bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3371: Iodoacetate and 3-bromopyruvate exert differential effects on human neuronal tumor SK-N-SH and U-87 cells
Authors: Bhushan Alok , Chatterji Tanushree , Wong Wendy , Rizvi Nisha , Balaraju Anurag K. , Neti Aishwarya , Lai James C.K. 
Published: May 2015

Abstract
Recent interests in the “Warburg effect” stimulated a variety of studies that have demonstrated many aggressive cancers have adapted to hypoxia and shifted to a glycolytic phenotype depending on their micro-environment. However, the mechanisms underlying their adaptive behavior have not been delineated. To further investigate our hypothesis that glycolytic enzymes are targets for new anti-cancer drug discovery, we have examined the effects of iodoacetate (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, and 3-bromopyruvate (3-BP), an inhibitor of hexokinase II, on human neuroblastoma SK-N-SH and astrocytoma U-87 cells. Our results from survival assays showed that both IAA and 3-BP induced concentration- and time-dependent lowering of survival of both cell types, with the effects of IAA being more potent than those of 3-BP in both cell types while SK-N-SH cells being more susceptible than U-87 cells to 3-BP-induced cytotoxicity. Employing lactate dehydrogenase release from cells to medium as a marker for necrosis, we also found IAA was more potent than 3-BP in inducing necrosis in both cells types. Further investigation employing flow cytometric analysis revealed that at 1-10 µM, IAA induced more apoptosis in SK-N-SH than in U-87 cells while at the higher levels in this range, IAA induced more necrosis relative to apoptosis in both cell types. However, at 10-40 µM, 3-BP induced mainly apoptosis but little necrosis in both cell types. Our results are therefore consistent with the notion that IAA and 3-BP exert differential effects in inducing apoptosis and necrosis in SK-K-SH and U-87 cells. Studies are ongoing to further elucidate the signaling mechanisms mediating these effects induced by IAA and 3-BP. Thus, our findings may have pathophysiological and therapeutic implications in employing glycolysis as a target for discovering new drugs for treating aggressive brain tumors.
Citation Format: Alok Bhushan, Tanushree Chatterji, Wendy Wong, Nisha Rizvi, Anurag K. Balaraju, Aishwarya Neti, James C.K. Lai. Iodoacetate and 3-bromopyruvate exert differential effects on human neuronal tumor SK-N-SH and U-87 cells. [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 3371. doi:10.1158/1538-7445.AM2014-3371
Abstract 3373: Contribution of microRNA-122 to the homeostasis of liver energy metabolism
Authors: Tsou Ann-Ping , Wang Shuo-Ting , Tao Tse-Wen 
Published: May 2015

Abstract
MicroRNA-122 (miR-122) is a liver specific miRNA known to regulate lipid metabolism and to prevent liver tumorigenesis. Recent data suggest that miR-122 regulates the metabolism of mitochondria but its mechanistic role is unclear. We investigated how energy metabolism is regulated by miR-122 using the Mir122a-/- mouse model. We identified a distinctive expression profile of mitochondrially localized genes between WT and Mir122a-/- mice by both microarray and proteomics. KEGG and IPA database analysis further showed decreased mitochondrial respiration activity and Acetyl-CoA synthesis. Besides, the expression of genes involved in antioxidant mechanism is increased.
The primary hepatocytes were used to study the energy metabolism. The physiological activities measured by XF-24 extracellular flux analyzer revealed a higher mitochondrial respiration activity (OCR) accompanied with a proton leak in the mitochondrial inner membrane of the Mir122a-/- hepatocytes. In addition, a higher glycolytic activity (ECAR) was detected in Mir122a-/- hepatocytes. Poor ATP production was detected from Mir122a-/- mitochondria. Several lines of evidence demonstrated that Mir122a-/- hepatocytes have low mitochondria membrane potential: excess cytosolic reactive oxygen species, less mitochondrial superoxide anion and lower staining with Rhodamine 123 and Mitotracker red. We further treated cells with mitochondrial inhibitors and found an excellent antioxidant capacity and ATP homeostasis in Mir122a-/- primary hepatocytes. Interestingly, we detected lower protein expression of pyruvate dehydrogenase complex subunit E1, which may partly contribute to the defective mitochondrial activity. The liver homeostasis of Mir122a-/- mice, however, is stabilized by a vigorous antioxidant activity and higher glycolysis capacity. As a result, the livers of young Mir122a-/- mice appear to have switched to aerobic glycolysis (Warburg effect), which is the hallmark of cancer cells. Therefore, correction of mitochondrial dysfunction is likely to become one of new therapeutic means for hepatocellular carcinoma (HCC).
Citation Format: Ann-Ping Tsou, Shuo-Ting Wang, Tse-Wen Tao. Contribution of microRNA-122 to the homeostasis of liver energy 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 3373. doi:10.1158/1538-7445.AM2014-3373
Abstract 3377: Glutamine mediated aggressiveness and drug sensitivity in ovarian cancer cells
Authors: Yang Lifeng , Moss Tyler J. , Marini Juan C. , Mangala Selanere , Wahlig Stephen , Win Julia , Su Dan , Sood Anil K. , Ram Prahlad T. , Nagrath Deepak 
Published: May 2015

