bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3770: tRNA-mediated regulation of nutrient-responsive pathways in breast cancer cell
Authors: Huynh Le-Nguyen , Neil Maria , Muthusamy Thangavel , Luu Hiep , Nair Devi , Ibba Mette P. 
Published: June 2012

Abstract
Autophagy or macroautophagy plays a crucial role in the survival of metabolic-stressed tumor cells by providing sufficient intracellular nutrients and energy to sustain growth. Cancer cells experiencing nutritional stress take advantage of the autophagic pathway to maintain viability. When cells experience nutritional stress, the activity of the serine/threonine kinase mTOR is downregulated, leading to reduced protein synthesis and subsequently increased autophagy. Under these conditions tRNAs, which are essential components of the protein synthesis machinery, accumulate in the nucleus. Cancer cells are often nutrient-starved, yet they still grow and proliferate, which indicates that sufficient amino acid-charged tRNAs are present in the cytosol to support protein synthesis. Our studies in human fibroblasts have shown that accumulation of tRNA in the nucleus, caused by reduced expression of the tRNA-transporting karyopherin Xpo-t, induces a starvation-like response, i.e. activity of the mTOR1C1 pathway is reduced and autophagy upregulated. Thus, we hypothesize that nuclear accumulation of tRNA signals cellular starvation.
In this work, we aim to determine if tRNA accumulation in the nucleus, accomplished by reduced expression of tRNA transporting karyopherin Xpo-t, induces a starvation response in breast cancer cells. Using MDA-MB-231 breast cancer cells as a model system for our in-vitro studies, we have shown significant response to nutrient starvation with regard to autophagy. We are currently analyzing if shRNA-mediated knockdown of Xpo-t in MDA-MB-231 cells triggers a starvation-response. Subsequently, we will determine if starvation in combination with Xpo-t knockdown lead to upregulation of autophagy and reduction of mTOR to such level that induces cancer cell death. Additional studies will be done to examine such response in other breast cancer cells and will be presented.
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 3770. doi:10.1158/1538-7445.AM2011-3770
Abstract 3771: Identification of novel small molecule inhibitors of the inducible heat shock protein Hsp70
Authors: Balaburski Gregor M. , Leu Julie , Hayik Seth A. , Andrake Mark , Dunbrack Roland , George Donna , Murphy Maureen E. 
Published: June 2012

Abstract
The stress induced molecular chaperone Hsp70 has a role in protein folding, assembly of multi-protein complexes and transport of proteins across membranes. Overall, this protein possesses significant cytoprotective and anti-apoptotic functions. High levels of Hsp70 can be found in many cancers, and these are associated with resistance to radiation and chemotherapy. Not surprisingly, overexpression of Hsp70 is generally a marker of poor patient prognosis. These combined data suggest that Hsp70, in addition to being a potential tumor prognostic marker, may also be a desirable molecular therapeutic target. 2-phenylethynesulfonamide (PES) was previously identified as a compound that inhibits apoptosis in thymocytes, by virtue of its ability to inhibit the direct p53 mitochondrial pathway. However, the mechanism of action of PES remained unknown. We recently demonstrated that PES specifically interacts with Hsp70, disrupts the interaction between Hsp70 and its co-chaperones and client proteins, and inhibits Hsp70 function at the lysosome. We further showed that PES exhibits selective toxicity to transformed cells by virtue of its ability to inhibit autophagy, a key survival pathway utilized by tumor cells. Here-in we report that we have used deletion mapping and molecular modeling to elucidate the domain of Hsp70 that interacts with PES. Additionally, to further elucidate the mechanism of action of PES, we generated and tested several analogues of PES. We find that the ability of PES to induce the death of tumor cells consistently correlates with its ability to inhibit autophagy. Further, we identified one analogue that has superior ability to induce programmed cell death in tumor cells. We are currently analyzing the efficacy and mechanism of action of this analogue in pre-clinical models.
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 3771. doi:10.1158/1538-7445.AM2011-3771
Abstract 3774: A novel drug discovery assay for analyzing autophagy in living cells
Authors: Shen Dee , Chan Eric , Pande Praveen , Coleman Jack , Patton Wayne F. 
Published: June 2012

