK1 activity plays a major role in breast cancer tumorigenesis.
First two authors are equally contributed
Citation Format: Subhasis Das, Rakesh Sathish Nair, Rajakishore Mishra, Tanmoy Bhowmik, Basabi Rana, Ajay Rana. When MLK3 meets PAK1: Its implication in breast cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2390.
Abstract 2392: Evaluation of synergistic PI3K/Akt and MEK5/ERK5 inhibition in triple-negative breast cancer
Authors: Wright Thomas D. , Raybuck Christopher , Gartland Nathan , Wendekier Katy , Monlish Darlene , Chakrabarty Suravi , Flaherty Patrick T. , Burow Matthew E. , Cavanaugh Jane E. 
Published: August 2018

Abstract
Triple negative breast cancers (TNBCs) represent 15-20% of all breast cancers and are often associated with a poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Therefore, there is a need to identify survival pathways that may be targeted in TNBCs. Aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. The crosstalk between PI3K/Akt and MEK1/2/ERK1/2 has been characterized in several systems. However, new evidence suggests that MEK5/ERK5, a member of the MAPK family, is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in three TNBC cell lines: MDA-MB-231, BT549, and MDA-MB-468. We achieved Akt inhibition by using the clinically relevant inhibitors MK-2206 and Ipatasertib. We used a novel compound synthesized in our lab, SC-1-181, and the research tool, XMD8-92, to inhibit MEK5 and ERK5, respectively. Our results indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Interestingly, this signaling pattern was observed without disturbing the ERK1/2 pathway. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. Additionally, the dual inhibition strategy was determined to be synergistic in TNBCs and was nontoxic in non-neoplastic cell lines. Lastly, we evaluated the contributions of Bromodomain 4 (BDR4), an off-target effect of XMD8-92, to the synergy mechanism. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs.
Citation Format: Thomas D. Wright, Christopher Raybuck, Nathan Gartland, Katy Wendekier, Darlene Monlish, Suravi Chakrabarty, Patrick T. Flaherty, Matthew E. Burow, Jane E. Cavanaugh. Evaluation of synergistic PI3K/Akt and MEK5/ERK5 inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2392.
Abstract 2401: Effects of carcinoma-associated fibroblasts on cancer metabolism
Authors: Nguyen Tu , Kirsch Jimmy , Nabi Karim , Sazeides Christos , Quinones Addison , Tan Jessica , Antonio Marjorie , Camelo Felipe , Jung Jin , Le Anne 
Published: August 2018

Abstract
Rationale: In previous studies, it has been found that cancer-associated fibroblasts (CAFs) interaction with carcinoma cells and helped cancer cell grow which contributed to cancer progression and aggressiveness. However, how CAFs helped cancer cells grow, specifically what nutrition CAFs provides to tumors has not yet been fully understood.
Objectives: We are studying cancer metabolism to identify pathways to target for cancer therapy. Therefore, in this study, we sought to determine which key metabolites in glucose metabolism, specifically glycolysis and the tricarboxylic acid (TCA) cycle metabolites that CAFs feed cancer cells in order for pancreatic cancer cells (P198), to grow better.
Measurement Methods and Main Results: We first assessed pancreatic cancer cell proliferation (P198 cells) with and without the presence of CAFs through the co-culture technique. We assessed P198 cell number after the co-culture. We found that P198 cells grew better when co-cultured with CAFs as compared to P198 that was grown alone. We next investigated which metabolites produced from the CAFs cells are feeding P198 cells. In order to determine which metabolites from glucose were provided from CAFs to P198 cells, we first grew CAFs in 13C6-labeled glucose, removed the labeling medium, then co-cultured P198 with CAFs. The collected metabolites were assessed using Agilent 6520 Quadrupole-Time-of-Flight (Q-TOF) mass spectrometer with Agilent 1260 HPLC and a 6490 triple-quadrupole (QQQ) mass spectrometer. Metabolites were identified by retention time using in-house compound standard databases. In parallel, metabolites were identified using MS/MS fragmentation data under identical conditions. Metabolic pathways were reconstructed and analyzed in three categories: bioenergetics, biosynthesis and redox homeostasis of glucose metabolism to study these metabolic pathways exchanged between CAF and P198. Metabolite peak intensities were normalized to the protein concentration and cell number. We observed an increase in intensities of metabolites in the TCA cycle and glycolysis in P198 after co-culture with CAFs.
Conclusion: These data supports growth benefits of pancreatic cancer in the presence of CAFs. We also found evidence of the metabolic exchange between CAFs and pancreatic cancer cells, which potentially explains the growth benefit.
Citation Format: Tu Nguyen, Jimmy Kirsch, Karim Nabi, Christos Sazeides, Addison Quinones, Jessica Tan, Marjorie Antonio, Felipe Camelo, Jin Jung, Anne Le. Effects of carcinoma-associated fibroblasts on cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2401.
Abstract 2447: Loss of mitochondrial function and increases in levels of oxidative stress pinpointed in human lung cell cultures exposed to particulate matter from September 11, 2001
Authors: DiLorenzo Ann Marie , Seder Lara , Madrid Rebekah , Tobias Eric , Ortiz Jonathan , Gatson Vern 
Published: August 2018

