bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3314: Co-regulation of srGAP1 by Wnt and androgen receptor signaling in castration resistant prostate cancer
Authors: Yokoyama Noriko N. , Sakai Toshinori , Sun Zheng , Shao Shujuan , Huang Jiaoti , Hoang Bang H. , Zi Xiaolin 
Published: May 2015

Abstract
Androgen receptor (AR) and Wnt signaling both play a critical role during prostate cancer progression to castration-resistance prostate cancer (CRPC). Over expression of AR can activate transcriptional activities of Wnt signaling pathway and promote CRPC. Recent data in our laboratory showed a potential co-regulation of srGAP1 (Slit-Robo-GTPase activating protein1) and active Wnt and AR signaling in CRPC. srGAP1 is a downstream component of Slit-Robo signaling. Our data showed that srGAP1 is overexpressed in CRPC cell lines (androgen-insensitive prostate cancer) while absent in both androgen-sensitive cells and in normal prostate epithelial cells. We also detected increased srGAP1 expression in human CRPC tissues compared with normal epithelial prostate and androgen sensitive prostate cancer tissues by immunohistochemistry analysis. When androgen-sensitive LNCaP cells were grown under androgen deprived condition, we observed induced expression of srGAP1. Interestingly, srGAP1 expression was also increased when LNCaP cells were grown under Wnt stimulated conditions. And, srGAP1 expression was decreased when Wnt signaling was inhibited by a Wnt antagonist Wnt-inhibitory factor-1 (WIF-1) in CRPC cell lines. Functional studies using chromatin immmunoprecipitation and luciferase assays were performed to examine whether Wnt transcription factor LEF-1 or TCF-4 binds and activates the srGAP1 promoter. Overexpression of WIF-1 inhibited the promoter activity of srGAP1. Taken together, our results indicated that srGAP1 is co-regulated by both Wnt and AR signaling and srGAP1 may be a new potential Wnt target gene in castration-resistance prostate cancer.
Citation Format: Noriko N. Yokoyama, Toshinori Sakai, Zheng Sun, Shujuan Shao, Jiaoti Huang, Bang H. Hoang, Xiaolin Zi. Co-regulation of srGAP1 by Wnt and androgen receptor signaling in castration resistant prostate 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 3314. doi:10.1158/1538-7445.AM2014-3314
Abstract 3318: Using synthetic lethal screening to identify therapeutic targets for innately platinum resistant lung cancer
Authors: Marini Kieren D. , Rossello Fernando J. , Martelotto Luciano G. , Watkins D. Neil 
Published: May 2015

Abstract
Although platinum-based chemotherapy is the standard of care for most cases of advanced lung adenocarcinoma, its effectiveness is limited by the frequent incidence of innate chemoresistance. As a result, response rates rarely exceed 20%, even though cis-platinum and carboplatin are highly effective in other settings such as small cell lung, ovarian and testicular cancers. We hypothesized that innate chemoresistance in lung adenocarcinoma is mediated by one or more signalling pathways dependent on the expression of a single gene, and that these pathways could ultimately be targeted therapeutically. To address this question, we developed a synthetic-lethal high throughput siRNA screen using the innately resistant A549 lung adenocarcinoma cell line. Optimisation of the screen was performed using a siRNA death control (PLK1), which induced cell death in the absence of platinum, and a sensitization control (MTOR), which enhanced cell death only in combination with a sublethal concentration of carboplatin. These independent controls revealed that the screening protocol performed within acceptable limits of variability, quality and reproducibility as determined by Z’ factor analysis. Screening was then performed using a pool of four siRNAs targeting a single gene in conjunction with vehicle treatment, or with carboplatin. After screening siRNAs targeting the 720 kinases, 256 phosphatases and 4794 “druggable” targets of the human genome, we identified 50 candidate targets based on fold change difference between platinum and vehicle treatments, and statistical significance determined by multiple t-test corrected for false discovery rate. Preliminary integrated pathway analysis of RNA expression array and screening datasets revealed a highly significant enrichment of sensitizing genes in previously identified pathways as well as novel pathways. These data demonstrate that a synthetic-lethal approach can be used to identify therapeutic targets that could potentially sensitize lung adenocarcinoma to platinum-based chemotherapy.
