bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 335: Aspirin, di-aspirin and their toxicity to colorectal cancer
Authors: Kankipati Chandra S. , Perry Christopher J. , Nicholl Iain D. 
Published: May 2015

Abstract
Introduction
The lifetime risk for developing colorectal cancer (CRC) is approximately 7%. In the USA over 140,000 people a year develop CRC, with approximately 51,000 deaths/year. Epidemiological studies indicate that long-term aspirin usage reduces the incidence of CRC, and may be protective against other non-CRC related adenocarcinoma, including esophageal cancer. We have investigated the mechanism by which aspirin exhibits toxicity to CRC by synthesising novel analogues of aspirin in an effort to identify functionally significant moieties. We previously suggested that “di-aspirin” (bis-carboxyphenol succinate, BCS) and analogues thereof retain relatively specific toxicity to colorectal cancer cells cultured in vitro.
The cellular functions of the Inhibitors of Apoptosis (IAPs) correlate with suppression of apoptotic cell death, tumor progression and metastases. Aspirin triggered apoptosis correlates with its capacity to decrease expression of Survivin, a member of the IAP family. Survivin exhibits dual functions; as an inhibitor of apoptosis and regulator of mitosis. We hypothesised that studying the alterations in the expression of IAPs would give an insight into the cytotoxic nature of the compounds.
Experimental procedure
A cell viability assay (MTT) was employed to investigate the cytotoxicity of the analogues in various CRC (SW480, HCT116 and LoVo) and non-CRC cell lines (A549, MCF7 and EA.hy926). Expression levels of IAPs (c-IAP1, cIAP2, XIAP, Livin and Survivin) were examined in the SW480 cell line by immunoblotting. Survivin expression was further examined by immunofluorescence analysis. Changes in Survivin expression in the CRC and non-CRC cell lines was also determined by immunoblotting.
Summary of data
Herein, we show that the “di-aspirin” analogues are relatively more toxic to colorectal cancer cells compared to non-colorectal cancer cell lines. In addition we suggest that these analogues can potently reduce the expression of Survivin in comparison to other IAPs.
Conclusion
We conclude that the analogues of aspirin used in the study promote cell death in CRC and non-CRC cell lines. We propose that the compounds induce apoptosis by decreasing the expression of Survivin. We also propose that the anti-proliferative activity of “di-aspirins” and their analogues have potential benefit in tackling human cancer.
Citation Format: Chandra S. Kankipati, Christopher J. Perry, Iain D. Nicholl. Aspirin, di-aspirin and their toxicity to colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 335. doi:10.1158/1538-7445.AM2014-335
Abstract 3350: CIP2A regulates cell proliferation via akt signaling pathway in human lung cancer
Authors: Lei Ningjing , Peng Bo , Zhang Jiangying 
Published: May 2015

Abstract
CIP2A is an intracellular endogenous protein phosphatase 2A (PP2A) inhibitor with oncogenic activities. CIP2A was initially identified as a tumor-associated antigen (TAA) in gastric and liver cancer patients, and it was overexpressed in a variety of cancer types. Recently, we found that CIP2A was overexpressed in human lung cancer specimens as compared to normal lung tissues. The elevated expression of CIP2A in lung cancer cells results in an increased cell proliferation. The observation on the association between CIP2A and AKT phosphorylation at S473 in our lab and other labs suggested the role of CIP2A in regulating AKT phosphorylation. Our preliminary data indicated that CIP2A might promote cell proliferation through AKT signaling pathway under growth factor stimulation. Interestingly, the depletion of CIP2A in lung cancer cells did not induce a global change of AKT phosphatase activity, which implied that CIP2A might recognize specific AKT targets and play certain roles in the signaling pathway. In this study, we identified several AKT substrates specifically targeted by CIP2A, such as Hsp70 and mTOR, by proteomic-based systematic screening. The candidates obtained from our study will expand the understanding on protein-substrate interaction and therefore direct the cancer drug design. Therefore, our study addressed a novel role of CIP2A in mediating cancer progression through interacting with AKT pathway in a substrate-dependent manner.
Citation Format: Ningjing Lei, Bo Peng, Jiangying Zhang. CIP2A regulates cell proliferation via akt signaling pathway in human lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3350. doi:10.1158/1538-7445.AM2014-3350
Abstract 3356: Temozolomide resistance in human glioblastoma is associated with marked increase in PDK1 and MGMT expression
Authors: Lee William , Velpula Kiran Kumar , Tsung Andrew J. 
Published: May 2015