Abstract
Autophagy is a normal degradative pathway that involves the sequestration of entire organelles, protein complexes, and misfolded proteins in a membrane vacuole called the autophagosome. The autophagosomal vesicle is subsequently delivered to the lysosome where it is degraded into its essential constituents and recycled back to the cytoplasm. Autophagy plays an important role in diverse biological events, not only during conditions of nutrient limitation, but it also functions in tumor suppression, the immune response, and the prevention of certain types of neurodegeneration. However, experimental methods to monitor this process in mammalian cells are limited due to lack of autophagic markers. Recently, LC3, a mammalian homologue of the ubiquitin-like (UBL) protein Atg8, has been used as a specific marker of autophagosomes in mammals. However, current methods to quantify autophagic activity using LC3 are time-consuming and labor-intensive. We have developed and validated a novel cell-based autophagy assay using a 488 nm-excitable green-emitting fluorescent probe to highlight the various vacuolar components of the autophagy pathway. We demonstrated that the accumulation of autophagy probe was specifically induced by amino acid deprivation and was inhibited by 3-methlyadenine, a classical inhibitor of the autophagic pathway. Furthermore, a population of this dye-labeled vesicle co-localizes with LC3. We have validated this fluorescent probe with a wide range of conditions known to modulate autophagy pathways. The assay is compatible with flow cytometry, allowing, for the first time, easy quantitation of autophagy. This assay enables kinetic analysis of the autophagy pathway and is able to distinguish between increases in autophagic flux vs. autophagic vacuole accumulation.
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 3774. doi:10.1158/1538-7445.AM2011-3774
Abstract 3779: ARHI-induced autophagy is mediated through activation of FoxO3a and induction of its target genes to promote the formation of autophagic complexes
Authors: Liao Warren S. , Lu Zhen , Gao Fengqin , Yang Maojie , Bast Robert C. 
Published: June 2012

Abstract
The role of autophagy in oncogenesis remains ambiguous and the mechanisms that induce autophagy and regulate its outcome in human cancer are poorly understood. ARHI (DIRAS3), a Ras-related tumor suppressor, is downregulated in &gt;60% of ovarian cancers. Re-expression of ARHI in ovarian cancer cells induces autophagy in culture and in xenografts, by blocking Ras activation and inhibiting PI3 kinase activity. ARHI also participates directly in the formation of autophagosomes by upregulating Atg4 and co-localizing with processed LC-3 II. Here we show that inhibition of PI3 kinase/Akt signaling and Ras activation by ARHI is mediated, in part, by down regulation of EGFR expression and EGFR phosphorylation. Inhibition of these signaling pathways reduced phosphorylation of FoxO3a and enhanced nuclear accumulation of FoxO3a transcription factor, resulting in increased transcription of Atg4, MAP-LC-3, and PUMA. Knockdown of FoxO3a by siRNA reduced ARHI- and rapamycin-induced autophagy. Whereas ARHI inhibits Class I PI3K activity, its expression induces Class III PI3K activity and contributes to the enhanced autophagy. Thus, ARHI-induced autophagy is through activation of the transcription factor FoxO3a, which increases the expression of several autophagy-related genes that contribute to the formation of the autophagic complexes.
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 3779. doi:10.1158/1538-7445.AM2011-3779
Abstract 3784: HMGB1 affects plasma amino acid profiles in colon carcinogenesis
Authors: Kuniyasu Hiroki , Luo Yi , Ohmori Hitoshi , Fujii Kiyomu , Sasahira Tomonori , Chihara Yoshitomo , Yoneda Junya , Shimbo Kazutaka , Eto Sachise 
Published: June 2012

