bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1255: Role of choline in adaptive mechanisms in choline phospholipid metabolism of human breast cancer cells
Authors: Krishnamachary Balaji , Mori Noriko , Gadiya Mayur , Mironchik Yelena , Glunde Kristine , Bhujwalla Zaver M. 
Published: June 2012

Abstract
Proton magnetic resonance spectroscopy studies of cancer have consistently detected increased cellular phosphocholine (PC) and total choline-containing compounds (tCho), which are closely related to malignant transformation, invasion and metastasis [1]. Enzymes in choline metabolism present attractive targets that can be exploited for treatment [2]. Two of these enzymes, choline kinase-α (Chk) and phosphatidylcholine specific phospholipase D (PC-PLD) have been associated with increased malignancy [1, 3]. Chk is a cytosolic enzyme that is responsible for phosphorylation and converting free choline to phosphocholine. Two mammalian isoforms of PC-PLD, PLD1 and PLD2 have currently been identified. While PLD2 is restricted to cytoplasm, PLD1 shuttles between cytoplasm and membrane upon activation by G proteins such as ARF, Rho and Rac [4]. Here we used small interfering RNA (siRNA) against Chk and PLD1 alone or in combination in triple negative MDA-MB-231 human breast cancer cells to silence these two genes. Effective downregulation was confirmed at both protein and mRNA levels. However, downregulation of Chk with siRNA resulted in increased PLD1 expression, and downregulation of PLD1 resulted in increased Chk expression, typifying the ability of cancer cells to adapt. We sought to further understand mechanisms underlying this interdependence by changing the concentrations of free choline in the media. We observed a reduction in the increase of PLD1 protein expression and mRNA levels following Chk downregulation with higher concentration of free choline (107.1µM), suggesting that free choline plays a role in mediating the increase of PLD1 observed following Chk downregulation. Understanding the complex networks of pathways that participate following downregulation of a specific target is critical in a complex disease like cancer. These participating pathways provide novel opportunities to target in concert with the primary target to achieve improved control and minimize compensatory responses that allow cancer cells to survive or adapt. This is especially important if the downregulation of one ‘oncogenic target’, e.g. Chk, results in the upregulation of another, e.g. PLD1.
Acknowledgements: This work was supported by NIH P50 CA103175.
References: 1. Glunde, K. et al., Expert Rev Mol Diagn, 2006; 2. Bañez-Coronel M. et al., Curr Cancer Drug Targets, 2008; 3. Toschi, A. et al., Cancer Letters, 2010; 4. Huang, P. and Frohman, MA., Expert Opin Therapy, 2007.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1255. doi:10.1158/1538-7445.AM2011-1255
Abstract 1258: Regulation of energy metabolism and protein synthesis by the Pim protein kinases
Authors: Zemskova Marina Yu , Beharry Zanna , Mahajan Sandeep , Kraft Andrew S. 
Published: June 2012

Abstract
The serine/threonine Pim kinases are overexpressed in solid cancers and hematologic malignancies and promote cell growth and survival. Here, we find that a novel Pim kinase inhibitor, SMI-4a, or Pim-1 siRNA blocked mTORC1 activity by stimulating the phosphorylation, and thus activating the mTORC1 negative regulator AMP-dependent protein kinase (AMPK). Mouse embryonic fibroblasts (MEFs) deficient for all three Pim kinases (TKO MEFs) demonstrated activated AMPK driven by elevated ratios of AMP:ATP relative to wild type MEFs. Consistent with these findings, TKO MEFs were found to grow slowly in culture and have decreased rates of protein synthesis secondary to a diminished amount of 5′-cap dependent translation. Pim-3 expression alone in TKO MEFs was sufficient to reverse AMPK activation, increase protein synthesis, and drive MEF growth similar to wild type. Pim-3 expression was found to markedly increase the protein levels of both c-Myc and PGC-1α, enzymes capable of regulating glycolysis and mitochondrial biogenesis, which were diminished in TKO MEFs. These results demonstrate the Pim kinase -mediated control of energy metabolism through regulation of AMPK activity, and identify a new and important role for Pim-3 in modulating c-Myc and PGC-1α protein levels and cell growth. In prostate cancer cell lines we find that the Pim-3 protein kinase is elevated in those cells that are highly metastatic including PC3-LN4, ARCaPM and M12 when compared to PC-3, ARCaPE and p69 and the amount of Pim-3 correlates with c-Myc levels. Further experiments will be needed to determine whether the Pim-3 protein kinase expression regulates the metastatic potential of prostate cancer cells through control of energy metabolism and protein synthesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1258. doi:10.1158/1538-7445.AM2011-1258
Abstract 1259: c-Myc influences mitochondrial structure and function by regulating fusion and fission
Authors: Graves J. Anthony , Rothermund Kristi D. , Wang Yudong , Elster Jennifer , Vockley Jerry , Van Houten Bennett , Prochownik Edward V. 
Published: June 2012