Abstract
Temozolomide has become the standard of care in glioblastoma (GBM) treatment, but a significant number of patients despite optimal treatment are met with recurrence. It is important to understand the molecular mechanisms underlying TMZ resistance for the development of better treatment strategies. In the present study, we evaluated the dynamic relationship between MGMT and resistance to TMZ. We generated a TMZ-resistant 5310R cell line by continuous treatment with 100 µM concentrations of TMZ (3 months) to parent 5310 cells. We tested the efficacy of TMZ on 5310R cells by FACS analysis. 5310R cells showed increased expression of MGMT when compared to parental controls. Also, we observed that the 5310R cells showed alterations in cell morphology, enhanced cell adhesion, increased migration and invasion capacities. Moreover, we observed PDK1, MGMT and EGFR expression to be up-regulated in 5310R cells compared to parental controls. Our previous data suggested that inhibition of PDK1 reverses the Warburg effect, and here we demonstrate that the acquired TMZ resistance in glioma may be associated with promotion of the malignant phenotype. Furthermore, we observed a significant correlation between PDK1, MGMT and EGFR expression in human GBM specimens using immunohistochemistry and Western blot analysis. As treatment with TMZ becomes more ubiquitous in GBM treatment, the significance of the resistant 5310R cell line and an understanding of the metabolic and epigenetic changes will become critical in the development of targeted and effective therapies.
Citation Format: William Lee, Kiran Kumar Velpula, Andrew J. Tsung. Temozolomide resistance in human glioblastoma is associated with marked increase in PDK1 and MGMT expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3356. doi:10.1158/1538-7445.AM2014-3356
Abstract 3358: Significant increase in survival of triple negative breast cancer animal model in response to BPM31510 alone or in combination with standard of care: BPM31510 mediated dynamic metabolic (Warburg) shift in breast cancer as potential mechanism
Authors: Narain Niven R. , Diers Anne R. , Walshe Tony E. , Lee Arleide , Ouro-Djobo Rakib , Vishnudas Vivek K. , Benaim Ely , Sarangarajan Rangaprasad 
Published: May 2015

Abstract
This study demonstrates that BPM 31510, a Coenzyme Q10 containing proprietary formulation to influences cellular metabolism that is deregulated in cancers and is now considered to be a “hallmark of cancer”. These studies demonstrate that BPM 31510 alone or in combination with standard of care significantly improved survival of triple negative breast cancer (TNBC) animal model. To further tease out beneficial effects of BPM31510, human breast cancer cells of varying receptor status (SKBR3, MDA-MB231) were subjected to either (a) pretreatment with BPM 31510 (6 h) followed co-incubation with chemotherapeutic agents for 48-72 h or (b) co-treatment with BPM 31510 and chemotherapeutic agents, and cancer cell responses were compared to non-tumorigenic mammary cells (MCF12A). Cellular bioenergetics profiling revealed that BPM 31510 shifted cellular metabolism from glycolysis to mitochondrial metabolism, and this metabolic shift was associated with significant increases in reactive oxygen species (ROS). Both BPM 31510 alone or pretreatment and cotreatment strategies with BPM 31510 plus standard of care resulted in significant decreases in viable breast cancer cells when compared to chemotherapeutic agents; however, minimal effects were observed in MCF12A cells. In contrast, BPM 31510 in combination with chemotherapeutic agents amplified caspase 3 activation and apoptotic cell death, indicating BPM 31510 enhances apoptotic signaling. Taken together, these data demonstrate that BPM 31510 is a novel agent that reengages the cellular metabolic and apoptotic machinery of cancer cells independent of genetic make-up underlying malignancy. In addition, BPM 31510 enhances the cytotoxicity of standard-of-care chemotherapeutic agents in breast cancer cells through regulation of mitochondrial metabolism and oxidative stress. These findings confirm that BPM 31510 is a novel, paradigm shifting agent with multiple utility (as a single agent or in combination) in breast cancer including TNBCs that otherwise have poor prognosis and limited therapeutic options.
Citation Format: Niven R. Narain, Anne R. Diers, Tony E. Walshe, Arleide Lee, Rakib Ouro-Djobo, Vivek K. Vishnudas, Ely Benaim, Rangaprasad Sarangarajan. Significant increase in survival of triple negative breast cancer animal model in response to BPM31510 alone or in combination with standard of care: BPM31510 mediated dynamic metabolic (Warburg) shift in breast cancer as potential mechanism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3358. doi:10.1158/1538-7445.AM2014-3358
Abstract 3361: EGFR signaling regulates aerobic glycolysis in EGFR-mutated lung adenocarcinoma
Authors: Makinoshima Hideki , Takita Masahiro , Matsumoto Shingo , Yagishita Atsushi , Owada Satoshi , Esumi Hiroyasu , Tsuchihara Katsuya 
Published: May 2015