Abstract
Platinum-based drugs such as cisplatin, carboplatin and xoaliplatin hav been introduced into clinical trials and their outcomes has progressed the treatment on several tumors, including ovarian cancer. However, cancer cells acquire chemo-resistance in the long term incubation of drugs, which turns out to be the major limitation for cancer therapy. Recent studies have shown that cisplatin can accumulate in mitochondria and induce cytochrome C release, thereby resulting in apoptosis. We found that glutamine plays a vital role in maintaining mitochondrial integrity and function by regulating NAD+ and NADH. Using bioenergetics and isotopomer analysis we show that chemodrugs in presence of glutamine affect oxidative phosphorylation in drug sensitive parental ovarian cancer cells. Addition of NAD+ substrates increased NAD/NADH ratio abrogating cisplatin's effect on cell death and mitochondrial dysfunction. Furthermore, drug resistant cancer cells had relatively higher glutamine dependence when compared with parental cells. Importantly, we found that when glutamine's entry into TCA cycle was inhibited ovarian cancer cells became more sensitive to chemotherapy. Our findings are based on the quantification of metabolites, related to glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acids and nucleotide metabolism, and comparison of these pathways fluxes in drug sensitive and drug resistant ovarian cancer. The insights obtained present a unique opportunity for overcoming the drug resistance limitation in clinical trials in ovarian cancers.
Citation Format: Lifeng Yang, Tyler J. Moss, Juan C. Marini, Selanere Mangala, Stephen Wahlig, Julia Win, Dan Su, Anil K. Sood, Prahlad T. Ram, Deepak Nagrath. Glutamine mediated aggressiveness and drug sensitivity in ovarian cancer cells. [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 3377. doi:10.1158/1538-7445.AM2014-3377
Abstract 3379: Metabolic influences of pancreatic tumor microenvironment on pancreatic cancer cell's metabolism
Authors: Baddour Joelle , Yang Lifeng , Marini Juan C. , Franco-Barraza Janusz , Cukierman Edna , Hu Chaoxin , Maitra Anirban , Nagrath Deepak 
Published: May 2015

Abstract
Pancreatic cancer, the most lethal of solid tumors, is associated with a five-year survival rate and high mortality. The lethality of this tumor stems from lack of early symptoms, inability for detection of cancerous pancreatic lesions, and a diagnosis window that is accompanied by tumor resistance and metastasis. The bulk of the tumor mass, the fibrotic stroma, has been deemed an active player in the initiation and progression of pancreatic ductal adinocarcinoma (PDAC). A number of studies have elucidated the interactions between stromal cells and pancreatic cancer cells (PCCs), and the extracellular matrix (ECM) and PCCs. However, the role of the tumor microenvironment on the metabolic machinery of PCCs remains an active field of investigation. In this study, we investigate the effect of pancreatic stellate cells (PSCs), cancer-associated fibroblasts (CAFs), with or without ECM components, in a two-dimensional or three-dimensional setting on the glycolytic and mitochondrial pathways of patient-derived PCCs. The modulation of the expression levels of metabolic enzymes by the tumor microenvironment was also investigated. The metabolic reprogramming induced in PCCs by normal and reactive pancreatic stroma was investigated by isotopomer flux analysis. Our results reveal that pancreatic reactive stroma differentially upregulates glutamine and arginine metabolism in PCCs. The insights obtained from our work will lead to the development of targeted therapies for stroma and pancreatic cancer cells.
Citation Format: Joelle Baddour, Lifeng Yang, Juan C. Marini, Janusz Franco-Barraza, Edna Cukierman, Chaoxin Hu, Anirban Maitra, Deepak Nagrath. Metabolic influences of pancreatic tumor microenvironment on pancreatic cancer cell's 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 3379. doi:10.1158/1538-7445.AM2014-3379
Abstract 3388: The CD44s splice isoform is essential for breast tumor initiating cell properties
Authors: Brown Rhonda , Liu Sali , Reinke Lauren , Cheng Chonghui 
Published: May 2015

