bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 952: The SCF F box protein, Skp2, is a key component of an E3 ubiqutin ligase that governs estrogen receptor ≤ stability
Authors: Zhou Wen , Sun Jun , Slingerland Joyce M. 
Published: August 2012

Abstract
Breast carcinoma is the most common cancer among women in developed countries, and about 70% of these tumors express estrogen receptor ≤ (ERα). ERα is a transcription factor and master regulator of estrogen stimulated proliferation and its expression indicates potential for response to estrogenic stimulation. A majority of ERα positive breast cancers initially respond well to selective estrogen receptor modulators (such as tamoxifen) or to aromatase inhibitors. Understanding the regulation of ERα levels and its role in transcription of estrogen driven genes is thus highy germane to breast cancer therapy. There is evidence that for many transcription factors, activation is linked to factor degradation. Moreover, estrogen stimulation is known to activate ERα proteolysis. Given the importance of estrogen as a driver of breast cancer progression, we have investigated mechanisms governing ERα proteolysis. S phase kinase-associated protein 2 (Skp2) is an F box component of a multi-protein SCF ubiquitin ligase that acts on multiple substrates. Levels of Skp2 have been reported to be inversely related with the levels of ERα in breast cancer. Here we report that SCFSkp2, comprised of Skp2, in association with Skp1, Cul1 and Rbx1, is an E3 ubiquitin ligase for ERα. Ectopic expression of dominant negative Cul1 increases ERα levels by impeding ERα degradation in breast cancer cells. Knockdown of Skp2 impairs estrogen-triggered ERα proteolysis, while ectopic Skp2 expression decreased ERα stability. We show that Skp2, Skp1, Rbx1 and Cul1 co-precipitate with cellular ERα and the formation of this ERα/SCFSkp2 complex is cell cycle regulated and parallels CDK2 activation. We also show ER is an in vitro substrate that is ubiquitylated and degraded by SCFSkp2. The involvement of CDK2-dependent ERα phosphorylation in estrogen activated ERα/SCFSkp2 binding, ERα proteolysis and the functional consequences of this on ERα transcriptional activity are under investigation. These data suggest that Skp2 plays an important role in the regulation of ERα stability, and potentially in the biologic action of this key steroid hormone receptor in breast cancer.
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 952. doi:1538-7445.AM2012-952
Abstract LB-1: Discovery and optimization of orally bioavailable, selective and potent ATP-independent Akt inhibitors
Authors: Chan Thomas C.K. , Ashwell Mark A. , Lapierre Jean-Marc , Brassard Christopher , Bull Cathy , Cornell-Kennon Susan , Eathiraj Sudharshan , France Dennis S. , Hill Jason , Koerner Steffi , Kelleher Eoin , Kizer Darin , Liu Yanbin , Link Jeff , Makhija Sapna , Moussa Magdi , Namdev Nivedita , Nicewonger Robert , Uppalapati Uma , Palma Rocio , Szwaya Jeff , Tandon Manish , Vensel David , Volak Laurie , Volckova Erika , Westland Neil , Wu Hui , Yang Rui-Yang 
Published: August 2012

Abstract
Herein we describe the implementation of a biochemical and biophysical screening strategy to discover small molecules that inhibit Akt through a mechanism distinct from ATP-competitive inhibitors. A series of novel derivatives of the core scaffold 3H-imidazo[4,5-b]pyridine were identified and optimized. These Akt inhibitors demonstrated potent inhibition of intracellular Akt and downstream targets including PRAS40 activation in vitro. Pharmacodynamic and pharmacokinetic studies in vivo demonstrated the effectiveness of the series at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice. Co-crystallization studies with un-phosphorylated Akt1 revealed that as a consequence of binding these novel, potent and selective, ATP-independent inhibitors the ATP binding cleft is occupied by non-polar residues which are associated as tight clusters. The cleft is closed with a ‘hydrophobic lock’ which may function to sterically exclude the binding of both ATP and ATP-competitive inhibitors.
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-1. doi:1538-7445.AM2012-LB-1
Abstract LB-106: A novel TCL1-Tg:p53−/− mouse model of human CLL
Authors: Liu Jinyun , Chen Gang , Feng Li , Zhang Wan , Pelicano Helene , Lu Weiqing , Amin Hesham , Keating Michael , Croce Carlo M. , Huang Peng 
Published: August 2012

Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Europe. CLL patients with loss of p53 due to chromosome 17p deletion often exhibit more malignant disease phenotype, are refractory to standard treatment, and have poor clinical outcomes. Although there are several mouse models that resemble the chronic disease processes of CLL, no animal model has been reported that mimic the aggressive disease phenotype of CLL with loss of p53. To facilitate the investigation of the biology of aggressive CLL with loss of p53 and the underlying mechanisms, we generated a mouse model with Eu-TCL1-Tg:p53−/− genotype by crossing the Eu-TCL1-Tg mice with p53 knockout mice. The Eu-TCL1-Tg:p53−/- mice developed CLL disease at 3-4 months, significantly earlier than the parental Eu-TCL1-Tg mice that developed CLL disease at 8-12 months. Flow cytometry analysis showed that the IgM+/CD5+ cell population appeared in the peritoneal cavity, bone marrow, and the spleens of Eu-TCL1-Tg:p53−/- mice significantly earlier than that of the parental Eu-TCL1-Tg mice. Massive infiltration and accumulation of leukemia cells were found in the spleen, liver, and peritoneal cavity. In vitro study showed that the leukemia cells isolated from the Eu-TCL1-Tg:p53−/- mice were more resistant to fludarabine treatment than the leukemia cells isolated from spleens of TCL1-Tg mice. Interestingly, TUNEL assay revealed that there was higher apoptotic cell death found in the TCL1-Tg spleen tissue compared to the spleens of the Eu-TCL1-Tg:p53−/- mice, suggesting that the loss of p53 compromises the apoptotic process in vivo, and this might in part explain the drug resistant phenotype of CLL cells with 17p deletion. Further molecular analysis showed that the expression of MCL-1, a key survival molecule for CLL, was significantly increased at the mRNA and protein levels in the leukemia cells isolated from Eu-TCL1-Tg:p53−/- mice, which seemed to be associated with the abnormal expression of certain microRNAs including miR15a and miR-16. Overall, the Eu-TCL1-Tg:p53−/- mice display a disease phenotypes that resemble human CLL with 17p deletion, and represent a useful animal model for mechanistic study as well as evaluation of in vivo therapeutic efficacy of anti-CLL agents.
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-106. doi:1538-7445.AM2012-LB-106
Abstract LB-154: Nuclear export of CALM-AF10 is essential for leukemogenesis
Authors: Conway Amanda E. , Scotland Paula B. , Lavau Catherine P. , Wechsler Daniel S. 
Published: August 2012

Abstract
Background: The t(10;11) chromosomal translocation gives rise to the CALM-AF10 fusion gene and is recurrently found in patients with aggressive and difficult-to-treat hematopoietic malignancies (AML and T-ALL). CALM-AF10 leukemias are characterized by upregulation of Hoxa cluster genes and a reduction in H3K79 methylation. The native AF10 protein localizes to the nucleus, while native CALM protein is found predominantly in the cytoplasm. It has been shown that the OM-LZ domain of AF10 interacts with the histone methyltransferase, Dot1L, and that this interaction is necessary for CALM-AF10-mediated transformation. Although it is known that CALM functions as an accessory endocytic protein, the precise role of CALM in leukemogenesis is unclear. Objective: To determine the role of CALM in CALM-AF10-mediated transformation in an effort to identify novel therapeutic targets. Results: Through structure-function analyses, we determined that a minimal region of CALM (aa 520-583) is critical for CALM-AF10-mediated transformation of murine hematopoietic progenitor cells (HPCs). Further analysis of this sequence identified a nuclear export signal (NES) encoded by CALM aa 544-553. The CALM NES mediates the cytoplasmic localization of CALM-AF10; point mutation of the CALM NES (NES*) results in exclusive CALM(NES*)-AF10 accumulation in the nucleus. In contrast to CALM-AF10, transduction of primary murine HPCs with CALM(NES*)-AF10 fails to cause in vitro transformation. Fusion of an 18 aa peptide that includes the CALM NES in frame with AF10 (NESCALM-AF10) is sufficient to induce transformation in vitro and leukemogenesis in vivo. Leukemias induced by NESCALM-AF10 recapitulated the phenotype of CALM-AF10 leukemias, including aberrant Hoxa cluster upregulation and decreased H3K79 methylation. Strikingly, fusion of the NES from different proteins, such as PKI-α and APC, to AF10 also conferred cytoplasmic localization and resulted in transformation in vitro. Finally, human CALM-AF10 leukemia cell lines (U937 and P31-FUJI) display increased sensitivity to a compound that inhibits nuclear export, Leptomycin B. Conclusions: We have determined that a CALM-derived nuclear export signal is both necessary and sufficient for CALM-AF10-mediated transformation. These findings reveal a novel mechanism by which nuclear export of CALM-AF10 mediates leukemogenesis. We postulate that nuclear export inhibitor (NEI) compounds may offer new therapeutic possibilities for patients with aggressive CALM-AF10 leukemias.
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-154. doi:1538-7445.AM2012-LB-154
Abstract LB-162: DNA-damage foci persistence and accelerated senescence as determinants of radiosensitization by glycolysis inhibitors
Authors: Efimova Elena V. , Labay Edwardine , Mauceri Helena J. , Darga Thomas E. , Ulanovskaya Olesya A. , Kozmin Sergey A. , Weichselbaum Ralph R. , Kron Stephen J. 
Published: August 2012

