bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3782: Chloroquine induces defective autophagic flux and enhances pancreatic cancer cell death induced by pegylated-arginine deiminase
Authors: Daylami Rouzbeh , Virudachalam Subbulakshmi , Bold Richard J. 
Published: June 2012

Abstract
We have previously shown that a majority of human pancreatic adenocarcinomas are deficient in argininosuccinate synthetase (ASS), a key enzyme in arginine synthesis and therefore sensitive to arginine deprivation by arginine deiminase (ADI). ASS deficient cell lines undergo cell death when deprived of arginine, but also undergo autophagy. The role of autophagy and its contribution to cell death is controversial. We hypothesized that autophagy is protective in the setting of arginine deprivation and that inhibition of autophagy by hydroxychloroquine (ChQ) would increase cell death. Methods: The human pancreatic cancer cell line MIA-PaCa2 was treated in vitro and in vivo with pegylated arginine deiminase (PEG-ADI) alone or in the presence of ChQ. Cell death was measured by propidium iodide-FACS and apoptosis was evaluated by Annexin V-PI flow cytometry. Caspase 3 cleavage was evaluated by western blotting and ELISA as was expression of LC3. In vivo experiments were conducted by creation of subcutaneous xenografts in athymic mice followed by treatment with intraperitoneal injections of PBS, PEG-ADI, ChQ and combination of PEG-ADI and ChQ. At sacrifice, tumors were removed for analysis. Tumor lysates were analyzed by western blot for caspase 3 and p62. Immunohistochemistry for activated caspase 3 and DNA fragmentation (TUNEL) were also performed. Results: In vitro treatment of MIA-PaCa2 with PEG-ADI induced caspase dependent cell death as well as autophagy at 72 hours. ChQ at low doses inhibited autophagy induced by PEG-ADI, but increased cell death. In vivo, addition of ChQ to a sub-therapeutic dose of PEG-ADI increased tumor suppression decreased autophagy and increased caspase 3 activation compared to either treatment alone. Conclusion: Arginine deprivation induces autophagy and cell death in cell lines deficient in ASS. Autophagy appears to play a protective role, and its inactivation by hydroxychloroquine leads to enhanced tumor suppression.
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 3782. doi:10.1158/1538-7445.AM2011-3782
Abstract 3786: LC3B-positive autophagosomes are a common feature of solid tumors and associated with proliferation, metastasis and poor outcome
Authors: Lazova Rossitza , Camp Robert , Siddiqui Summar , Klump Vincent , Pawelek John M. 
Published: June 2012

Abstract
Interest in autophagy and cancer has surged in recent years. Autophagy provides a source of nutrients in times of metabolic stress. A paradox for autophagy in cancer is that while autophagy is a conserved pro-survival mechanism, it can also act in tumor suppression as is the case with the autophagy-associated beclin-1 protein. However, there is growing evidence supporting a pro-survival role for autophagy in tumor progression, for example in gastrointestinal tumors and invasive melanomas wherein autophagosomes are abundant. Here we expanded previous studies on autophagosomes in malignancies to include nearly 2000 pathology specimens from 20 different cancers, analyzing for associations of autophagosomes with tumor progression. Methods. Individual pathology specimens and tumor tissue microarrays (TMAs) were stained for the autophagosome marker LC3B and the proliferation marker Ki-67 through standard IHC procedures. Automated quantitative analyses (AQUA) used fluorescence-tagged antibodies. Results: In multitumor TMAs, about 85% of all tumors showed positive staining of LC3B in a granular pattern. In melanoma TMAs, LC3B was elevated in lymph node metastases. In breast carcinoma TMAs LC3B was elevated in node-positive compared to node-negative primaries and associated with increased nuclear grade, and worse patient outcome. LC3B and Ki-67 expression correlated in both melanoma and breast carcinoma (p &lt; 0.0001), indicating a strong association between autophagy and proliferation. Supporting this, mitotic figures were largely detected in LC3B-positive tumor cells. Conclusions. While it is clear that autophagy can play a tumor suppressor role in some settings, we posit that these results are most consistent with a pro-survival role for autophagy, at least in advanced malignancies. In cancer, autophagy is thought to be part of the pro-survival integrated stress response known as aerobic glycolysis or the Warburg effect whereby cells utilize glycolysis rather than aerobic respiration for ATP production. Since some 90% of malignancies constituitively express the Warburg effect and, as shown herein, a similar number express LC3B-positive autophagosomes, the results are most consistent with autophagy being an integral, active part of this response. That autophagosomes are expressed in proliferating tumor cells further supports this proposal. In any case, the widespread occurrence of autophagosomes in cancer shown herein, and by others, underscores the importance of autophagy as a target in the design of new anti-cancer therapies.
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 3786. doi:10.1158/1538-7445.AM2011-3786
Abstract 3789: Induction of autophagy increases the radiation sensitivity of head and neck cancer cells via growth arrest
Authors: Nam Hae Yun , Lee Yoon Sun , Lee Hyang Ju , Im I-Rang , Kwak Jihye , Kim Seong Who , Kim Sang Yoon 
Published: June 2012

