bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 982: Malate dehydrogenase 2 confers resistance to docetaxel chemotherapy in prostate cancer through JNK pathway
Authors: Liu Qiong , Geng Hao , Xue Changhui , Beer Tomasz , Qian David Z. 
Published: August 2012

Abstract
Resistance to chemotherapy represents a significant obstacle in cancer therapeutics. Novel mechanistic understandings in cancer cell chemotherapeutic sensitivity and resistance can optimize treatment and improve patient outcome. Molecular alterations in the metabolic pathways are associated with cancer development; however, the role of these alterations in chemotherapy efficacy is largely unknown. In this study, we identified a novel role for mitochondrial malate dehydrogenase 2 (MDH2) in mediating prostate cancer resistance to docetaxel-chemotherapy. We performed gene expression microarray analyses on frozen needle biopsies from prostate cancer patients before they underwent neoadjuvant chemotherapy. We observed that genes in the metabolic pathways are significantly altered in the cancer epithelium versus the matched- tumor adjacent benign epithelium. In addition, some of the metabolic gene expression alterations are associated with the long-term treatment outcome. Patients with MDH2 overexpression in cancer cells had a significantly lower relapse-free survival (RFS) based on the Kaplan-Meier analysis. To investigate the underlying mechanism responsible for this clinical observation, we found that MDH2 expression was elevated in prostate cancer cell lines compared to benign prostate epithelial cells. Then we established stable MDH2 knock-down prostate cancer lines and evaluated cell proliferation and cell viability within the context of chemotherapy. We found that MDH2 knockdown significantly enhanced the docetaxel sensitivity in prostate cancer cell lines LNCaP, C42B and PC3. Metabolic and redox measurement showed that MDH2 knockdown significantly reduced cellular ATP levels and increased the ADP/ATP and NAD+/NADH level. In addition, MDH2 knockdown significantly increased reactive oxygen specifies (ROS) while maintaining the oxygen consumption rate. These metabolic alterations were associated with the sustained activation of JNK signaling cascade after docetaxel treatment and the inactivation of apoptosis inhibitor BCL2. Taken together, these data suggest a novel function for MDH2 in prostate cancer development and chemotherapy, in which the cancer associated metabolic and redox alteration confers resistance to chemotherapy by regulating pathways of signal transduction and cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 982. doi:1538-7445.AM2012-982
Abstract 986: Reverse-engineered, forward-simulation of MEK-dependent molecular networks reveal novel regulators of cell cycle and cancer cell survival
Authors: Gendelman Rina , Xing Heming , Sarde Preeti , Mirzoeva Olga K. , Feiler Heidi , Gray Joe W. , McDonagh Paul , Khalil Iya , Michael W. 
Published: August 2012

Abstract
ABSTRACT Molecular networks governing responses to targeted therapies in cancer cells are complex dynamic systems that demonstrate non-intuitive behaviors. We applied a novel computational strategy to decipher causal relationships between signaling network components. Gene networks were constructed MEK from global gene expression profiles to model G1-S cell cycle arrest as a consequence of inhibition of MEK, a key component of the oncogenic RAF-MEK-ERK signal transduction pathway. Through forward-simulation of reverse-engineered networks candidate MEK-dependent regulators of the cell cycle were identified. The potential of the approach to infer causality is demonstrated by confirmed predictions of differential effects of two early-response transcription factors, IER2 and EGR1. Conventional linear regression analysis shows strong correlation of expression of both with MEK inhibition and cell cycle distribution, while only IER2 is predicted by our model and experimentally validated to have a causal effect on G1-S transition. Furthermore, we identify TRIB1 (tribbles homologue 1 drosophila) as a potent and novel cell cycle regulator. TRIB1 also mediates cross-talk to the NFkB pathway by enhancing p100 and IkBa-phosphorylation and degradation thus regulating cell survival and expression of cytokines crucial for tumor-stroma interaction. In agreement with this, knock-down of TRIB1 results in induction of apoptosis and sensitizes cells to cell killing induced by the death-receptor agonist TRAIL via upregulation of TRAIL receptor, DR5. Thus TRIB1 is a central regulator of cell cycle and survival and represents a potential therapeutic target.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 986. doi:1538-7445.AM2012-986
Abstract LB-10: Distribution and potency of anti-proliferative arachidonic acid metabolites
Authors: Revello Sonia D. , Snyder Nathaniel W. , Liu Xiaojing , Zhang Suhong , Arora Jasbir S. , Blair Ian A. 
Published: August 2012