Abstract
Tumor initiating cells (TICs) constitute a small fraction of tumor cells that display stem cell characteristics, including the ability to self-renew and generate heterogeneous tumors. A CD44+/CD24- profile has been widely used to identify TICs in a variety of tumors. However, it has remained unknown whether CD44 is functionally required for TICs and whether a specific CD44 isoform is enriched in TICs. Here, we report that the CD44s isoform is the major splice isoform expressed in a CD44+/CD24- breast stem cell population. Functionally, CD44s is required for expression of a breast stem cell (BSC) gene signature and is essential for mammosphere formation. Modulation of CD44 alternative splicing by the splicing regulator ESRP1 prevents CD44s production and, in turn, inhibits mammosphere formation and expression of the BSC signature. Furthermore, CD44s is required for limiting numbers of TICs to form tumors in an animal model of breast cancer progression. Together, these data illustrate that the CD44s splice isoform is enriched in CD44+/CD24- breast stem cells and serves as an important regulator of stem cell properties. Our results also suggest that CD44s-dependent TIC properties can be controlled at the level of alternative splicing by splicing factors that regulate production of specific CD44 isoforms.
Citation Format: Rhonda Brown, Sali Liu, Lauren Reinke, Chonghui Cheng. The CD44s splice isoform is essential for breast tumor initiating cell properties. [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 3388. doi:10.1158/1538-7445.AM2014-3388
Abstract 3391: Alteration of mammary tumor cell behavior by FLIZ1
Authors: Anderson Torri , Cali Christopher , Bell Katherine , Danielson Keith G. , Klein Ashley , Martin Christina , Radecki Sara , Santoro Adam , Schmidt John A. , Knepper Janice E. 
Published: May 2015

Abstract
Fetal liver zinc finger protein (FLIZ1, ZC3H8) was previously described as a negative regulator of GATA3 expression in T cells. GATA3 also is an important determinant of mammary cell fate and breast tumor cell behavior. We hypothesized that FLIZ1 also regulates GATA3 in the mammary gland, thereby influencing normal and tumor cell processes controlled by GATA3. We identified tumor cell lines with high levels of FLIZ1 expression, and transfected them with vectors driving expression of FLIZ1-interfering RNAs. Stable transfectants (Flizout cells) were evaluated for ability to migrate in a wound healing assay, and were found to have decreased mobility. Flizout cells also grew more slowly and with more pronounced epithelial morphology in media containing charcoal-stripped serum, suggesting increased dependence on steroid hormones. Flizout cells were compared to control cells in proliferation assays, and were found to grow at equivalent rates in standard media, but Flizout cells grew at decreased rates in the presence of tamoxifen. We implanted Flizout cells and controls into the mammary glands of syngeneic female mice, which were then treated with tamoxifen or peanut oil vehicle alone. Flizout cells grew more slowly in tamoxifen-treated animals, and tissue weights were significantly less than controls. In order to determine if FLIZ1 plays a role in the normal mammary gland, we assessed its expression during stages of mouse mammary gland development by immunoblot, and found FLIZ1 expression increased during mammary involution. These data are consistent with a role for FLIZ1 in regulation of mammary cell growth and tumor cell behavior.
Citation Format: Torri Anderson, Christopher Cali, Katherine Bell, Keith G. Danielson, Ashley Klein, Christina Martin, Sara Radecki, Adam Santoro, John A. Schmidt, Janice E. Knepper. Alteration of mammary tumor cell behavior by FLIZ1. [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 3391. doi:10.1158/1538-7445.AM2014-3391
Abstract 3392: Thromboxane-A2 receptor β-isoform regulates the activity of the tumor suppressor FOXO3 via phosphorylation by ERK in urothelial cancer
Authors: Sobolesky Philip M. , Halushka Perry V. , Garrett-Mayer Elizabeth , Moussa Omar 
Published: May 2015