Abstract
Autophagy is frequently activated in cancer cells resistant to various apoptotic stimuli such as ionizing radiation, which supports the premise of enhancing the efficiency of radiotherapy by interventional means of autophagy regulation. In this study, we investigated whether autophagy pathway mediates the radio-sensitizing effect in head and neck cancer cells, and how the mechanism underlying the enhanced sensitivity works in cancer cells.
The cellular responses following the ionizing radiation were examined by cell morphologic change, cell proliferation, clonogenic survival, cell cycle distribution, and expression level of several corresponding marker proteins in head and neck cancer HN-9 cells. Induction of autophagy was performed by down-regulating the mTOR signaling pathway using mTOR inhibitors such as rapamycin and PP242. Also, autophagy was inhibited by blocking the formation of autophagic vacuole (3-MA) or by disturbing the autophagosome maturation (bafilomycin A1, pepstatin A/E-46d). The change of autophagic flux was evidenced by the level of autophagy-related proteins and the morphological manifestation of autophagy. Upon exposure to radiation, the number of autophagic vacuoles was increased greatly in radiation dose- and time-dependent manners; however, the increase of apoptotic cells was not observed even in cells exposed to 12 Gy. In the meanwhile, the initial inhibition of cell cycle was maintained at slightly enhanced G1 phase. In some of the cases, it was restored to normal states, which implied that HN-9 cells adopted the mode of autophagy as a survival strategy against radiation. However, unexpectedly, further augmentation of autophagy pathway through the combination of either rapamycin or PP242 and radiation toward HN-9 cells hindered rather than enhanced clonogenic survival and cell proliferation, accompanying prolonged G1 arrest. Taken together, these results suggest that either induction of autophagy could serve as a therapeutic strategy to enhance radio-sensitivity, which is possibly due to irreversible cell cycle arrest following the excessive activation of autophagy.
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 3789. doi:10.1158/1538-7445.AM2011-3789
Abstract 379: Target delivery of multistage nanovectors to tumor-associated macrophages and endothelial cells in orthotopic model of human pancreatic cancer
Authors: Yokoi Kenji , Godin Biana , Alexander Jenolyn F. , Hu Tony , Liu Xuewu , Fidler Isaiah , Ferrari Mauro 
Published: June 2012