Abstract
One of the most striking characteristics of cancer cells is their altered glucose metabolism. Many cancer cells display a dramatic elevation in glucose utilization, independent of the availability of oxygen or the activity of oxidative phosphorylation. Cancers often display the Warburg effect, wherein glycolysis drives fermentation of pyruvate to lactate even under aerobic conditions. Aerobic glycolysis has been widely investigated and it is now considered a metabolic hallmark of transformation and a key driver for cancer cell proliferation, malignancy, metastasis, and therapeutic resistance. En route to cancer, pre-malignant cancer cells have to overcome cellular senescence which is recognized as a barrier for tumorigenesis. Recent data link both replicative and accelerated senescence to persistent DNA damage signals that arise from domains of modified chromatin at sites of un-repairable double strand breaks. Our prior work has established the kinetics of resolution of these chromatin domains, dubbed ionizing radiation induced foci (IRIF), and resulting effects on accelerated senescence as determinants of radiation sensitivity and as a target that can sensitize cancer cells to genotoxic therapy. To obtain probes that impinge on the DNA damage response and senescence, we developed a cell based assay for high throughput, high content screening based on the detection of IRIF persistence. Screening over 2500 drugs, including natural products and drug-like compounds identified known DNA damaging agents as well as novel candidates. To gain mechanistic insight, we tested these “hits” in combination with the mitochondrial inhibitor antimycin A and discovered several that blocked ATP synthesis. Combining bona fide glycolytic pathway inhibitors with radiation enhanced IRIF persistence and accelerated senescence in vitro. The glucokinase inhibitor 2-DG increased IRIF persistence and senescence after irradiation of tumor xenografts. These data suggest a critical role for aerobic glycolysis in the proliferation and survival of cancer cells to prevent stress-induced premature senescence, specifically by blocking the formation of DNA damage foci and/or preventing their persistence. Rather than simply satisfying energy needs, aerobic glycolysis likely serves an important survival and immortalization function for cancer cells. As such, targeting the Warburg effect to promote cancer cell senescence appears to be an attractive strategy for therapeutic intervention, particularly in combination with genotoxic 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-162. doi:1538-7445.AM2012-LB-162
Abstract LB-163: Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells
Authors: Tamada Mayumi , Suematsu Makoto , Saya Hideyuki 
Published: August 2012