Citation Format: Kieren D. Marini, Fernando J. Rossello, Luciano G. Martelotto, D. Neil Watkins. Using synthetic lethal screening to identify therapeutic targets for innately platinum resistant 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 3318. doi:10.1158/1538-7445.AM2014-3318
Abstract 3353: Docosahexaenoic acid enhances 2-deoxyglucose treatment in breast and lung cancer cells in vitro
Authors: Mouradian Michael , Ma Irvin V. , Vicente Erika D. , Chattin Amy M. , Pardini Ronald S. 
Published: May 2015

Abstract
Increased aerobic glycolysis is a common phenotype of cancer cells and is known as the Warburg effect. Recent studies have focused on targeting cellular metabolism to impede cancer cell growth. Previous findings in our laboratory have demonstrated that docosahexaenoic acid (DHA; C22:6 n-3), a long-chain omega-3 polyunsaturated fatty acid (PUFA), can inhibit cancer cell metabolism and reduce intracellular ATP levels. This study investigated the effects of concurrent treatment with DHA with 2-deoxyglucose (2DG), an inhibitor of glucose metabolism, in multiple cancer cell models in vitro, BT-474 human breast ductal carcinoma, MDA-MB-231 human breast adenocarcinoma, and A549 human lung adenocarcinoma. Dose-dependent decreases in intracellular ATP levels were observed with DHA and 2DG, both alone and in combination. In addition to the significant decreases in ATP levels, large decreases in extracellular lactate concentrations were observed in all three cell lines as well, suggesting that the combination of 2DG and DHA can augment treatment, mimic glucose deprivation and play a role in reducing the Warburg effect. Moreover, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were significantly reduced with the combination of DHA and 2DG, which suggests that the combination of DHA with other metabolic inhibitors, like 2DG, may sensitize cells to current treatment. Our findings show that combining DHA with 2DG enhances the efficacy of 2DG treatment alone, which may help to reduce the cytotoxic effects by 2DG on normal cells. Other metabolic inhibitors are being employed in combination with DHA to determine the mechanisms behind the DHA-induced sensitizing effects, which will provide additional treatment strategies for oncologists and cancer patients.
Citation Format: Michael Mouradian, Irvin V. Ma, Erika D. Vicente, Amy M. Chattin, Ronald S. Pardini. Docosahexaenoic acid enhances 2-deoxyglucose treatment in breast and lung cancer cells in vitro. [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 3353. doi:10.1158/1538-7445.AM2014-3353
Abstract 3359: JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism
Authors: Wang Hung-Jung , Hsieh Ya-Ju , Cheng Wen-Chi , Lin Chun-Pu , Lin Yu-Shan , Yang So-Fang , Chen Chung-Ching , Izumiya Yoshihiro , Yu Jau-Song , Kung Hsing-Jien , Wang Wen-Ching 
Published: May 2015

Abstract
JMJD5, a JmjC-domain containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia-induced cell proliferation. JMJD5 interacts directly with PKM2, pyruvate kinase M2, to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes HIF-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α are all recruited to the HRE (hypoxia response element) site in the LDHA and PKM2 loci, and mediates the recruitment of the latter two proteins. Our data uncovers a new mechanism whereby PKM2 can be regulated by factor-binding induced homo/hetero-oligomeric restructuring, paving the way to cell metabolic reprogram.