Abstract
Pancreatic cancer is one of the most aggressive malignancies in humans with a 1-year survival rate of 18%, and a 5-year survival rate of less than 3%. Clearly, there is an urgent need to develop novel therapies for this disease. In patients, the tumor microenviroments consist of 70 to 90% stroma tissue supporting growth, invasion and metastasis of cancer. Therefore stroma is a potential target for therapy. The stroma consists of various cellular elements, including tumor associated macrophages and endothelial cells. Identification of molecular targets overexpressed in stroma cells holds great potential for design of specific nanocarriers to attain homing of therapeutic and imaging agents to the tumor. Physico-chemical characteristics of the nanovectors greatly affect their in vivo behavior and we have recently shown that carrier geometry plays an important role in its biodistribution.
In this study, we found increased expression of CD59 in tumor associated endothelial cells as well as infiltrating cells in the stroma as compared to uninvolved pancreas in clinical specimen of pancreatic cancer patients. We explored this dual targeting effect using L3.6pl human pancreatic cancer cells implanted into the pancreas of nude mice. To produce a chronic disease with high proportion of stroma, we injected only 5 × 104 viable cells that produced visible tumors after three months (chronic disease model). Increased stroma formation was found only in the chronic disease model, but not when 1 × 106 cells were injected (acute model). In the chronic model, immunofluorescence analysis of tumor confirmed the increased expression of Ly6C, mouse homolog of CD59, in tumor associated endothelial cells as well as in macrophages in stroma. In the next experiment, we decorated the surface of porous silicon nanovectors with Ly6C antibody. Targeted nanovectors injected intravenously accumulated to tumor associated endothelial cells expressing Ly6C 15 minute after injection. At 4 hours after administration, 9.8 ± 2.3 % of injected dose/g tumor of the Ly6C targeting nanovectors accumulated in the pancreatic tumors as opposed to 0.5 ± 1.8 % of control nanovectors with non targeting antibody. Immunofluorescence analysis of tumor revealed that Ly6C targeting nanovectors were engulfed by tumor associated macrophages which also express Ly6C in stroma.
Collectively, these results suggest that Ly6C (or CD59) expressed on tumor associated endothelial cells and macrophages can serve as a novel dual target for pancreatic cancer. These experiments are on going.
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 379. doi:10.1158/1538-7445.AM2011-379
Abstract 3792: Specific amino acid restriction differentially induces autophagy in DU145 and PC3 human prostate cancer cell lines
Authors: Fu Ya-Min , Lin Huimin , Meadows Gary G. 
Published: June 2012

Abstract
We previously found that selective amino acid restriction differentially induces death of DU145 and PC3 human prostate cancer cells. Herein we examined the hypothesis that this differential cell death was associated with induction of autophagy. By detecting the immunofluorescence of microtubule-associated protein 1A/1B light chain 3 (LC3) by confocal microscopy, this study shows that selective amino acid restriction also differentially induces autophagy in DU145 and PC3 human prostate cancer cell lines.
In DU145 cells, restriction of tyrosine and phenylalanine (Tyr/Phe), glutamine (Gln), and methionine (Met) induces autophagy. Addition of pyruvate significantly increases Tyr/Phe restriction-induced autophagy and significantly reduces Met and Gln restriction-induced autophagy. All of the amino acid restrictions induce cell death in DU145 cells. Pyruvate, a major metabolite of glucose metabolism, significantly reduces Tyr/Phe and Gln restriction-mediated cell death, but not Met restriction-medicated cell death.
Tyr/Phe and Gln restriction induces autophagy in PC3 cells. Addition of pyruvate does not alter Tyr/Phe restriction-induced autophagy but significantly increases Met and Gln restriction-induced autophagy. Only Met restriction induces cell death in this cell line, and pyruvate addition reverses this effect.
In summary, the present study indicates 1) cell line specific differences between DU145 and PC3 cells in the induction of autophagy by specific amino acid restriction, 2) lack of association between induction of autophagy and cell death, and 3) differential effects of pyruvate on autophagy and cell death. (This study was supported by grant R01CA101035 from the National Cancer Institute).
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 3792. doi:10.1158/1538-7445.AM2011-3792
Abstract 3801: Rhomboid domain containing 2 (RHBDD2) over-expression is associated to colorectal cancer progression and drug sensitivity to 5-FU treatment
Authors: Lacunza Ezequiel , Croce Maria V. , Zwenger Ariel , Segal-Eiras Amada , Abba Martín C. 
Published: June 2012