Abstract
Not only did more than 2,753 individuals pass away the morning of September 11,2001, but there have been individuals suffering from mental and physical illness ever since. Thousands of individuals suffered from breathing complications, asthma, and lung cancer. Clinical trials on cancer patients, including a patient who was exposed to the World Trade Center Dust (WTCD), have seen a decrease in the progression of tumor growth with use of oral nicotinamide adenine dinucleotide (NADH). NADH is naturally occurring within a cell's mitochondria and aids in the production of adenosine triphosphate (ATP), the energy of the cell. NADH is an anti-aging, energy enhancing, substance that also reduces fatigue and successfully treats degenerative medical conditions. NADH is becoming a possible treatment for tumor regression but it is still unknown, on a cellular level, why NADH reacts with these cells to prevent further tumor growth. In this study, the amount of NADH produced by normal MRC-5 lung fibroblast cells will be compared to lung cells exposed to World Trade Center Dust (WTCD), using a Promega NAD/NADH-Glo Assay. The same cells will be evaluated to note the decline in Glutathione to determine the amount Reactive Oxidative Species ( ROS) brought on to lung cells by WTCD. ROS can decrease GSH levels by causing oxidative stress that leads to apoptosis. It is important for the cells to maintain high levels of reduced GSH and low levels of oxidized GSH. PROMEGA GSH Glo Glutathione assay will be used to determine if the toxic, mutagenic and apoptotic effects of WTC dust can be shown as the result of oxidative stress. The cells will be exposed to various concentrations of WTCD, ranging from 25-250 ppm. It is hypothesized that the cells with the highest concentrations of this toxic particulate matter will experience the most accumulation of oxidative stress, resulting in less NAD+, being reduced to NADH, within the mitochondria and simultaneous decrease in protective antioxidants as shown in changes in levels of Glutatione. This should allow correlations to be made on a more precise cellular mechanism between exposure to this WTCD, oxidative stress, and loss of mitochondrial function seen in the diseases of the exposed first responder population.
Citation Format: Ann Marie DiLorenzo, Lara Seder, Rebekah Madrid, Eric Tobias, Jonathan Ortiz, Vern Gatson. Loss of mitochondrial function and increases in levels of oxidative stress pinpointed in human lung cell cultures exposed to particulate matter from September 11, 2001 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2447.
Abstract 2463: Long noncoding RNAs in tumor responses toward lovastatin
Authors: Alanisi Entkhab M. , Wang Jiuhui , Guo Yande , Nie Daotai 
Published: August 2018