Abstract
Eicosanoids participate in the dysregulation of cell proliferation during tumorigenesis. The up-regulation of cyclooxygenase-2 (COX-2) and down-regulation of 15-prostaglandin dehydrogenase (15-PGDH) have been linked to the switch for a pro-proliferative and pro-angiogenic tumor microenvironment. Previous studies have characterized the effects of increased prostaglandin E2 in tumor progression but the role of many other endogenous lipid mediators has yet to be determined. COX-2 can metabolize arachidonic acid (AA) to hydroxyeicosatetraenoic acids (HETEs), which in turn can be further oxidized by dehydrogenases into oxo-eicosatetraenoic acids (oxo-ETEs). We have previously reported that 11-oxo-ETE and 15-oxo-ETE are major COX-2/15-PGDH derived metabolites formed from human cells expressing COX-2 treated with AA. Although no known G-protein coupled receptor has been reported for either of these metabolites, both 11-oxo- and 15-oxo-ETE have been described from human clinical samples. This study provides a description of the uptake and distribution of 11-oxo-ETE and 15-oxo-ETE as well as their anti-proliferative activity in both human umbilical vein endothelial cells (HUVECs) and LoVo human colon adenocarcinoma cells. Quantification of the intracellular and extracellular levels of 11-oxo- and 15-oxo-ETE was conducted using liquid chromatography electron capture atmospheric pressure chemical ionization mass spectrometry with [13C]-labeled 15-oxo-ETE as an internal standard. The intracellular concentrations of 11-oxo- and 15-oxo-ETE reached peak amounts within 1h followed by a rapid decline. Earlier studies have indicated that glutathione (GSH)-S-transferase further metabolized 11-oxo-ETE to form the 11-oxo-ETE-GSH (OEG)-adduct. In additional experiments, pretreatment with ethacrynic acid (EA), a known inhibitor of GSTs, increased recovery from the cellular extract. In addition, the methyl-ester of both 11-oxo- and 15-oxo-ETE was used for the targeted intracellular delivery of these COX-2/15-PGDH derived eicosanoids. Finally, we have shown that both 11-oxo- and 15-oxo-ETE as well as their methyl ester derivatives significantly inhibit cell proliferation as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assay and Bromodeoxyuridine (BrdU) incorporation in multiple human cell lines. The present study has established the cellular uptake of the short-lived COX-2/15-PGDH derived eicosanoids 11-oxo- and 15-oxo-ETE and potent inhibition of new DNA synthesis and proliferation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-10. doi:1538-7445.AM2012-LB-10
Abstract LB-109: MDV3100, an androgen receptor signaling inhibitor, inhibits tumor growth in breast cancer preclinical models regardless of estrogen receptor status
Authors: Cochrane Dawn R. , Jacobsen Britta M. , Cittelly Diana M. , Howe Erin N. , Jean Annie , Spoelstra Nicole S. , Bernales Sebastian , Protter Andrew A. , Elias Anthony D. , Richer Jennifer K. 
Published: August 2012

Abstract
Background: The androgen receptor (AR) is detected by immunohistochemistry in approximately 75% of all invasive breast cancer, with ∼88% of estrogen receptor (ER) positive (ER+) tumors also expressing AR and ∼20 to 30% of ER negative (ER-) tumors also retaining AR expression. Potent inhibition of AR activity could be a therapeutic strategy in AR+ ER+ breast cancer. MDV3100 is an androgen receptor signaling inhibitor (ARSI), which inhibits AR activity via three mechanisms: 1) inhibition of androgen binding to AR, 2) inhibition of AR nuclear translocation, and 3) inhibition of nuclear AR-DNA binding; and has demonstrated an overall survival benefit in men with post-docetaxel prostate cancer. Methods: Two ER+/AR+ breast cancer cell lines, MCF7and BCK4 (recently derived from a pleurocentesis), were used to assess the proliferative effect of dihydrotestosterone (DHT) and estradiol (E2) in ovariectomized mice. MDV3100 was compared to bicalutamide and tamoxifen. Growth effects of MDV3100 on ER-/AR+ cells in tissue culture and in xenografts were also examined. Results: Both bicalutamide and MDV3100 inhibited DHT-mediated proliferation of ER+/AR+ cell lines. Although MDV3100 binds AR very effectively and does not bind ER, it inhibited E2-mediated proliferation. MDV3100 also blocked E2 mediated upregulation of AR, PR, and SDF-1. MDV3100 inhibited E2-stimulated tumor growth of MCF7 mammary xenografts as effectively as tamoxifen. With ER-/AR+ cells (MDA-MB-453), MDV3100 reduced DHT-induced nuclear translocation, cell growth in tissue culture and tumor growth in mouse orthotopic xenografts. Conclusions: MDV3100 blocked both DHT- and E2-mediated growth of breast cancer cells, whereas bicalutamide enhanced E2-mediated proliferation. MDV3100 may have unique therapeutic utility in patients with AR+ breast cancer, regardless of ER status. Funding: DOD Breast Cancer Program Idea Award BC074403, Avon Foundation for Women, and University of Colorado Cancer Center pilot project funds to JKR.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-109. doi:1538-7445.AM2012-LB-109
Abstract LB-112: Ex vivo lung cancer nodule model shows efficacy of nanoparticle delivery
Authors: Mishra Dhruva K. , Shen Haifa , Mai Junhua , Ott Harald C. , Baird Brandi N. , Kurie Jonathan M. , Kim Min P. 
Published: August 2012