Abstract
An increased glycolytic flux accompanied by activation of the pentose phosphate pathway (PPP) is implicated in chemoresistance of cancer cells. In this study, we found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia. CD44 ablation by RNA interference increased metabolic flux to mitochondrial respiration and concomitantly inhibited entry into glycolysis and the PPP. Such metabolic changes induced by CD44 ablation resulted in marked depletion of cellular reduced glutathione (GSH) and increased the intracellular level of reactive oxygen species (ROS) in glycolytic cancer cells. Furthermore, CD44 ablation enhanced the effect of chemotherapeutic drugs in p53-deficient or hypoxic cancer cells. Taken together, our findings suggest that metabolic modulation by CD44 is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance.
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-163. doi:1538-7445.AM2012-LB-163
Abstract LB-168: A hexane fraction of American ginseng suppresses colon cancer associated with colitis
Authors: Poudyal Deepak , Cui Xiangli , Hofseth Anne B. , Chumanevich Alena , Chumanevich Alexander A. , Wargovich Michael J. , Windust Anthony , Nagarkatti Mitzi , Nagarkatti Prakash , Hofseth Lorne J. 
Published: August 2012

Abstract
Patients with Ulcerative Colitis (UC) have a high risk of colon cancer. We have recently shown American Ginseng (AG) suppresses colitis, and prevents colon cancer in mice. In the present study we isolated a Hexane Fraction of AG and found this to have particularly potent anti-oxidant and pro-apoptotic properties. The Hexane Fraction of AG was effective in inducing apoptosis of human epithelial colon cancer cell, HCT-116 and inflammatory cells. As well, this fraction was shown to suppress azoxymethane (AOM)/DSS-induced colon cancer. We performed two studies with mice: a short term (Day 35) and long term (Day 50) cancer prevention study. Mice fed the Hexane fraction of AG had significantly less inflammatory and ulcerative lesions, as well as cancerous lesions compared with the vehicle-treated group in both the short and long-term cancer prevention studies. Results are consistent with the hypothesis that the Hexane fraction of AG has anti-inflammatory and anti-cancer properties, and prevents the progression of colon cancer in AOM/DSS mouse model. Interestingly, at Day 35, following isolation of CD45- epithelial cells from colons of mice treated with either AOM+DSS+Vehicle or AOM+DSS+Hexane fraction of AG, there was a 24% increase in the putatative tumor suppressor miRNA-16 with treatment with the Hexane fraction of AG. When looking at putative miRNAs with oncogenic properties (miRNA-21 and -155), levels were decreased in epithelial cells by 25% and 12% respectively in the Hexane fraction of AG-treated mice. This study provides additional pre-clincal data, and mechanistic studies that support the possible use of this complementary and alternative medicine in the treatment of colitis, and the prevention of colon cancer associated with colitis.
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-168. doi:1538-7445.AM2012-LB-168
Abstract LB-170: A role of sphingosine kinase 1 in peritoneal macrophages on the early stages of colon carcinogenesis
Authors: Kawamori Toshihiko , Furuya Hideki , Shimizu Yoshiko , Yamada Paulette M. 
Published: August 2012

Abstract
Our previous studies indicate that the Sphingosine kinase 1 (SphK1)/Sphingosine 1-phosphate (S1P) pathway mediates colon carcinogenesis at least by regulating COX-2 expression and prostaglandin E2 (PGE2) production. However, the mechanisms by which this pathway regulates colon carcinogenesis are still unclear. First, we show that SphK1 deficient mice significantly attenuated azoxymethane (AOM)-induced colon carcinogenesis as measured by colon tumor incidence, multiplicity, and volume. We found that AOM activates peritoneal macrophages to induce SphK1, COX-2, and TNF-α expression in WT mice. Interestingly, SphK1 KO mice revealed significant reduction of COX-2 and TNF-α expression from AOM-activated peritoneal macrophages, suggesting that SphK1 regulates COX-2 and TNF-α expression in peritoneal macrophages. Finally, we found that inoculation of WT peritoneal macrophages “rescued” the carcinogenic effect of AOM in Sphk1 KO mice as measured by aberrant crypt foci (ACF) formation, preneoplastic lesions of colon cancer, indicating that SphK1 expression in peritoneal macrophages is required in the early stages of colon carcinogenesis when induced by AOM. These results suggest that SphK1 expression plays a pivotal role in the early stages of colon carcinogenesis through regulating COX-2 and TNF-α expression from activated peritoneal macrophages.
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-170. doi:1538-7445.AM2012-LB-170
Abstract LB-271: Loss of the transcription factor REST promotes breast cancer tumorigenicity in a LIN28-dependent manner
Authors: Gunsalus Kearney T. W. , Wagoner Matthew P. , Meyer Kassondra M. , Potter Wyatt B. , Kim Soyoung , Schoenike Barry , Alexander Caroline M. , Freidl Andreas , Roopra Avtar 
Published: August 2012