Abstract
Recent accumulating evidences suggest that genetic mutations in tumor cells cause several unique metabolic phenotypes that are critical for cancerous cell proliferation. Mutations in the tyrosine kinase epidermal growth factor receptor (EGFR) induce oncogenic addiction in lung adenocarcinoma (LAD). However, the linkage between oncogenic mutated EGFR and cancer metabolism has not yet been clearly elucidated. In this study, we measured extracellular lactate production, glucose consumption and the glucose-induced extracellular acidification rate (ECAR) after the inhibition of EGFR signaling in LAD cell culture. Using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolomic techniques, the major intracellular metabolites in EGFR-mutated LAD cells were quantified in the absence or presence of the tyrosine kinase inhibitor (TKIs) erlotinib. The molecular profile regulating the metabolic enzymes at the transcriptional and post-translational levels was characterized by RT-PCR, Western blotting and flow cytometry. We demonstrated that EGFR signaling was required for lactate production, glucose consumption and glucose-induced ECAR, indicating that EGFR signaling promoted the Warburg effect in LAD cells. Moreover, comprehensive metabolomic analysis revealed that the levels of key intermediate metabolites in glycolysis and the pentose phosphate pathway (PPP) were decreased after treatment with EGFR inhibitors. The glucose transport carried out by GLUT1 and GLUT3 was the most rapid and critically regulated function of glucose metabolism linked to EGFR signaling, although the expression of MYC-dependent glycolytic genes and the phosphorylation of pyruvate kinase muscle (PKM2) were down-regulated by EGFR inhibition at a later time point. A modest down-regulation of both total and membrane-bound GLUT3 was also observed after EGFR inhibition. Despite an equivalent total amount of GLUT1 in LAD cells, the levels of membrane-bound GLUT1 was decreased by EGFR-TKI treatment, suggesting that EGFR signaling controlled GLUT1 function through post-translational modification. We concluded that EGFR signaling regulated aerobic glycolysis in EGFR-mutated LAD cells. Our data suggests that the glycolytic pathway plays a central role in the pathogenesis of EGFR-mutated lung cancer. This regulatory pathway could be an attractive target for the development of targeted therapies to better treat patients with EGFR-mutated LAD.
Citation Format: Hideki Makinoshima, Masahiro Takita, Shingo Matsumoto, Atsushi Yagishita, Satoshi Owada, Hiroyasu Esumi, Katsuya Tsuchihara. EGFR signaling regulates aerobic glycolysis in EGFR-mutated lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3361. doi:10.1158/1538-7445.AM2014-3361
Abstract 3362: Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex and promote the Warburg effect
Authors: Fan Jun , Gu Ting-Lei , Boggon Titus , Kang Sumin , Chen Jing 
Published: May 2015