Abstract
Nanoparticles have the potential of being used for treatment of lung cancer. However, it is difficult to determine how nanoparticles target cancer cells in a poorly vascularized tumor nodule. In our study, we hypothesize that we can develop an ex vivo human lung cancer nodule model with a perfusable vascular bed that can be used to test distribution of nanoparticles. To create this ex vivo human lung cancer nodule model, we isolated the rat heart-lung block from a 6-week-old Sprague-Dawley rat. We then removed the native rat cells from the lung using sodium dodecyl sulfate and Triton-X-100 in a customized decelluarization chamber. We then placed human lung cancer cell lines H460 and H1299 through the trachea of the acellular rat lung scaffold in a bioreactor. After three days of growth in the bioreactor, we placed 700 million nanoparticles into the scaffold through the circulation labeled with fluorescent tags. We performed lobectomy 1 and 3 days following placement of the nanoparticles. We examined the distribution of the nanoparticles in the nodules using hematoxylin and eosin (H&E) stain and confocal microscopy. There were numerous tumor nodules on both lung scaffolds, measuring 2 mm, three days after placement of the cells. One day after placement of the nanoparticles the lobectomy specimen on the H&E showed that the scaffold with H460 cells had features of poorly differentiated non-small cell lung cancer with sheet-like growth of polygonal cells and the scaffold with H1299 cells had features of very poorly differentiated malignant cells. Moreover, most of the nanoparticles were distributed along the vascular structures with paucity of nanoparticles in the center of the tumor nodules. The confocal microscopy showed that in some areas, nanoparticles were found inside the cytoplasm and nucleus of the cells. Three days after the placement of the nanoparticles, the H&E showed increased number of cells in the tumor nodules with uptake of nanoparticles. Given these results, we believe that the ex vivo human lung cancer nodule model can be used to show delivery of nanoparticles in a complex nodule and determine its efficacy. This can aid in determining appropriate dose of nanoparticles, design of nanoparticles and efficiency of delivery of nanoparticles to heterogeneous tumor nodules, which would aid in vivo treatment studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-112. doi:1538-7445.AM2012-LB-112
Abstract LB-155: Smad4 negatively regulates beta-catenin signaling through proteasomal degradation of Aurora A in human cancer cells
Authors: Jia LIina , Lee Hun Seok , Park Sang Gyu , Kundu Juthika , Shin Young Kee 
Published: August 2012

Abstract
Aurora kinase A (AURKA), a centrosomal serine/threonine protein kinase, is frequently over-expressed in a wide range of human cancers. In the present study, we showed that the expression of AURKA is downregulated in human cancer cells upon over-expression of the tumor suppressor protein Smad4. Bimolecular Fluorescence Complementation (BiFC) assay revealed that full-length Smad4 and linker region interacts with C terminal (kinase domain) domain of AURKA. Ectopic expression of Smad4 down-regulated the expression of AURKA and attenuated phosphorylation of glycogen synthase kinase-3β (GSK3β) at serine-9 residue in HeLa and AGS cells, which resulted in the reduced protein expression and the transcriptional activity of β-catenin. Pre-incubation with MG132 abrogated the degradation rate of AURKA in Smad4 over-expressing HeLa and AGS cells. Conversely, silencing of Smad4 in HeLa cells up-regulated the expression of AURKA and inactivated GSK3β, and subsequently increased the expression of β-catenin. In addition, transient over-expression of Smad4 in Smad4-deficient SW480 colon cancer cells diminished the expression of AURKA and negated GSK3β phosphorylation, resulting in the reduced protein expression and the transcriptional activity of β-catenin. In contrast, siRNA-mediated silencing of AURKA in Smad4 over-expressed cells failed to alter the expression of β-catenin. Taken together, our study demonstrates that restoration of Smad4 inhibits tumor progression by blocking AURKA -mediated signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-155. doi:1538-7445.AM2012-LB-155
Abstract LB-165: The role of sphingolipid metabolism in the treatment of acute myeloid leukemia
Authors: Smith Eric L. , Schuchman Edward , Hoffman Ronald 
Published: August 2012