Abstract
The tumor suppressor FOXO3 is a transcription factor whose activity and stability are regulated by phosphorylation on S294 via extracellular regulated kinases (ERK1/2). Previous data by our group has demonstrated overexpressing the thromboxane A2 isoform-β receptor (TPβ) increased ERK activation and induced malignant transformation of immortalized bladder cells. These data describe a novel mechanism of TPβ mediated regulation of FOXO3 via phosphorylation by ERK. Immunohistochemical studies revealed increased expression of nuclear pFOXO3-S294 in late stage bladder tumors, whereas total FOXO3 nuclear expression was reduced in high grade tumors. Both cytoplasmic and nuclear pFOXO3-S294 staining scores positively correlated with TPβ staining scores. Overexpressing TPβ in non-transformed urothelial cell lines, UROsta and SV-HUC, induced phosphorylation of FOXO3 at -S294. Knockdown of FOXO3 expression by shRNA increased cell migration and invasion. Conversely, overexpression of mutated FOXO3 that is resistant to ERK phosphorylation reduced the overall and TP agonist (U46619) mediated increase in malignant UMUC3 cell migration and invasion. Stimulation of UMUC3 cells with U46619 increased pFOXO3-S294 expression which could be attenuated with TP antagonist (PTXA2) pre-treatment. A dual luciferase assay demonstrated that U46619 stimulation decreased overall FOXO3 transcriptional activity. Additionally, U46619 stimulation initially caused nuclear accumulation of pFOXO3-S294, but prolonged stimulation increased FOXO3 cytoplasmic localization. In summary, the data describe a novel mechanism of TPβ signaling in bladder cancer that results in the ERK mediated regulation of FOXO3 activity, which could contribute to tumor progression.
Citation Format: Philip M. Sobolesky, Perry V. Halushka, Elizabeth Garrett-Mayer, Omar Moussa. Thromboxane-A2 receptor β-isoform regulates the activity of the tumor suppressor FOXO3 via phosphorylation by ERK in urothelial 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 3392. doi:10.1158/1538-7445.AM2014-3392
Abstract 3394: In-depth gene expression profiling of seminomatous testicular germ cell tumors
Authors: Patel Sunali , Chu Shirley , Degoricija Lovorka , Lee Kathy Y. , Gillis Ad J.M , Rijlaarsdam Martin , Dorssers Lambert C.J , Looijenga Leendert H.J 
Published: May 2015

Abstract
In depth Whole Transcriptome Analysis by RNA-Seq was used to compare the expression profile of testicular germ cell tumors with the histology of seminoma and normal testis. From this analysis we identified a large number of genes that showed differential expression with statistically high significance, (p&lt;0.01, &gt;2X FC). The list included genes related to stem cell pleuripotency (NANOG, POU5F1), proliferation (KRAS, CCND2), a number of non-coding RNAs (snoRNAs, miRNA precursors, XIST), and testicular cancer related genes (LDHB, AKAP4). From this list we identified a subset of genes for validation and further screening. We used the OpenArray® RT-qPCR platform to quantitatively screen up to 224 coding and non-coding genes using samples from different testicular germ cell tumors (seminoma and non-seminoma) and normal tissue. Results from these screening experiments will be presented.
For research use only. Not for diagnostic procedures.
Citation Format: Sunali Patel, Shirley Chu, Lovorka Degoricija, Kathy Y. Lee, Ad J.M Gillis, Martin Rijlaarsdam, Lambert C.J Dorssers, Leendert H.J Looijenga. In-depth gene expression profiling of seminomatous testicular germ cell 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 3394. doi:10.1158/1538-7445.AM2014-3394
Abstract 3395: Role of the activating protein 2 transcription factor in regulating cell invasion and migration in malignant glioma
Authors: Jain Saket , Poon Ho Yin , Godbout Roseline 
Published: May 2015