Abstract
Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homoeostasis in mammalian cells. The current understanding of PDC regulation involves serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDHK), which inhibits PDH and subsequently PDC, whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here we report that lysine acetylation of PDHA1 and PDP1 is induced by EGF-stimulation in human cells, and is common in diverse human cancer cells. We found that K321 acetylation inhibits PDHA1 by recruiting PDHK1 and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important for the metabolic switch to glycolysis in cancer cells and promote tumor growth. Moreover, we identified mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) as the upstream acetyltransferase of PDHA1 and PDP1 using a novel shRNA library that targets the majority of acetyltransferases in the human genome, and SIRT3 as the deacetylase. Knockdown of ACAT1 results in decreased cancer cell proliferation and tumor growth. Furthermore, we found that EGFR and other tyrosine kinases including FGFR1 that are frequently dysregulated in human cancers phosphorylate PDP1 at Y381, which dissociates SIRT3 and recruits ACAT1 to PDC.
Our findings suggest a novel mechanism where lysine acetylation of PDHA1 and PDP occurs in both normal and cancer cells, and contributes to inhibitory regulation of PDC, providing complementary insight into the current understanding of PDHA1 regulation. We also demonstrate that hierarchical, distinct post-translational modifications crosstalk to regulate PDC by controlling its molecular composition. Moreover, our findings for the first time link a mitochondrial acetyltransferase, ACAT1, to the Warburg effect and tumor growth, suggesting that the ACAT1-PDP1-PDHA axis represents a promising anti-cancer target.
Citation Format: Jun Fan, Ting-Lei Gu, Titus Boggon, Sumin Kang, Jing Chen. Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex and promote the Warburg effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2014-3362
Abstract 3363: Inhibition of glycolysis and proliferation of colon cancer cells by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) an inhibitor of 6-phosphofructo-2-kinase (PFKFB3)
Authors: Lea Michael A. , Geherty Raymond , David Rachelle , desBordes Charles 
Published: May 2015

Abstract
In human colon cancer cells, glycolytic activity shows a positive correlation with proliferation. PFKFB3 is an important enzyme regulating glycolysis in many tumor cells. We have studied the action of an established inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) as a single agent and in combination with other molecules that affect glycolysis and proliferation in four colon cancer cell lines (Caco-2, HCT116, HT29 and SW1116). Glucose uptake and cell proliferation were inhibited by 3PO and butyrate and additive effects were seen with 10 µM 3PO and 1 mM butyrate. Induction of alkaline phosphatase activity serves as a marker of differentiation in colon cancer cells. The large induction of alkaline phosphatase activity by butyrate seen in most colon cancer cell lines was not observed with 3PO. Similar contrasting effects on induction of alkaline phosphatase activity were seen with rat Morris hepatoma 7777 cells where 2-3 fold induction was seen with 1 µM vorinostat or 1 mM butyrate but no significant effect was seen with 3PO in the range of 5-30 µM. The biguanides, metformin and phenformin, increase glycolysis but inhibit proliferation of colon cancer cells. After combination treatment with 3PO, glycolysis was inhibited, as judged by glucose uptake and acidification of the medium, and additive inhibitory effects on cell proliferation could be observed. For example, after a 72 hour incubation of Caco-2 cells with 10 µM 3PO, 25 µM phenformin or 1 mM metformin, as single agents, proliferation relative to controls was decreased 20%, 17% and 34%, respectively. For combinations of 3PO and phenformin or 3PO and metformin the decreases relative to controls were 48% and 58%, respectively. In conclusion, 3PO was an inhibitor of proliferation of colon cancer cells, especially the rapidly growing HCT116 and HT29 cell lines. 3PO may be a useful agent in combination with other drugs that inhibit colon cancer cell proliferation.
Citation Format: Michael A. Lea, Raymond Geherty, Rachelle David, Charles desBordes. Inhibition of glycolysis and proliferation of colon cancer cells by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) an inhibitor of 6-phosphofructo-2-kinase (PFKFB3). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2014-3363
Abstract 3368: Down-regulation of LDH-A reduced lactate production and changed the expression of glycolysis-associated transporters
Authors: Schroer Henrike , Fabian Christian G. , Kreutz Marina , Goetze Kristina , Mueller-Klieser Wolfgang 
Published: May 2015