Abstract
Alteration of the plasma free amino acid profile was reported to be a potential marker of colorectal cancer and breast cancer. The plasma amino acid profile has been reported as a relevant marker for early detection of colorectal cancer (Okamoto N et al. Int J Med Med Sci, 2009). In the present study, we examined the plasma amino acid profile as a marker for evaluating colon cancer risk. The amino acid profiles were examined in the mouse plasma using DMH-induced C57BL6 mouse colon carcinogenesis model. The plasma amino acid profiles of DMH-treated mice were different from that in control mice. Importantly, the plasma amino acid profile at procarcinogenic phase was also distinguished from the control. We focused on HMGB1, which was timely increased in serum and colon mucosa of the DMH-treated mice. In HMGB1-adeministrated mice, the plasma amino acid profiles showed a resemble pattern with that in the procarcinogenic phase mice. Decrease of most amino acids in the liver and skeletal muscle suggested an increase of catabolism in HMGB1-treated mice. In the mouse liver and muscle tissues, HMGB1 decreased pyruvate kinase M1 expression, and tetrazolium desoxydation, whereas lactate production was not increased. HMGB1 decreased phosphorylation levels of mTOR and increased protein levels of Beclin1 and LC3 in mouse liver and muscle tissue, whereas a mitochondrial marker, Diablo was not affected. Inhibitor of p38 MAPK abrogated HMGB1-induced autophagy signals. These findings suggest that HMGB1 affects energy production in mitochondria and activates autophagy signals, which might induce protein degradation and subsequent alteration of plasma amino acid profiles. The change of the plasma amino acid profiles might be a key finding detecting procarcinogenic status of the colon.
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 3784. doi:10.1158/1538-7445.AM2011-3784
Abstract 3794: BAX maintains mitochondrial bioenergetics in colon cancer cells
Authors: Boohaker Rebecca J. , Zhang Ge , Carlson Adina L. , Nemec Kathleen N. , Khaled Annette R. 
Published: June 2012

Abstract
The dual functionality of the tumor suppressor, BAX, is implied by the non-apoptotic functions of other pro-apoptotic BCL-2 family proteins. To explore this, the mitochondrial morphology and ATP producing capability in both BAX-containing and BAX-deficient HCT-116 colon cancer cells were examined. While BAX deficient cells maintain the same mitochondrial mass as their BAX containing counterparts, these mitochondria were visibly smaller, more compact, and unable to maintain an organized network. Oxygen consumption and ATP levels were also reduced in these cells, a phenomenon that was replicated upon treatment of BAX-containing cells with the uncoupling agent, FCCP. These results, coupled with a marked decrease in citrate synthase activity, suggested that cells lacking BAX have a deficiency in the ability to generate ATP through oxidative phosphorylation. Inhibition of endogenous BAX through treatment with small interfering RNAs reinforced the necessity of BAX activity in the maintenance of aerobic respiration and the production of ATP. An examination of the localization of full length and C-terminal truncated BAX in non-apoptotic, BAX deficient cells, indicated that a small fraction of the existing cytosolic BAX is needed at the mitochondrial membrane to maintain ATP production. However, this function is not dependent upon the C-terminal helix. Co-expression of BAX and BCL-2 resulted in a subsequent loss of ATP production, implying that, even under non-apoptotic conditions, an antagonistic interaction exists between the two proteins. These findings infer that a basal amount of BAX associated with the mitochondria is necessary to maintain mitochondrial bioenergetics. The discovery of this novel, non-apoptotic role for BAX in the maintenance of ATP synthesis and suggests that complete abrogation of BAX would be detrimental to cancer cells dependent on energy production via aerobic respiration.
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 3794. doi:10.1158/1538-7445.AM2011-3794
Abstract 3803: Potential role of multidrug resistance associated protein (MRPs) in hypoxia-induced drug resistance of non-small cell lung cancer cells (H460)
Authors: Chen Yu-Lun , Chang Chia-Lun , Lin Li-Chiung , Hsueh Chi-Mei 
Published: June 2012

