bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5049: Functional significance of L1CAM in non-small cell lung cancer
Authors: Hai Josephine , Radulovich Nikolina , Zhu Chang-Qi , Der Sandy D. , Jurisica Igor , Tsao Ming-Sound 
Published: February 2011

Abstract
Background: Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers. Early stage NSCLC patients are treated by complete surgical resection, but the 5-year survival rate remains relatively poor at 50%. Deaths are mainly due to metastatic recurrence. Post-surgery (adjuvant) chemotherapy may significantly improve survival, but improved selection methods for patients who are most likely to benefit from the adjuvant treatment are required. Our laboratory has recently identified a 15-gene expression signature capable of classifying patients based on risk of death and at the same time predicting benefits of adjuvant chemotherapy in high-risk patients (J Clin Oncol 26: 2008, May 20 suppl; abstr 7510). We hypothesize that genes whose expression are de-regulated significantly in patients with a poor prognosis may play important roles in tumorigenesis and metastasis. Our goal is to functionally characterize the roles of these prognostic genes in the growth and metastatic potential of NSCLC. One of these signature genes is L1CAM, a cell adhesion molecule. Although extensively characterized in the nervous system, the role of L1CAM in NSCLC has not been defined.
Methods: We stably modified the expression of L1CAM at both the RNA and protein levels in NSCLC cell lines using the lentiviral cDNA/shRNA system. In vitro matrigel assays were used to assess invasion and cell migration by wound-healing assays.
Results: Downregulation of L1CAM expression resulted in decreased invasiveness and motility of metastatic NSCLC cell lines. In contrast, loss of L1CAM did not alter the growth rate on plastic. Studies on anchorage-independent growth and in vivo tumorigenicity and metastatic potential are ongoing and the results will be presented.
Conclusion: Considering the importance of migratory phenotype in the first steps of metastasis, the results suggest that L1CAM contributes to malignancy in NSCLC and may be a novel therapeutic gene for this disease. (Supported by Canadian Cancer Society Research Institute grant #020527)
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 5049.
Abstract 5050: Functional characterization of a newly identified growth regulatory gene SKCG-1 in human kidney cancer
Authors: Singh Kamaleshwar P. , Sarkar Shubhashish , Roy Deodutta 
Published: February 2011

Abstract
The mechanism of human kidney cancer development is not completely understood. Recently, we have identified a new growth regulatory gene, SKCG-1 and its expression was found to be decreased or lossed in human Wilms tumor. The objective of this study was to further characterize this gene and determine whether it has growth inhibitory function in human kidney cancer. The role of DNA hypermethylation in the inhibition of SKCG-1 expression in tumorigenic kidney epithelial cells was investigated by 5′-aza-2′-deoxycytidine (demethylating agent) treatment. The role of SKCG-1 in cell growth was tested by both, silencing its expression in normal cells, and overexpressing it in tumorigenic kidney epithelial cells. Reactivation of SKCG-1 transcripts in 5′ Aza-2′-deoxycytidine -treated HEK293 cells as compared to the untreated HEK293 cells suggest the hypermethylation as one of the causes for loss of SKCG-1expression in human kidney cancer cells. Colony formation assay revealed that ectopic expression of SKCG-1 suppresses the growth of tumorigenic HEK293 cells. Small interfering RNA (siRNA)-mediated silencing of SKCG-1 in HEK293 resulted in increased cell growth and this was further confirmed by increased DNA synthesis as revealed by Brdu assay. Silencing of SKCG-1 also resulted in increased expression of cell cycle gene CyclinD1 and decreased expression of P53. Immunocytochemical staining of SKCG-1 confirmed its localization in the nuclear membrane. Immunohistochemical staining further confirmed the loss of SKCG-1 expression in human kidney tumors (RCC) and its presence in surrounding normal human kidney tissue. These results suggest that the presence of SKCG-1 inhibits the growth of cancer cells and its absence allows the growth of cancer cells. The findings of this study further support the tumor suppressor role of SKCG-1 in kidney cancer. Therefore, the restoration of SKCG-1 function and its signaling pathway(s) represents a possible therapeutic target in kidney cancer.
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 5050.
Abstract 5058: Phosphatase Nuclear Targeting Subunit (PNUTS) is phosphorylated by AKT kinase
Authors: Krucher Nancy A. , Perry Brittany , Lentine Brandon , Dzaferovic Violeta , Cardoso Filipa 
Published: February 2011