Abstract
In the clinic, tumors showing a pronounced Warburg effect (high lactate tumors) are associated with a higher risk of metastasis and a decreased probability of survival of patients. Therefore, manipulations of the glycolytic pathway may alter tumor cell metabolism and might be a way to influence tumors’ aggressiveness, e.g. by down-regulating intracellular lactate levels.
To test for this hypothesis B16.SIY E12 murine melanoma cells were stably transfected with shRNA down-regulating LDH-A expression (Lac Low cells). As a control cell line B16.SIY E12 was transfected with a scrambled shRNA construct (Lac High cells). These cell lines were characterized regarding their metabolic properties in vitro, especially lactate production in medium supernatants, the extracellular acidification rates (ECAR) and oxygen consumption rates (OCR). Furthermore, the expression of glycolysis-associated transporters (GLUT1, GLUT3, MCT1, MCT4 and CD147) was determined at the protein level. In a first in vivo set-up ATP, lactate and glucose content of syngeneic experimental tumors were measured using induced metabolic bioluminescence imaging (imBI).
Changing LDH-A expression induced differences in lactate production in the two tumor cell lines in vitro with Lac Low cells producing significantly less lactate in 24 h than Lac High cells. Accordingly, Lac Low cells revealed a significantly lower ECAR and a higher OCR than Lac High cells. The protein expression of glycolysis-associated transporters was also influenced by changes in LDH-A expression with Lac High cells showing a significantly higher protein expression of MCT1 and MCT4. The general expression of GLUT1 was unchanged (Western Blot) but membrane localization was higher in Lac High cells (immunofluorescence staining). Measuring metabolite content in experimental tumors of the same cell lines showed that the cells maintained their glycolytic properties with Lac Low tumors showing lower lactate content than Lac High tumors.
In summary, down-regulation of LDH-A expression reduced lactate production and membrane localization of glycolysis-associated transporters. The fact, that these characteristic are maintained during the transition from in vitro to in vivo makes this model system useful for systematic studies on therapeutic manipulation of tumor glycolysis and associated pathways.
Supported by the Deutsche Forschungsgemeinschaft KFO262, DE 835/2-1 (WMK) + KR1418/8-1 (MK)
Citation Format: Henrike Schroer, Christian G. Fabian, Marina Kreutz, Kristina Goetze, Wolfgang Mueller-Klieser. Down-regulation of LDH-A reduced lactate production and changed the expression of glycolysis-associated transporters. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2014-3368
Abstract 3369: Differential biotherapeutic advantages of honey in targeting the Warburg effect and survival of MRC-5 and A549 cell lines
Authors: Farah Ibrahim O. , Lewis Veshell L. , Ayensu Wellington K. , Cameron Joseph A. 
Published: May 2015

Abstract
Lung cancer is a one of the most prevalent and deadly cancers in United States. Experimental evidence support that cancer cells do exhibit higher glycolytic rates than normal cells (Warburg effect). To exploit this unique cancer-dependent ATP generation phenomenon, we hypothesize that exposure of cancer cells to organic inhibitors of glycolysis would negatively impact their survival and alter their growth and viability resulting from the vast decrease in their essential glycolytic ATP production; no negative consequences will be seen on normal lung cells. The human lung fibroblast cell line MRC-5 and the human alveolar epithelial cell line A549 were used as models for normal lung and lung cancer in vitro in this study. Using standard methods, both cell lines were maintained and exposed to honey and D-glucose reagents at concentration levels ranging from 31.3-2,000 µg/ml in 96 well plates in quadruplets and experiments repeated at least three times using MTT, and cell counting (T4 Cellometer) assays as well as phase-contrast photo-imaging. Our results indicate that exposure of both cell lines to these natural nutraceutic organics resulted in concentration dependent cell destruction/cell survival depending on the cell line exposed. Honey and D-glucose showed statistically significant (p&lt;0.05) differential negative effects on the A549 line in comparison to its unexposed control as well as to their effects on the MRC-5 cell line. Results show a promising role of honey and D-glucose as metabolites of interest for selective management of cancerous cells.
Citation Format: Ibrahim O. Farah, Veshell L. Lewis, Wellington K. Ayensu, Joseph A. Cameron. Differential biotherapeutic advantages of honey in targeting the Warburg effect and survival of MRC-5 and A549 cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3369. doi:10.1158/1538-7445.AM2014-3369