Abstract
Background: c-Myc (Myc) is a global transcription factor that controls the expression of a large part of the human genome. The numerous Myc target genes function in a variety of normal cellular processes whose collective expression of these processes is referred to as the “Myc phenotype”. One such cellular process is the regulation of mitochondrial biogenesis. Objectives: To understand the specific influence that Myc has on mitochondrial structure and function. We hypothesize that Myc is involved in the regulation of both the production and destruction of mitochondria, and that the ability of Myc to maintain this balance has an impact on cellular transformation. Design/Method: Various cell lines that allow for the manipulation of Myc levels have been used. These include cells that have been engineered to have inducible Myc over-expression as well as inducible expression of Myc shRNA. These strains were used in a series of assays that measured different aspects of the Myc effect on mitochondrial structure and function. Most notably, metabolic pathways were measured by an extracellular flux analyzer and electron and confocal microscopy was performed to examine the structure of the mitochondria in detail. Results: The induction of Myc results in dramatic increases in overall mitochondrial mass, as well as increasing individual mitochondrial size and cristae density. This increase in recognizable mitochondria correlates to increases in oxidative phosphorylation and decreased mitochondrial loss through mitophagy. Finally, Myc levels correlate to increased mitochondrial inter-connectivity. This appears to be related to the ability of Myc to influence the expression of the mitochondrial fusion protein, Opa1 and the fission protein, DLP1. Conclusions Reached: The changes in mitochondrial structure and function are directly influenced by the expression of Myc. There appear to be multiple pathways involved in maintaining a specific mitochondrial mass, which emphasizes the importance of this organelle in cellular homeostasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1259. doi:10.1158/1538-7445.AM2011-1259
Abstract 1272: Role of c-Myc, Oct1 and KLF4 in cell metabolism: Involvement of pluripotency factors in metabolic remodeling during tumorigenesis
Authors: Bellance Nadege , Karedath Thasni , Caneba Christine , Pabst Lisa , Asad Syed , Nagrath Deepak 
Published: June 2012