Abstract
Phosphorylation of the tumor suppressor protein, Retinoblastoma (Rb) is associated with a highly proliferative state of the cell and cancer. Rb phosphorylation state is partly controlled by the activity of Protein Phosphatase 1 (PP1) which is regulated by Phosphatase Nuclear Targeting Subunit (PNUTS). It is likely that PNUTS plays a role in cell survival and/or apoptosis because siRNA mediated knockdown of PNUTS causes apoptosis in breast and colon cancer cells. This occurs through activation of PP1 phosphatase activity toward Rb which leads to Rb dephosphorylation which can trigger apoptosis. Here we show that PNUTS may be regulated by the PI3K-AKT pathway which has been shown to be involved in many cellular functions including proliferation, growth and survival. In addition, signaling in this pathway has been shown to be disrupted in several cancers. In response to a sub-lethal dose of UV radiation of HCT116 colon cancer cells, activation of the AKT kinase occurs, with phosphorylation of known AKT substrates GSK-3 and mdm2 observed. Phosphorylation of Ser473 of AKT further verifies AKT activation. Under these conditions PNUTS is phosphorylated by the AKT kinase. Inhibition of PNUTS phosphorylation occurs when cells are treated with the LY294002 PI3K-AKT pathway inhibitor. Thus PNUTS is a putative substrate of AKT, and may play an important role in the survival of cells in response to stress.
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 5058.
Abstract 5061: Induction of B cell acute lymphoblastic leukemia by BCR/ABL requires c-Myb and its activation of Bmi-1
Authors: Waldron Todd J. , Soliera Angele R. , Zhang Ying , Martinez Robert , Hyslop Terry , Bender Timothy , Calabretta Bruno 
Published: February 2011

Abstract
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL), carrying the e1a2 fusion BCR/ABL oncogene, is typically an aggressive B cell leukemia, often resistant to current treatment options. The transcription factor c-Myb plays a critical role in B cell development, but its role in B cell leukemia is unknown. To study the role of c-Myb in BCR/ABL-induced lymphoblastic leukemia, we compared disease induction, latency and survival in mice expressing the BCR/ABL transgene in a c-Myb knockout versus a wild-type background. BCR/ABL+Myb+/− mice show a distinct leukemia-resistant phenotype, whereas, BCR/ABL+Myb+/+ mice exhibit rapid induction of disease with shortened survival. Using microarray analysis to examine differential gene expression, we have identified putative downstream targets of c-Myb which play a role in leukemogenesis. Subsequent use of gene overexpression, RNAi for target gene knockdown and chIP have identified the polycomb gene, Bmi-1, as a target of c-Myb transactivation. Furthermore, inhibition of the p19ARF tumor suppressor, a Bmi-1 target, may be essential to the induction of ALL by BCR/ABL. In this report, we describe the essential role that c-Myb and its activation of Bmi-1, play in BCR/ABL-induced leukemogenesis.
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 5061.
Abstract 5062: Rac1 signaling is up-regulated in normal tissue adjacent to recurrent respiratory papillomas
Authors: Lucs Alexandra V. , Wu Rong , Symons Marc H. , Abramson Allan L. , Steinberg Bettie M. 
Published: February 2011

Abstract
Recurrent respiratory papillomas, caused by human papillomavirus infection, are benign tumors that block the airway and have significant potential for malignant conversion. Previously we have shown that the epidermal growth factor receptor (EGFR) is overexpressed in papillomas. This overexpression leads to the activation of a novel signaling pathway involving increased expression of the Rho-family member GTPase Rac1, activation of the p38 mitogen activated kinase and increased expression of cyclooxygenase 2 (COX-2). This pathway is not activated in normal laryngeal epithelial tissue samples from individuals without the disease, but is constitutively active in papilloma tissue. Here we have investigated the extent to which the EGFR → Rac1 → p38 → COX-2 pathway is activated in clinically normal airway tissue from patients with respiratory papillomas. Surprisingly, we found that the Rac1 and COX-2 levels are comparable in “normal” and papilloma tissues, suggesting widespread activation of this pathway in the laryngeal mucosa, without marked elevation of the EGFR in the “normal” adjacent tissue. Moreover, preliminary data suggests that overexpression of Rac1 in these patients may be systemic, as it is also found at higher levels in peripheral blood mononuclear cells. We hypothesize that Rac1 overexpression may be a rare genetic trait that predisposes these patients to develop recurrent respiratory papillomatosis. Furthermore, investigation into Rac1 levels revealed the presence of a splice variant known as Rac1b. This constitutively active form of Rac1 is found at higher levels in papilloma tissue when compared to “normal” adjacent tissue from the same patient, possibly contributing to the growth of the tumors. Our current research is focused on determining the mechanism of Rac1 overexpression and elucidating the role of the Rac1 isoforms in papilloma cells.
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 5062.
Abstract 5066: Transformation of pancreatic epithelial cells by BrafV600E
Authors: Appleman Vicky , Klimstra David , Lewis Brian C. 
Published: February 2011