Abstract
Colorectal carcinoma (CRC) is the second leading cause of death among malignancies in the world. Postoperative chemotherapy is widely accepted as the standard modality for the treatment of this disease; however 50% of patients within an oncology protocol will develop tumor metastatic dissemination. The drug 5-fluorouracil (5-FU) is one of the most commonly used agents for the treatment of CRC at early and advanced tumor stages, but clinical resistance is a major limitation. The identification of novel predictive biomarkers of resistance to 5-FU treatment would allow developing new therapies and improving the quality of life for CRC patients.
The aim of this study was to evaluate the role of RHBDD2 gene expression in human colorectal carcinogenesis and its effect on treatment with chemotherapeutic agent 5-FU. Firstly, we analyzed a dataset of 430 colorectal samples (32 healthy control, 355 primary CRC and 43 metastatic CRC) derived from two independent public available gene expression studies: Bittner et al., 2005 (GEO Acc.#GSE2109), and Sabates-Bellver et al., 2007 (GEO Acc.#GSE8671). A statistical significant increase in RHBDD2 expression was detected between normal colorectal samples and CRC specimens with and without metastasis (p&lt;0.001). In order to validate these data, we performed an immunohistochemical analysis on 140 colorectal tissue samples (5 normal tissues, 20 benign lesions and 115 colorectal carcinomas). We detected high RHBDD2 protein expression in tumor samples compared with normal and benign lesions (p&lt;0.005). Interestingly, a subset of 33 CRC specimens which were obtained from patients treated with 5-FU prior to surgery, showed a higher intensity of reaction compared with the other CRC samples (p&lt;0.001). To analyze this finding, RHBDD2 5-FU sensitivity was evaluated by Real Time quantitative RT-PCR in the colon carcinoma cell lines Colo205 and Caco-2. Cells were incubated with 5-FU (50 to 200 µM) for 48 and 72Hs. We detected a dramatic up-regulation of RHBDD2 mRNA levels in both cell lines after being exposed to 5-FU (p&lt;0.001). Furthermore, we analyzed the phenotypic effects of silencing RHBDD2 gene expression with and without 5-FU treatment in both cell lines over cell proliferation and apoptosis.
In conclusion, our findings suggest that RHBDD2 over-expression might play a role in colorectal neoplastic progression, modulating the response of colon cancer cells to 5-FU treatment. Further studies are needed to evaluate the relevance of RHBDD2 gene expression as a predictive biomarker as well as a therapeutic target to enhance drug efficacy.
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 3801. doi:10.1158/1538-7445.AM2011-3801
Abstract 3813: Metabolites as biomarkers for ovarian cancer diagnosis and treatment
Authors: Kakar Sham S. , Fong Miranda Y. 
Published: June 2012

Abstract
Ovarian cancer is the most lethal malignancy of the female reproductive track, mainly due to a lack of a reliable detection method during the early stages of this disease when it is most treatable. Currently, most cases of ovarian cancer are detected at stage IV due to a lack of symptoms. As current detection methods identify 50-60% of early stage ovarian cancer, it is important to identify novel biomarkers that are both specific and sensitive. In this study, we compared the comprehensive metabolic profile in normal, primary epithelial ovarian cancer (EOC), and metastatic tumors resulting from primary ovarian cancer (MOC) using gas chromatograph mass spectroscopy (GC/MS) or liquid chromatograph mass spectroscopy (LC/MS). Despite a small sample size, we were able to detect significant changes in energy utilization, shifting from oxidative phosphorylation to fatty acid utilization marked by increases in several fatty acids and carnitine metabolism_such as carnitine, acetylcarnitine, and propionylcartine _and by increases in fatty acid metabolism. EOC and MOC also displayed an enhanced oxidative stress response as indicated by increases in 2-aminobutyrate, phenylpyruvate, phenyllactate (PLA), and several isoforms of tocopherols. By using this method, we have also identified novel metabolites in the ovary, specifically N-acetylasparate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), for which a biological function has yet to be determined. Using these findings, potential biomarkers can be identified for both preliminary cancer diagnosis and metastatic disease progression.
Supported by NCI CA 124630 (SSK).
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 3813. doi:10.1158/1538-7445.AM2011-3813
Abstract 3816: Genetic variants within JAZF1 are associated with differential binding of androgen receptor, altered mRNA expression and risk of prostate cancer
Authors: Tarway McAnthony D. , Tang Wei , Fu Yi-Ping , Liu Luyang , Porter-Gill Patricia , Hall Jennifer , Ambs Stefan , Prokunina-Olsson Ludmila 
Published: June 2012