Abstract
H460 is a non-small cell lung cancer (NSCLC) cell with multidrug resistance (MDR) against a variety of anti-cancer drugs such as cisplatin and transforming growth factor-beta (TGF-beta). It has been reported that hypoxia can trigger the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and the subsequent production of P-glycoprotein (P-gp, the archetype of MDR associated proteins or MRPs) that eventually lead to chemotherapeutic resistance of various cancer cell lines as well as NSCLC patients. The primary concern of this study was to know would hypoxia promote drug resistance of H460 cells via MRPs (MRP1 and MRP3). The experimental strategies applied were to evaluate the hypoxic impacts upon: 1) the drug resistance of H460 cells against doxorubicin (DOX, a commonly used chemotherapeutic drug in many cancer treatments), using MTT assay; 2) the expression of MRP1, MRP3 and HIF-1alpha of H460 cells in the absence or presence of DOX, using Western blot analysis; 3) the intracellular accumulation of DOX in H460 cells, using flow cytometry. The current results showed that DOX triggered a dose- and time-dependent cell death of H460. A hypoxia-induced DOX resistance was observed in H460 cells. Western blot analysis further showed that DOX-decreased MRP1 was further exacerbated under hypoxic condition that precluded the possible involvement of MRP1 in hypoxia-induced drug resistance. DOX on contrary increased the expression of MRP3. The potential contribution of MRP3 to hypoxia-induced DOX resistance and its role in pumping out of DOX from H460 cells are currently investigated in our laboratory. Finally, hypoxia-induced HIF-1alpha remained still high in the presence of DOX, suggesting a potential role of HIF-1alpha in promoting the DOX resistance of H460. Results from the study can uncover the molecular mechanisms underneath hypoxia-induced DOX resistance of H460 that consequently can lead to therapeutic target(s) for treatment of NSCLC cells (H460).
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 3803. doi:10.1158/1538-7445.AM2011-3803
Abstract 3809: TMPRSS2-ERG gene fusion is strongly associated with elevated androgen receptor expression in early prostate cancer
Authors: Minner Sarah Jane Pauline , Sirma Hueseyin , Simon Ronald , Krohn Antje , Burandt Eike , Tennstedt Pierre , Becker Michael , Schlueter Hartmut , Graefen Markus , Huland Hartwig , Schlomm Thorsten , Sauter Guido 
Published: June 2012

Abstract
Introduction and Objective: About 50% of prostate cancers have TMPRSS2-ERG fusions resulting in ERG overexpression. The aim of this study was to determine whether prostate cancer of “fusion-type” differs from “non-fusion” prostate cancer both clinically and molecularly.
Methods: A prostate cancer tissue microarray (TMA) consisting of over 2,500 cancer samples was analyzed for ERG protein expression and TMPRSS2-ERG gene fusion by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Results were compared with tumor phenotype, clinical outcome, and molecular features previously determined in studies using the same TMA. Furthermore, a fresh frozen prostate cancer TMA containing 41 “fusion-type” and 21 “non-fusion” prostate cancers was analyzed by MALDI (Matrix Assisted Laser Desorption/Ionisation) mass spectrometric imaging, a technology analyzing proteomic patterns directly on tissue sections. Functional analyses included comparisons of androgen receptor (AR) mRNA levels in LNCaP cells before and after induced ectopic ERG overexpression through lentiviral vectors.
Results: Detectable ERG protein expression was found in 52% of 2818 interpretable cancers on our TMA and TMPRSS2-ERG fusion was observed by FISH in 42% of 947 interpretable cases. The data did not reveal any clinical or prognostic significance of ERG protein expression and TMPRSS2-ERG fusion. However, several molecular features differed between “”fusion-type” and “non-fusion” prostate cancers, including AR, AMACR, Annexin A3, Bcl2, CD10, CD166, Chromogranin A, EGFR, HER2 and mTOR. The strongest difference was found for AR expression, which was considered strong in 62.9% of ERG negative but in 81.0% of ERG positive cancers. In the LNCaP cell line, ectopic ERG overexpression lead to a marked downregulation of androgen receptor dependent transcription. MALDI imaging identified several additional masses that differed significantly between “fusion-type” and “non-fusion” tumors.
Conclusions: There is no particular clinical behavior of “fusion-type” and “non-fusion” cancers in surgically treated patients. The TMPRSS2-ERG fusion determines a distinct subgroup of prostate cancers, which strongly differ on the molecular level as detected by immunohistochemistry and MALDI imaging. Furthermore, our data indicate that ERG modulates the transcription of AR-dependent genes in prostate 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 3809. doi:10.1158/1538-7445.AM2011-3809
Abstract 3817: Chromosome specific telomeres and breast cancer risk
Authors: Zheng Yun-Ling , Zhou Xin , Loffredo Christopher A. , Shields Peter G. , Sun Bing 
Published: June 2012