Abstract
Background: Malignant gliomas (MG) or high-grade astrocytomas are highly infiltrative brain tumors. Our previous work has shown that brain fatty acid binding protein (B-FABP) regulates the migratory properties of MG cells. B-FABP expression can be controlled by transcription factors such as NF1 and AP2. AP2 is a family of transcription factors involved in the regulation of genes responsible for cellular growth and differentiation during early development. Five AP2 genes have been identified in mice and humans: AP2α, AP2β, AP2γ, AP2δ and AP2ε. AP2 transcription factors are predominantly localized in the nucleus where they bind as homodimers or heterodimers to the consensus sequence GCCNNNGGC. Recent studies have shown that AP2α expression is inversely correlated with astrocytoma grade and that there are higher levels of AP2α in the cytoplasm of high-grade astrocytomas compared to low-grade astrocytomas.
Objective: To study the regulation of B-FABP expression in response to AP2 in MG.
Methodology: A panel of 10 MG cell lines was used to examine AP2α protein levels. Five of these cell lines were B-FABP +ve and five were B-FABP-ve. The effect of AP2 expression on endogenous B-FABP was examined by transfecting AP2 expression constructs into the B-FABP +ve U251 MG cell line. B-FABP levels were examined by western blot analysis and the subcellular localization of AP2 was studied by immunofluorescence analysis.
Results: Western blot analysis indicates that AP2α is expressed in four out of five B-FABP-ve MG cell lines but in only one of the five B-FABP +ve MG cell lines tested. AP2 overexpression studies indicate that B-FABP levels are significantly reduced upon overexpression of AP2α, AP2β or AP2ε. Immunofluorescence data suggest preferential localization of AP2β in the cytoplasm of B-FABP +ve U251 MG cells. Our preliminary result shows difference in affinity towards heterodimerization between AP2 family members.
Conclusion and future directions: AP2 is a negative regulator of B-FABP expression. Exclusion of AP2 from the nucleus allows transcription of B-FABP in MG cells, which in turn leads to increased cell migration. Experiments will be carried out to see the effect of AP2 heterodimerization on regulation of B-FABP transcription. Phosphorylation studies will be carried out to see whether AP2 phosphorylation affects its subcellular localization. This study may lead to new approaches to reduce B-FABP expression in MG, thereby reducing or preventing cell migration and tumor infiltration.
Citation Format: Saket Jain, Ho Yin Poon, Roseline Godbout. Role of the activating protein 2 transcription factor in regulating cell invasion and migration in malignant glioma. [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 3395. doi:10.1158/1538-7445.AM2014-3395
Abstract 3397: Rational targeting of protein translation for cancer treatments
Authors: Chang Elizabeth , Nguyen Duc , Yang Qingyuan , Carrier France 
Published: May 2015

Abstract
Deregulation of protein translation is associated with a growing number of human diseases including tumorigenesis. New anti cancer therapies targeting the protein translation regulator mammalian Target Of Rapamycin (mTOR) highlight the importance of this signaling pathway. However, feedback mechanisms that can compensate for this general protein translation pathway limit the clinical efficiency of this approach. New drugs that could rationally target protein translation in cancer cells are therefore needed. We have identified the heterogenous ribonucleoprotein A18 (hnRNP A18) as a new regulator of protein translation in cancer cells. hnRNP A18 is up regulated in several human tumors including prostate, breast, colon and as shown here in melanoma tumors. hnRNP A18 regulates protein translation of its targeted transcripts by binding to a specific RNA signature motif in their 3’UTRs. Our data indicate that the hypoxia mimetic agent CoCl2 increases hnRNP A18 protein levels in melanoma cells but not in normal melanocytes. In addition, down regulation of hnRNP A18 sensitizes melanoma cells to CoCl2 and Temozolimide. The functional significance of this effect was evaluated in a mouse xenograft model where hnRNP A18 down regulation reduced melanoma tumor growth by more than 70%. RNA immunoprecipitation assay indicate that hnRNP A18 binds to a number of transcripts associated with tumor growth including the Hypoxia Inducible Factor 1α (HIF-1α). Levels of hnRNP A18 also directly affect HIF-1α protein levels in response to CoCl2. Taken together these data indicate that hnRNP A18 is a new regulator of protein translation that could be targeted to develop new mechanism based therapy for the rational inhibition of protein translation in cancer cells.
Citation Format: Elizabeth Chang, Duc Nguyen, Qingyuan Yang, France Carrier. Rational targeting of protein translation for cancer treatments. [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 3397. doi:10.1158/1538-7445.AM2014-3397