Abstract
Embryonic stem cells have the ability to give rise to different cell types and also the self reniewal capacity. Those features are essentially controlled by pluripotency factors which maintain cells into an undifferentiated state. Cancer cells are distinguished from normal cells by a dedifferentiation process in which the expression of pluripotency factors can be increased. c-Myc, Oct4 and KLF4 are pluripotency transcription factors. Oct-1, homologue of Oct-4, have been recently revealed to be pro-tumorigenic and his expression, such as c-Myc, is increased in various cancers. In this study, we investigated the role of this transcription factors into the cell metabolism. The role of the oncogene MYC on tumor cell metabolism has been largely studied. In cancer cells, c-Myc induces the expression of genes involved in glycolysis and glutaminolysis. However, the entire metabolic changes induced by c-Myc have not yet been elucidated. Furthermore, little is known about the role of Oct-1 and KLF4 in cancer metabolism. We have used the metabolic footprinting approach in order to characterize the Oct-1, c-Myc and KLF4 deficient cells and to identify the induced consecutive metabolic remodeling. Because of the variability of mutations observed in cancer cells, we investigated the effects induced by Oct-1, KLF4 and c-Myc deficiencies in mouse and rat embryonic fibroblasts by using UPLC (Ultra performance liquid chromatography). The uptake and release of metabolites was quantified by providing different substrates (glutamine or fatty acid). The glucose consumption and the lactate production which defined as the Warburg effect was measured. The mitochondrial function was investigated by oxygen consumption rate measurement. We found that the metabolites produced by Oct-1, KLF4 and c-Myc deficient cells seems to present a signature which can explain there over-expression in tumors. Our results suggest that embryonic stem cells related pluripotency transcription factors are implicated into the metabolic remodeling of cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1272. doi:10.1158/1538-7445.AM2011-1272
Abstract 1285: Genetic variations predicting cisplatin cytotoxicity associated with the overall survival in lung cancer patients receiving platinum-based chemotherapy
Authors: Tan Xiang-Lin , Moyer Ann M. , Schaid Daniel J. , Niu Nifang , Batzler Anthony , Li Liang , Sun Zhifu , Yang Ping , Wang Liewei 
Published: June 2012

Abstract
Background: Candidate gene and candidate pathway-based pharmacogenomic studies have been used to investigate the inherited variability of prognosis of lung cancer treated with platinum-based chemoptherapy. In order to make it possible to conduct an ‘unbiased’ query across the entire genome, a genome-wide association study (GWAS) in 283 lymphoblastoid cell lines (LCLs) was carried out to help identify candidate SNPs associated with variation in cisplatin cytotoxicity. Furthermore, we set out to test the hypothesis that genetic variation resulting in differences in cisplatin cytotoxicity might influence the overall survival of patients with lung cancer treated with platinum-based antineoplastic agents.
Material and Methods: We applied ethnically diverse Coriell “Human Variation Panel” LCLs for GWAS. Then, we picked 168 top significant SNPs selected from GWAS in 283 LCLs and genotyped these SNPs in 1183 lung cancer patients (222 SCLC and 961 NSCLC) who received platinum-based chemotherapy. Genotyping was performed using the Illumina Golden Gate platform. The association of SNPs with lung cancer overall survival was analyzed by Cox regression model after adjusting for disease stage. Functional validation of candidate genes was performed by siRNA screening in NSCLC cell lines CRL5872, H1299 and SCLC cell line CRL5823.
Results: A total of 157 SNPs were successfully genotyped for 1183 lung cancer patient samples. The Cox regression analysis indicated that 9 and 10 different SNPs were associated with overall survival for NSCLC and SCLC patients, respectively (p value &lt;0.05). Fifteen genes including 7 genes located in the region of 200kb up or downstream of 4 SNPs (rs11169748, rs2440915, rs5952066 and rs7620841) and 8 genes for which the expression was correlated with three SNPs (rs11169748, rs2440915 and rs5952066) were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which the expression levels were correlated with the SNPs rs11169748 and rs2440915, significantly decreased cisplatin sensitivity in lung cancer cell lines CRL5872, H1299 and CRL5823.
Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes and SNPs that might help predict treatment outcomes of platinum-based therapy in lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2011-1285
Abstract 1313: Is serum free RNA available as a predictive biomarker for the response to chemotherapy in patients with lung cancer
Authors: Son Choonhee , Roh Mee-Sook , Um Soo-Jung , Kim Kyu Sik 
Published: June 2012