Citation Format: Hung-Jung Wang, Ya-Ju Hsieh, Wen-Chi Cheng, Chun-Pu Lin, Yu-Shan Lin, So-Fang Yang, Chung-Ching Chen, Yoshihiro Izumiya, Jau-Song Yu, Hsing-Jien Kung, Wen-Ching Wang. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. [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 3359. doi:10.1158/1538-7445.AM2014-3359
Abstract 3365: Aldolase A induces invasion/metastasis of lung cancer through modulating HIF1-α and is a marker for poor clinical outcome
Authors: Chang Yu-Chan 
Published: May 2015

Abstract
The dysregulated metabolism is an emerging hallmark of cancer. However, little is known about the metabolic requirements during cancer progression. Therefore, identifying metabolic genes that are critical for supporting cancer invasion/metastasis may provide novel targets for cancer diagnosis and therapy. By analyzing gene expression and proteomic profile of invasive lung cancer cells CL1-5 and its parental counterpart CL1-0, we identified Aldolase A (ALDOA), an enzyme of glycolysis pathway, is overexpressed in CL1-5 and is significantly associated with disease recurrence in lung cancer patient microarray datasets. Moreover, HIF-1α was identified as the most significant transcription factor in ALDOA-recurrence gene signature by IPA upstream regulator analysis. Furthermore, Immunohistochemistry analysis confirmed the expression of ALDOA was markedly higher in lung cancer tumors than in normal lung. High ALDOA expression was found significantly associated with lymph node involvement and disease recurrence. Moreover, overexpression of ALDOA was significantly associated with poor outcome in both overall and disease-free survival. Knockdown of ALDOA expression was found to suppress invasion potentials in highly invasive lung cancer cell lines while complementary overexpression of ALDOA in poorly invasive cells promoted it in vitro and in vivo. ALDOA overexpression also accelerated glucose consumption, ATP utilization and lactate production. Knockdown of ALDOA expression in CL1-5 abolished HIF-1α expression with concurrent Mesenchymal-to-Epithelial Transition (MET). Moreover, IHC analysis shows an inverse correlation between ALDOA and E-cadherin and combination of high ALDOA and low E-Cadherin showed an unfavorable outcome, in a sharp contrast, compared to patients with low ALDOA and high E-cadherin. Here, we identified ALDOA as a critical glycolytic enzyme involved in lung cancer progression and may be a marker for poor clinical outcome.
Citation Format: Yu-Chan Chang. Aldolase A induces invasion/metastasis of lung cancer through modulating HIF1-α and is a marker for poor clinical outcome. [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 3365. doi:10.1158/1538-7445.AM2014-3365
Abstract 3375: Targeting glucose metabolism by 2-deoxyglucose in gastrointestinal stromal tumors
Authors: Mühlenberg Thomas , Grunewald Susanne , Schuler Martin , Bauer Sebastian 
Published: May 2015

Abstract
Introduction
Most patients with gastrointestinal stromal tumors (GIST) respond to imatinib (IM) but eventually progress with then limited therapeutic options. Fluorodeoxyglucose (FDG) is used for visualizing tumors by positron emission tomography (PET) and has been particularly helpful for predicting tumor response in highly FDG-avid GIST. 2-deoxy-glucose (2DG) inhibits glucose metabolism in cancer cells, which depend exclusively on aerobe glycolysis for ATP production (Warburg Effect). 2DG is currently investigated in several clinical trials. Here we evaluated the therapeutic potential of 2DG in GIST in vitro and in vivo.
Methods
Two IM-sensitive (IM-S; GIST-T1, GIST882) and 3 IM-resistant (IM-R; GIST430, GIST48, GIST48B) cell lines were studied. Cell viability was evaluated by Sulforhodamin B (SRB) assay after 6 days of 2DG treatment and combinations with IM and ABT-263, a BH3-mimetic. Immunoblotting was done for KIT- and KIT-downstream signaling and markers of apoptosis. For in vivo experiments nude mice bearing GIST-T1 xenografts were treated for 21 days with 500mg/kg/d 2DG or vehicle control.
Results
Cell viability assays in KIT-expressing cell lines displayed IC50 values for 2DG between 0.5mM (GIST882) and 2.5mM (GIST48), while KIT-negative GIST48B was less sensitive (6mM). Notably, treating GIST-T1 in low-glucose media (1g/L, LG) reduced IC50 (1.1mM to 0.33mM) in a glucose dependent manner. Immunoblot studies revealed a dose- and glucose dependent inhibition of KIT glycosylation by 2DG with complete inhibition at 1mM in LG, which coincided with inhibition of KIT-phosphorylation and KIT-downstream signaling. The combination of 2DG with IM had additive antiproliferative effects in IM-S cell lines. In IM-R GIST430 a synergistic induction of apoptosis could be observed when combining KIT-inhibiting concentrations of 2DG with ABT-263 1µM. Treatment of mice with 2DG alone did not affect tumor growth. At this dose 2DG dependent inhibition of KIT-glycosylation or -phosphorylation was not observed.