Abstract
Background: Lovastatin is one of FDA-approved drugs used to treat hypercholesterolemia to reduce cardiovascular diseases. It is a compound of the statin family derived from type of species of Aspergillus terruses. Lovastatin targets hepatocytes and blocks the cholesterol synthesis pathway by inhibiting the rate-limiting enzyme 3-hydroxy-3-methyl glutaryl CoA reductase (HMG-CoA reductase). This leads to decreased production of cholesterol and many other biochemical end products, including ubiquinone and dolichol. These biochemical end products are important for cancer progression. When lovastatin blocks their production, it leads to increased apoptosis of cancer cells. Therefore, lovastatin has promising anticancer activities but the detailed mechanisms remain poorly understood. Long noncoding RNAs are originally thought as nonfunctional. Emerging evidence suggest that lncRNAs have crucial roles in many biologic functions like apoptosis and cell cycle, translation control, epigenetic regulation and splicing regulation. In this study, we set out to identify and determine Lnc-RNAs that can regulate tumor cell responses towards lovastatin treatment.
Methods: PC3, Heya8, HCT116 cells were obtained from ATCC. HCT116 p53-/- cells were gifts from Dr. Yin-Yuan Mo. The cytotoxic effects of lovastatin on those cell lines were evaluated by several approaches like MTS assays and morphologic changes. The qPCR array was used to identify lncRNAs whose levels are changed by lovastatin treatment. The regulation of lncRNA by lovastatin was further confirmed in multiple cell lines.
Results and Conclusion: Lovastatin treatment had cytotoxic effects in multiple cell lines we evaluated. Through profiling array, we have identified NEAT1, MALAT1, and RMST as a responder to lovastatin. The lncRNAs identified had a significant increase in the expression compared to the nontreated cells in a dose- and time-dependent manner. The RMST mRNA expression in the HCT116 p53-/- cell line was about 25-fold more than its level in the HCT116 wild-type cells after treatment of 20 μM lovastatin for 48 hours, suggesting a role of tumor suppressor p53 gene in regulating the RMST expression. We knocked out RMST using CRISPR-Cas9 approach and found that RMST is an important mediator for lovastatin to downregulate mTOR activities and reduce colony formation. Taken together, our data suggest that lncRNAs can be stimulated by lovastatin to elicit cellular responses.
Citation Format: Entkhab M. Alanisi, Jiuhui Wang, Yande Guo, Daotai Nie. Long noncoding RNAs in tumor responses toward lovastatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2463.
Abstract 2467: Role of PCA3 in prostate cancer cell proliferation and progression
Authors: Russel Bethanie , Wang Jiuhui , Zhang Yuanqin , Nie Daotai 
Published: August 2018

Abstract
Background
PCA3 is a long non-coding RNA used as an important biomarker in early prostate-cancer diagnosis but its biological functions are not understood. The aim of the study is to investigate the potential role of PCA3 in prostate cancer (PCa) initiation, growth and progression.
Methods
Human genomic DNA was used as templates for cloning of PCA3 gene. Primers were designed and polymerase chain reactions were performed. The 3 exons of PCA3 were cloned and confirmed by sequencing. To determine the impact of PCA3 and its individual exon in PCa cell growth and survival, we over-expressed them respectively in PC-3 and DU145 cell lines via transduction with lentiviral vector. qPCR was performed to examine the expression level of PCA3. To investigate the effects of PCA3 on prostate cancer cells, cell proliferation assay was performed by using trepan blue staining. Colony formation assays were performed to measure the clonogenic capacity of the cells after PCA3 overexpression and treatments with docetaxel.
Results and conclusions
Sequencing of PCA3 gene amplified from human tumor cells did not find mutations when compared to RefSeq. We overexpressed PCA3 in prostate cancer cells and found that increased PCA3 expression did not have significant impacts on DU145 or PC-3 cell proliferation. However, PCA3 exon 3 did increase the clonogenic capacity of DU145 cells when compared to the controls. DU145 cells with increased PCA3 exon 3 also presented increased resistance to docetaxel. No significance was observed in clonogenic capacity in transduced PC-3 cells, but PCA3 increased the motility of PC-3 cells. Our studies suggest that PCA3 can modulate prostate cancer cell clonogenic capacity, docetaxel resistance, and motility. Further studies are ongoing to determine the mechanisms involved.
Citation Format: Bethanie Russel, Jiuhui Wang, Yuanqin Zhang, Daotai Nie. Role of PCA3 in prostate cancer cell proliferation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2467.
Abstract 2468: Increased expression of snoRNA in the tumor vasculature
Authors: Sample Klarke M. , Nie Yingjie , Bicknell Roy 
Published: August 2018

Abstract
The tumor microenvironment has long been known to cause the differential expression of many genes within the endothelial cells that comprise the tumor vasculature. Yet, the differential expression of short nuclear RNA (snoRNA) has not previously been observed within tumor associated endothelial cells. A differential gene expression analysis was conducted on total RNAseq data derived from primary endothelial cell isolates and validated by qPCR. By these means, SNORD75, SNORD76, SCARNA7 and SNORA81 were demonstrated to be expressed at a higher level in liver, lung and colon associated tumor endothelial cells when compared to patient matched endothelial cells from healthy adjacent tissue. This data suggests that these four snoRNA molecules could be contributing to pathological angiogenesis and therefore tumor growth. Further work is currently being conducted to investigate this possibility.
Citation Format: Klarke M. Sample, Yingjie Nie, Roy Bicknell. Increased expression of snoRNA in the tumor vasculature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2468.