Abstract
About 20% of the nearly 300,000 American women diagnosed with breast cancer this year will have a particularly aggressive form of the disease characterized by a lack of the transcription factor REST. These “RESTless” tumors are associated with particularly poor patient prognosis; 50% of patients with RESTless tumors experience disease recurrence within the first three years post-diagnosis, compared with less than 20% of patients whose tumors still express REST. Here, we use cell culture and xenograft models of RESTless breast cancer to demonstrate that REST loss causes the increased aggression of these tumors. Using lentiviral delivery of shRNAs, we generated several breast cell lines with a stable REST knockdown (“RESTlow” cells; a non-targeting shRNA was used to generate control “RESTnorm” cells). We find that REST knockdown increases focus formation in MCF10A, MCF7 and MDA-MB-231 cells. RESTlow MCF10A and MCF7 cells also show enhanced anchorage-independent growth in soft agar. We performed xenograft experiments with RESTlow and RESTnorm MCF7 cells; the RESTlow cells have a greatly enhanced capacity to form tumors in nude mice. We further explore the molecular mechanism underlying the tumorigenicity of cells lacking REST. We demonstrate that REST is a direct transcriptional repressor of the RNA binding protein LIN28 in breast cancer cell lines; as predicted, LIN28 expression is increased upon REST knockdown. Knockdown of LIN28 in RESTlow cells ablates the ability of RESTlow MCF7 cells to form foci in culture, colonies in soft agar, and tumors in nude mice. We therefore conclude that the aberrant upregulation of LIN28 that occurs when REST is lost is required for the tumorigenicity of RESTlow cells. Finally, we show that in human RESTless breast tumors, LIN28 expression is significantly increased. This is the first report to demonstrate that REST loss causes increased tumor aggression and to propose an underlying mechanism for the tumorigenicity of cells lacking REST.
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-271. doi:1538-7445.AM2012-LB-271
Abstract LB-310: Changes in the gene expression profile of A375 human melanoma cells induced by over-expression of multifunctional pigment epithelium-derived factor
Authors: Jimenez Benilde , Orgaz Jose L. 
Published: August 2012

Abstract
Pigment epithelium-derived factor (PEDF) is a broad-spectrum angiogenesis inhibitor that displays potent anti-metastatic activity in multiple tumor types. We have previously shown that PEDF prevents primary tumor growth and metastatic spread of human melanoma in mouse experimental models. Consistent with these observations, PEDF expression is lost at the late stages of melanoma progression, allowing melanoma cells to become angiogenic, migratory and invasive. PEDF's ability to modify the interplay between the host and tumor tissues strongly supports its use as a therapeutic agent for the treatment of metastatic melanoma. However, transition to the clinic requires a more detailed knowledge of the molecular mechanisms underpinning PEDF's activity. In this study we describe changes in the gene expression profile of A375 human melanoma cells induced by PEDF over-expression. PEDF modulated diverse categories of genes known to be involved in angiogenesis and migration. It downregulated cytokines like interleukin 8 and extracellular matrix proteins like collagen IV, while it upregulated fibronectin. Multiple transcripts previously described as contributing to the acquisition of malignant phenotype by melanoma were also diminished by PEDF over-expression, among which we validated galectin 3 and jagged 1. Additionally, PEDF downregulated S100β and melanoma inhibitory activity (MIA), which are widely used in the pathological diagnosis of melanoma. Interestingly, PEDF increased the expression of melanophilin and decreased rab27A, which are relevant targets for melanosome transport; suggesting that PEDF could directly impinge on melanocytic lineage-specific processes. Our study identifies new molecular targets and signaling pathways that may potentially contribute to determine PEDF's ability to restrict the aggressiveness of A375 human melanoma cells.
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-310. doi:1538-7445.AM2012-LB-310