Conclusions
2DG shows promising GIST-specific antiproliferative effects by inhibiting KIT-glycosylation and -phosphorylation in vitro. These effects were additive when combined with imatinib. Further studies will investigate alternate treatment schedules as well as drug combinations with the aim of translating 2DG into a clinical trial in GIST.
Citation Format: Thomas Mühlenberg, Susanne Grunewald, Martin Schuler, Sebastian Bauer. Targeting glucose metabolism by 2-deoxyglucose in gastrointestinal stromal tumors. [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 3375. doi:10.1158/1538-7445.AM2014-3375
Abstract 3376: Targeting metabolic flux of tumor cells to prevent pancreatic cancer associated cachexia
Authors: Shukla Surendra K. , Singh Pankaj K. 
Published: May 2015

Abstract
Cancer associated cachexia is a complex metabolic syndrome characterized by excessive loss of skeletal muscle and adipose tissue. Cancer-induced cachexia accounts for nearly 20% of all cancer-related deaths and is most prevalent in patients with gastric, pancreatic, colon and lung cancer. More than 80% pancreatic cancer patients exhibit cachectic phenotype. Although association of cachexia with cancer is known for a long time, the molecular mechanism of cancer-induced cachexia is still not well understood. Better understanding of the cancer-related cachexia syndrome may provide novel therapeutic targets for enhancing the quality of life of cancer patients. Several studies have demonstrated that multiple cytokines and cachectic factors secreted by tumor cells contribute to cancer associated cachexia. Because most of the cancer cells present metabolic alterations, which may contribute to secretion of cachectic cytokines and metabolites involved in cancer-induced cachexia. By culturing differentiated C2C12 and 3T3-L1 cells in the presence of pancreatic adenocarcinoma cell or immortalized epithelial cell supernatants, we established cell culture-based cachexia model systems to investigate the depletion of muscle mass and fatty acid content. To study the role of metabolic pathways in tumor cells on cachectic factor secretion, we pre-treated pancreatic cancer cells with different metabolic inhibitors like 2-Deoxy-D-glucose (2-DG), 3-Bromopyruvic acid (3-BrPA) , bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulphide (BPTES) and collected conditioned medium from pre-treated cancer cells at different time points. Further, we accessed the cachectic potential of these conditioned media along with control conditioned medium. Physiological and biochemical alterations during muscle fiber breakdown and adipocyte fat depletion were assayed by performing real-time PCR and cell imaging. We observed that inhibition of glycolysis with 3-BrPA & 2-DG and inhibition of glutaminolysis with BPTES in tumor cells causes decreased muscle fiber breakdown and adipocytes fat depletion. Our results demonstrates crucial role of tumor cell metabolic alterations in cancer-induced cachexia.
Citation Format: Surendra K. Shukla, Pankaj K. Singh. Targeting metabolic flux of tumor cells to prevent pancreatic cancer associated cachexia. [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 3376. doi:10.1158/1538-7445.AM2014-3376
Abstract 3378: Glutaminase activity determines cytotoxicity of L-asparaginases on leukemia cell lines
Authors: Parmentier Jean-Hugues , Maggi Maristella , Tarasco Erika , Scotti Claudia , Avramis Vassilios , Mittelman Steven D. 
Published: May 2015

Abstract
L-Asparaginase (ASNase) is a front-line chemotherapy for acute lymphoblastic leukemia (ALL), which acts by deaminating asparagine (Asn) and glutamine (Gln). We and others have shown that its cytotoxicity depends more on Gln than Asn depletion. Novel ASNases with different activities have been developed in an attempt to decrease side effects and allergic reaction. To evaluate the importance of glutaminase activity, we developed a novel form of Helicobacter pylori ASNase (dm HpA) using site-directed mutagenesis, with amino acid substitutions M121C/T169M. This mutant form was designed to have the same asparaginase activity as wild type (wt), but lack glutaminase activity. WT and dm HpA were compared with the clinically used ASNases from E. coli (EcA-II) and Erwinia chrysanthemi (ErA).
Asparaginase and glutaminase activities of each enzyme were measured with Nessler's assay at pH 8.6. The ratio of glutaminase/asparaginase activity was 1.4% for dm HPase, 7.5% for wt HPase, 41% for EcA-II, and 99% for ErA (at 0.6 IU), respectively.