Abstract
Introduction: It is well-known that cell-free nucleic acids rise in patients with many types of malignancies. Several recent studies have suggested that circulating, cell-free RNA (cRNA) correlates with tumor burden. Furthermore, experimental studies using cancer cell lines have shown that changes in cRNA are predictive of the response to chemotherapy. The objective of this study was to determine whether cRNA can be used as a biomarker for clinical responses to chemotherapy in patients with lung cancer.
Methods: Thirty-two patients with lung cancer (non-small cell lung cancer, n=24; small cell lung cancer, n=8) were divided into 2 groups according to the responses of chemotherapy (response group, n=19; non-response group, n=13). Blood samples were collected before and after two cycles of chemotherapy. Real-time quantitative RT-PCR was used for transcript quantification of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene.
Results: The pre- (Response group: 41.36 ± 1.72 vs. Non-response group: 41.33 ± 1.54, p=0.78) and post- (Response group: 39.92 ± 1.81 vs. Non-response group: 40.41 ± 1.47, p=0.40) chemotherapy cRNA concentration, expressed as the Ct GAPDH level, was not different between the two groups. There was no significant relationship between the change of the cRNA level and clinical response after chemotherapy (p=0.43).
Conclusion: We could not find a correlation between serum cRNA level and clinical responses to chemotherapy in patients with lung cancer. More further investigations are needed to prove cRNA level as a useful predictor of chemotherapy responses in patients with lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1313. doi:10.1158/1538-7445.AM2011-1313
Abstract 1314: Estrogen receptor-α is activated in breast ductal epithelial cells by CCN5 in CCN5-conditional tri-transgenic mice
Authors: Majumder Monami , Banerjee Snigdha , Mehta Smita , De Archana , Dhar Kakali , Tawfik Ossama , Larson Melissa A. , Banerjee Sushanta K. 
Published: June 2012

Abstract
Estrogen receptor-alpha (ER-α) is localized in the nuclei of approximately 3-7% of normal resting breast epithelial cells with a higher proportion in lobular cells than in ductal. This number is significantly increased in atypical ductal hyperplasia, ductal carcinoma in situ (DCIS), pure intraductal carcinoma, and intraductal carcinoma with invasive duct carcinoma. Despite having this information for last 15 years, it is still uncertain how ER-α is activated in the nuclei of breast epithelial cells. CCN5/WISP-2, a member of the CCN (Cysteine-rich61/Connective Tissue Growth Factor/Nephroblastoma overexpressed) family of growth factors, is becoming an increasingly important focus in breast cancer research. CCN5/WISP-2 is a two-faced signaling molecule and plays differently in breast carcinogenesis under different micro-environmental setups. Our previous studies have shown that the transcriptional and translational activation of the WISP-2/CCN5 gene is a characteristic of estrogen receptor positive non-invasive breast tumor cell lines. Expression of the WISP-2/CCN5 gene was virtually undetected in non-transformed mammary epithelial cells. Moreover, multiple studies suggest a fine tune between CCN5 signaling and ER-α pathways, but this has not yet been fully elucidated. The main objective of this work was to establish the effect of excessive activation of CCN5 on the ER-α signaling. To do so, we generated a tri-transgenic inducible mouse model that overexpresses CCN5 under the Doxycycline (dox) environment. After the confirmation of the conditional expression of CCN5 in a mammary-specific and dox-dependent manner, morphology as well as the status of ER-α was evaluated. We found that induced expression of CCN5 by Dox in breast epithelial cells significantly increased ER-α expression and activity along with no morphological changes. Collectively, these studies indentify CCN5 as a regulator of ER-α in breast epithelial cells in a tri-transgenic mouse model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1314. doi:10.1158/1538-7445.AM2011-1314
Abstract 1317: Estradiol and progesterone promotes breast tumor growth through induction of AKT/mTOR pathway and inhibition of apoptosis
Authors: Arumugam Arunkumar , Boopalan Thiyagarajan , Delgado Alejandro , Agullo Pamela A. , Parada Jacqueline , Lakshmanaswamy Rajkumar 
Published: June 2012