Abstract
Genome-wide association studies (GWAS) identified single nucleotide polymorphism (SNP) rs10486567 within the JAZF1 gene on chromosome 7p15 as being associated with increased risk of prostate cancer in individuals of European ancestry (p=2.14×10-6, Thomas, 2008; p=7.79×10-11, Prokunina-Olsson, 2010). We now examined two additional SNPs, rs7808935 and rs67152137 that are in strong linkage disequilibrium with rs10486567 (r2∼1.0) and located in a 2 Kb non-coding genomic region of intron 2 of JAZF1. By chromatin immunoprecipitation (ChIP) assays in LNCaP and DU-145 prostate cancer cell lines, we established that all three SNPs regions bind androgen receptor, but only rs7808935 increased allele-specific binding, with the risk T allele enhancing binding (1.4-fold, p=0.021). We cloned the 2Kb genomic region encoding various haplotypes of the three SNPs into a luceferase reporter assay, and discovered that the risk haplotype increased the reporter activity by 2-fold (p=6.98×10-5). mRNA expression of JAZF1 in normal prostate tissue samples was increased in carriers of the risk haplotype (1.51-fold, p=0.015, n=59). The three associated SNPs are located in large intron 2 and about 250 Kb away from JAZF1 promoter region. To further explore the molecular relationships between the three prostate-cancer associated SNPs, mRNA expression of JAZF1 and risk of prostate cancer, we are currently performing analysis of long-distance chromatin interactions that involves the associated JAZF1genomic region.
In conclusion, we hypothesize that the prostate-cancer associated variants of JAZF1 influence androgen receptor transcriptional activity and its effect on JAZF1. Our current research should identify mechanisms of how this affects JAZF1 mRNA expression and carcinogenesis.
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 3816. doi:10.1158/1538-7445.AM2011-3816
Abstract 3824: Molecular cytogenetic study of a new human rhabdomyosarcoma cell line, HS-RMS-2, with various highly- amplified DNA sequences
Authors: Taguchi Takahiro , Sonobe Hiroshi , Takaoka Eiji , Akimaru Kunihiro , Sakamoto Shuji , Shuin Taro , Daibata Masanori , Tominaga Akira 
Published: June 2012

Abstract
Molecular cytogenetic characterization was carried out on a rare pleomorphic type of the human rhabdomyosarcoma cell line, HS-RMS-2, which had been newly established in our laboratory. Conventional G-banding and multicolor-FISH (M-FISH) analyses showed that cells had a complicated chromosomal constitution. Comparative genomic hybridization (CGH) revealed seven highly amplified regions, which suggested a simultaneous amplification of several oncogenes in the same cell. The locations of highly amplified sequences were as follows; 1p36.1-36.2, 1p31-32, 1q21-31, 8q12-21, 8q24-qter, 11q12-13, 12q13-14, and 18q12-22. Reverse FISH painting, using the probe which was regenerated from long marker chromosomes by chromosome microdissection, showed that original sites of four of seven possible genes, which derived from highly amplified regions of chromosomes, located on chromosomes, 1p31-32, 11q13, 12q13 and 18q21. FISH using BAC and cosmid probes (int-2, c-jun and c-myc) which located on 11q12-13, 1p31-32 and 8q24, respectively, demonstrated that those oncogene DNA sequences were clearly amplified. By PCR, amplification of oncogenes of BCL1, BCL2, CHOP, hst-1, int-2, c-jun and c-myc were seened. Also RT-PCR analysis for gene expression showed that the genes located at 1p31-32 and 8q24 were overexpressed. These seven amplified genes may play a important role in the pathogenesis of this rare pleomorphic type of rhabdomyosarcoma.
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 3824. doi:10.1158/1538-7445.AM2011-3824