Abstract
While significant progress has been made in understanding the genetics of AML, treatment still consists of induction therapy that is toxic and not tolerated by the elderly. In this study we show in cell culture models that manipulating sphingolipid metabolism may provide a potential mechanism to increase the efficacy of induction therapy, thus possibly allowing the use of lower doses of cytotoxic chemotherapy while maintaining efficacy. Recently thousands of papers have revealed that sphingolipid metabolism has a major role in determining how a diverse group of cell types, including myeloid malignancies, respond to a variety of stresses, particularly chemotheraputics, through production of the pro-apoptotic lipid ceramide. Conversely, a downstream ceramide metabolite, sphingosine-1-phosphte (S1P), has been shown to have the opposite effect, promoting survival, multi-drug resistance, and proliferation. We hypothesize that through the use of small molecules that inhibit the metabolism of ceramide and the formation of S1P we can decrease the apoptotic threshold of leukemic cells. To investigate this we used inhibitors to two enzymes that metabolize ceramide, the ceramidase inhibitor, LCL-385, and the glucosylceramide synthase inhibitor, PDMP, as well as the sphingosine kinase inhibitor, SKI, alone and in combination with daunorubicin and cytarabine in common AML cell culture models, HL-60 and HEL. We found that at low nanomolar concentrations each of these inhibitors alone dramatically decreases proliferation and increases apoptosis in both cell types in a dose dependant manner. Most importantly, through analysis with the Chou and Talalay combination index model, we have shown that each of these molecules works synergistically with daunorubicin and cytarabine (see table below). This data highlights the importance of sphingolipid metabolism in the response of AML cells to chemotherapy and as a potential synergistic target for induction therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-165. doi:1538-7445.AM2012-LB-165
Abstract LB-167: Prepubertal or lifetime genistein intake reduces risk of tamoxifen resistance in rats
Authors: Zhang Xiyuan , Warri Anni , Cruz Idalia M. , Cook Katherine , Clarke Robert , Hilakivi-Clarke Leena 
Published: August 2012

Abstract
Using a preclinical model, we studied whether consumption of soy isoflavone genistein (GEN) during childhood modifies the effect of adult GEN intake on the ability of tamoxifen (TAM) to inhibit mammary tumor growth. Female rats were fed AIN93G control diet supplemented with 0 or 500 ppm genistein between postnatal days (PND) 15 and 30 (prepubertal exposure); on PND30 both groups received control diet. They were then exposed on PND50 to DMBA, and on PND57 divided to four dietary groups (n=20-40 per group) (see Table). Most rats in all four groups developed mammary tumors, but tumor latency was longer in the prepubertally GEN fed G-G (P&lt;0.003) and G-C groups (p&lt;0.095), compared to controls. TAM treatment (338 ppm in the diet) was started when tumor reached a size of 1.4 cm, and rats were followed for 18 weeks. The response to TAM was determined as complete response (CR), partial response (PR), or as being resistant. Adding GEN to the diet when TAM treatment started increased TAM resistance by 48%, compared to rats which were never fed GEN. Adult GEN intake (C-G group) further reduced CR. However, protein levels in the tumors of genes involved in unfolded-protein response and associated with TAM resistance (IRE1a, BIP, ATF4, BECLIN1, CHOP, ER), were not affected. Prepubertal GEN intake in G-C and G-G groups significantly increased the rate of CR and inhibited TAM resistance. Total tumor burden, which reflects the response of all tumors per rat to TAM, including those appearing during TAM treatment (de novo TAM resistant) was significantly higher in the rats which received GEN as adults, compared to the other three groups (p&lt;0.001); lowest tumor burden was seen in the rats which consumed GEN both during prepuberty and as adults. Our findings suggest that prepubertally GEN fed rats, also when they continue to consume GEN in adulthood, are at low risk of developing TAM resistance. In contrast, adult only GEN consumption significantly impaired response to TAM. Mechanisms explaining these data are currently being investigated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-167. doi:1538-7445.AM2012-LB-167
Abstract LB-169: Metformin reduces somatic cell mutation rate by inhibiting mitochondrial ROS production: relevance to cancer prevention
Authors: Pollak Michael N. , Algire carolyn , Ferbeyre Gerardo 
Published: August 2012

Abstract
Pharmacoepidemiological studies provide evidence that use of metformin, a drug commonly prescribed for type II diabetes, is associated with a substantial reduction in cancer risk. Experimental models show that metformin inhibits the growth of certain neoplasms by cell autonomous mechanisms such as activation of AMP kinase with secondary inhibition of protein synthesis, or by an indirect mechanism involving reduction in gluconeogenesis leading to a decline in insulin levels and reduced proliferation of insulin-responsive cancers. Here we show that metformin attenuates paraquat-induced elevations in reactive oxygen species (ROS), DNA damage and mutations, but has no effect on similar changes induced by H202, indicating a reduction in endogenous ROS production. Metformin also inhibited Ras-induced ROS production and DNA damage. Our results reveal previously unrecognized inhibitory effects of metformin on ROS production and somatic cell mutation, providing a novel mechanism for the reduction in cancer risk associated with exposure to this drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-169. doi:1538-7445.AM2012-LB-169