Abstract
Although telomere dysfunction is a characteristic of breast cancer cells, the relationship between deficiency on individual chromosomal telomeres in normal somatic cells and breast cancer risk has not been characterized. A case-control study was conducted to examine the associations between individual lengths of 92 telomeres in the human genome and the risk of breast cancer in 204 newly diagnosed breast cancer patients and 236 healthy controls. Chromosome arm-specific telomere lengths were measured by telomere quantitative fluorescent in situ hybridization (TQ-FISH). Unconditional logistic regression was used to estimate the risk associations. This genome-wide screen identified that shorter telomere lengths on chromosome Xp and 15p were associated with breast cancer risk in premenopausal women, with adjusted odds ratios (aOR) of 2.5 (95% CI = 1.3, 4.8), and 2.6 (1.3, 5.0), respectively. The study also revealed that greater length differences between homologous telomeres on chromosome 9p, 15p and 15q were associated with breast cancer risk in premenopausal women, with aORs of 4.6 (2.3, 9.2), 3.1 (1.6, 6.0), and 2.8 (1.4, 5.4) respectively. When the subjects were categorized into quartiles, a dose response relationship was observed for all of the above telomeres (P-for-trend &lt; 0.005). This study revealed that telomere deficiencies on chromosome 9p, 15p, 15q and Xp were associated with breast cancer risk in premenopausal women. If confirmed in future studies, chromosomal arm-specific telomeres are likely to be a useful panel of blood-based biomarkers for breast cancer risk assessment, given their strong associations with breast cancer risk.
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 3817. doi:10.1158/1538-7445.AM2011-3817
Abstract 3820: Deregulation of KEAP1-NRF axis in phenotypically type 2 papillary renal cell carcinoma
Authors: Ooi Aikseng , HM Bernice Wong , Wong JingChii , Perrier-Trudova Victoria , Petillo David , Roossien Douglas , Zhang Zhongfa , Tan Min-Han , Zhou Ming , Yang Ximing , Richard Stéphane , Teh Bin Tean , Furge Kyle A. 
Published: June 2012

Abstract
Type 2 papillary renal cell carcinoma (PRCC2) is an aggressive subtype of kidney cancer that has no known effective treatment modality. The hereditary form of the tumor is known to associate with the loss of fumarate hydratase (FH) gene function. However, FH gene mutation has yet to be found in sporadic PRCC2. Herein, we report the overexpression of antioxidant response element (ARE) controlled genes as a common feature that is shared between the hereditary and sporadic form of PRCC2. We demonstrate that fumarate stabilizes NRF1 and NRF2, which drive the upregulation of ARE controlled genes. We propose that fumarate stabilizes NRF1 and NRF2 through direct suppression of KEAP1. This finding better explains the phenotypical differences that are apparent between PRCC2 and CCRCC and may lead to the development of an effective therapeutic against PRCC2.
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 3820. doi:10.1158/1538-7445.AM2011-3820