Abstract
Breast cancer development is accomplished by unbalanced regulation of several signaling pathways. Studies indentifying potential targets for mammary cancer treatment and prevention are vital. Copenhagen strain of rat is a well known animal model which is resistant to carcinogen-induced mammary carcinogenesis. In our laboratory, we were able to induce a very high incidence of mammary cancers in these rats using combination of carcinogen N-methyl-N-nitrosourea (MNU), followed by estradiol and progesterone treatment. We have demonstrated that the resistance to mammary carcinogenesis in these rats is not due to inhibition of initiation but due to reduced hormone promotional environment and we further extend our research to investigate the molecular mechanisms involved behind this hormone-induced promotion. In the present study, we exposed 7 week old female Copenhagen rats to N-methyl-N-nitrosourea (MNU; 50mg/kg body weight). Immediately after MNU treatment the rats were divided into the following groups: 1) Control 2) 17β-estradiol (30mg) 3) progesterone (30mg) and 4) 17β-estradiol (30mg) plus progesterone (30mg). All hormone treatments were administered via individual silastic pellets for a period of 9 months post carcinogen treatment. At the end of the treatment period rat mammary tumors were excised and used for molecular analysis. Quantitative RT-PCR and western blot analysis showed that ovarian hormones treatment triggered the AKT/mTOR pathway along with increased cell cycle progression. Intra cellular MAPK signaling was increased through activation of AKT/PI3K pathway. Hormone administration decreased the levels of caspase-3, caspase-8 and caspase-9. Together, our result indicates that hormone treatment induces mammary tumor growth through activation of AKT/PI3K/mTOR pathways and simultaneously inhibiting apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1317. doi:10.1158/1538-7445.AM2011-1317
Abstract 1325: Organ, species and sex differences in mutagenesis induced by butyl-hydroxybutyl-N-nitrosamine in big blue transgenic rodents as the basis for the strict organ specificity of this environmental carcinogen metabolite
Authors: He Zhiming , Strasberg-Rieber Zhong-Lin Zhao , Kosinska Wieslawa , Wu Xue-Ru , Guttenplan Joseph B. 
Published: June 2012

Abstract
Although butyl-hydroxybutyl-N-nitrosamine (BBN) is a powerful carcinogen that specifically causes bladder cancer in rodents, the reason for such a high degree of organ specificity is unclear. Mutagenesis induced by BBN in a chromosomally incorporated mutagenesis reporter gene was measured in bladder urothelial cells and smooth muscle cells of mice or rats and compared with mutagenesis in liver, kidney, ureter and forestomach. BBN was administered as a 0.05% solution in water for 2 weeks followed by 4 weeks of water to 6 male and female mice and 4 male rats. All animals were euthanized at 6 weeks. Since mutagenesis in the reporter gene is a surrogate for mutagenesis in general, we hypothesized that mutations also induced in critical growth control genes would contribute to the tumor formation induced by BBN. The mutant fractions in urothelial cells were: 257 +/- 25 mutants / 105 pfu for male mice, 276 +/- 43 for female mice and 54 +/- 6 for rats. In contrast, the mutant fractions in bladder smooth muscle cells were 8-9 fold lower than these values in all animals. In non-bladder tissues such as liver, kidney, ureter and forestomach, the mutant fractions were between 2 and 5 mutants / 105 pfu, a level comparable to the control groups without BBN treatment. Hence mutagenesis correlated extremely well with the organ specificity for cancer induction by BBN. Additionally, mutagenesis level was found to be significantly higher in mice than in rats, consistent with the fact that BBN is a much more potent bladder carcinogen in mice. Finally, no significant difference in mutagenicity of BBN between male and female mice was observed, suggesting that post-initiation processes may be responsible for the gender difference in bladder tumor susceptibility. BBN is a primary metabolite of the environmental carcinogen, dibutylnitrosamine and hence a potential human carcinogen. These results provide molecular explanations to the bewildering organ and species specificity of BBN, and indicate that BBN-induced mutagenesis in the urinary bladder represents a highly appropriate model for initiation of bladder cancer, and combined with other models can help elucidate distinct steps in bladder carcinogenesis. Supported by an NYU Centers of Excellence Seed Grant.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1325. doi:10.1158/1538-7445.AM2011-1325