L-Asparaginases (0.01 to 3 IU/ml over 72 hrs) were tested on 8 human leukemia cell lines: pre B ALL (BV173, Nalm-6, RCH-ACV, RS4;11, SEM, SupB15), T cell ALL (Molt-4), and acute promyelocytic leukemia (HL-60). Viable cells were determined by trypan blue exclusion.
Two cell lines which we had previously shown to be Asn-dependent (RS4;11 and SupB15) were equally sensitive to the asparaginase isoforms (&gt;90% kill at 0.03 IU/mL). The other 6 lines were more sensitive to isoforms with higher glutaminase activities (Table). ErA was the most effective on all three cell lines on which it was tested.
These data show that asparaginase activity alone may not be sufficient for ASNase cytotoxicity, and that glutaminase activity may be required for full efficacy. These sensitivities to ASNases match previous data on Asn- and Gln-dependent cell proliferation (Ehsanipour et al., Cancer Research, 2013).
% cell growth inhibition at 3 IU/ml ASNase (n=1-2 for each cell line; nd: not done)Cell linedm HpAwt HpAEcA-IIErARS4;11919291ndSupB15919193ndRCH-ACV13362866SEM22484165BV17324326ndNalm-61621574HL-60204033ndMolt4325963nd
Citation Format: Jean-Hugues Parmentier, Maristella Maggi, Erika Tarasco, Claudia Scotti, Vassilios Avramis, Steven D. Mittelman. Glutaminase activity determines cytotoxicity of L-asparaginases on leukemia 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 3378. doi:10.1158/1538-7445.AM2014-3378
Abstract 338: Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response
Authors: Whitsett Timothy G. , Mathews Ian T. , Cardone Michael H. , Lena Ryan J. , Pierceall William E. , Bittner Michael , Sima Chao , LoBello Janine , Weiss Glen J. , Tran Nhan L. 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer-related mortality in the world killing more than one million people each year. Therapeutic resistance remains a significant clinical hurdle, contributing to a five-year survival rate of less than 5% in advanced lung cancer. The mechanisms of therapeutic resistance remain poorly understood and thus difficult to combat therapeutically. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling axis is known to promote cancer cell survival via NF-κB activation and up-regulation of pro-survival Bcl-2 family members. Mcl-1 is over-expressed across many tumor types and correlates with poor patient prognosis and therapeutic resistance. We hypothesize that activation of the TWEAK-Fn14 signaling axis can induce therapeutic resistance through Mcl-1, and that Mcl-1 suppression can sensitize lung cancer cells to therapeutic insult. Here we demonstrate that both Fn14 and Mcl-1 are over-expressed and correlated in primary patient lung tumors. Mcl-1 expression correlates with both advanced stage lung cancer and poor patient prognosis. TWEAK stimulation of non-small cell lung cancer (NSCLC) cell lines induces Mcl-1 protein expression in a NF-κB-dependent manner. TWEAK exposure completely abrogates the cell killing effects of cisplatin or radiation treatment in NSCLC cell lines, and this TWEAK-induced protection is dependent on Mcl-1 expression. The suppression of Mcl-1 through RNAi or a novel Mcl-1 inhibitor (EU-5148) enhances the cell killing effects of cisplatin or radiation and completely blocks TWEAK-induced cell survival, whereas Bcl-2 and Bcl-xL inhibition have lesser effect on TWEAK-induced survival. The specificity of EU5148 is demonstrated through abrogation of the protein-protein interaction of Mcl-1 and Bim, with no effect on the interaction of Bcl-xL and Bim. Moreover, EU-5148 treatment inhibits cell survival across a panel of NSCLC cell lines, representing a range of histological subtypes and driver mutations, such as EGFR and KRAS. Collectively, these results position TWEAK-Fn14 signaling through Mcl-1 as a significant mechanism for NSCLC tumor cell survival, and open new therapeutic avenues to abrogate the high mortality rate seen in advanced NSCLC.
Citation Format: Timothy G. Whitsett, Ian T. Mathews, Michael H. Cardone, Ryan J. Lena, William E. Pierceall, Michael Bittner, Chao Sima, Janine LoBello, Glen J. Weiss, Nhan L. Tran. Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response. [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 338. doi:10.1158/1538-7445.AM2014-338