Abstract
Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States, with an estimated 35,000 deaths expected in 2009. The vast majority of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC), and activating mutations in the KRAS oncogene are present in over 90% of these tumors. Interestingly, one third of all KRAS wild-type PDAC harbor activating mutations in the gene encoding the downstream Kras effector Braf. Yet, the roles of specific Kras-stimulated effector pathways in pancreatic tumor initiation and progression remain unclear. We therefore sought to determine the consequences of expressing an activated Braf molecule in primary pancreatic duct epithelial cells (PDECs). Expression of an activated BrafV600E mutant results in the activation of the Mek-Erk and PI3K-Akt signaling cascades as determined by phosphorylation of Erk on Thr202 and Akt on Ser473. Measurement of cell proliferation demonstrated that BrafV600E stimulates the proliferation of PDECs, albeit to a lesser extent than an activated KrasG12D mutant. Activated Braf also promotes the survival of PDECs after exposure to apoptotic stimuli such as cycloheximide treatment and ultraviolet irradiation. This survival is dependent on activation of both the Mek-Erk and PI3K-Akt signaling cascades, as inhibition of these pathways abrogated Braf-induced survival. Consistent with its ability to stimulate the proliferation and survival of PDECs, orthotopic transplantation of PDECs expressing BrafV600E, and deleted at the Ink4a/Arf and Trp53 tumor suppressor loci, resulted in tumor formation, albeit with delayed kinetics relative to KrasG12D expressing PDECs. Interestingly, cell lines derived from orthotopic tumors required the activation of the PI3K-Akt signaling axis, but not the Mek-Erk signaling pathway, for survival after exposure to apoptotic stimuli, suggesting differential roles for these pathways during pancreatic tumor initiation and progression. Thus, our studies provide evidence that activating Braf mutations lead to the transformation of pancreatic epithelial cells, and additionally suggest that downstream Ras effectors may play different roles during pancreatic tumor initiation and progression.
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 5066.
Abstract 5067: Neurofilament heavy polypeptide regulates the Akt-β-catenin pathway in human esophageal squamous cell carcinoma
Authors: Kim Myoung Sook , Chang Xiaofei , LeBron Cynthia , Nagpal Jatin K. , Lee Juna , Huang Yiping , Yamashita Keishi , Trink Barry , Ratovitski Edward A. , Sidransky David 
Published: February 2011

Abstract
Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/β-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of β-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/β-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.
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 5067.
Abstract 5087: Mirk/Dyrk1B kinase mediates survival of quiescent tumor cells and is downstream of the cellular energy sensor AMPK
Authors: Deng Xiaobing , Friedman Eileen 
Published: February 2011

Abstract
The Mirk kinase gene has been localized to the 19q13 amplicon and is amplified in a subset of pancreatic cancers and ovarian cancers, and less frequently in colon cancers. Mirk mediates survival of these cancers at least in part by reducing reactive oxygen species (ROS). Mirk is expressed at very low levels in most normal tissues. However, Mirk is highly expressed in normal skeletal muscles and in C2C12 myoblasts where it mediates differentiation and survival. Using immunofluorescence techniques we now show that Mirk is localized in fast twitch skeletal muscles. Such muscle endogenously produces ROS in response to repeated contractions. Depletion of Mirk from C2C12 myoblasts led to an increase in ROS, consistent with ROS control being a major role of Mirk in muscle development and function. This protective ROS-decreasing role is likely to have provided a selective pressure to upregulate Mirk expression in tumor cells. Mirk is a co-activator for several transcription factors and increases expression of a series of antioxidant proteins in cancer cells including superoxide dismutase 2 (SOD2), the ferroxidase ceruloplasmin, glutathione peroxidase 2, sulfiredoxin, peroxiredoxin 2, COX2 and archidonate 12-lipoxygenase (12-LOX), as assayed by either Northern blotting or quantitative RT-PCR or both measurements. Mirk is most abundant and active as a kinase when cells are in a quiescent G0 state. Low intracellular energy levels due to nutrient deprivation lead to transient cellular arrest in G0 through the function of AMPK (AMP-activated protein kinase). Mirk expression is controlled through AMPK which serves as a metabolic checkpoint kinase, arresting cell growth in response to low nutrient levels which depress intracellular ATP levels. Thus the serine/threonine kinase Mirk mediates tumor cell survival through maintenance of its original function in skeletal muscle cells, depletion of ROS, when cells are in a transient quiescent state, with both Mirk expression and cell arrest controlled by AMPK.
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 5087.
Abstract 5090: The role of p32 in brain metastasis
Authors: Staflin Karin , Fogal Valentina , Fernandez-Santidrian Antonio , Ruoslahti Erkki , Felding-Habermann Brunhilde 
Published: February 2011

Abstract
Brain metastases are among the most feared complication in cancer. To develop effective and targeted therapies for treatment of brain metastases, we need a better understanding of the mechanisms that control cancer cell growth within the brain microenvironment. We previously found evidence that brain metastatic cells have increased rates of oxidative phosphorylation and redox potential compared to tumor cells from extracranial lesions. Here we sought to identify mechanisms involved, and to identify potential targets for the inhibition of metastatic growth in the brain. Many of the genes involved in transformation such as Myc, AKT, and p53 have extensive effects on the metabolism, suggesting that tumors might be susceptible to antimetabolic drugs. One of the proteins that has been shown to be upregulated in many solid tumors is the protein p32. P32 is a multi-compartmental and multi-functional protein which has a regulatory function in oxidative phosphorylation, in addition to being involved in the regulation of apoptosis and autophagy. We found p32 expressed in human cancer cells capable of seeding brain metastases in immune deficient mice, and we hypothesized that p32 contributes to cell survival and proliferation within the brain microenvironment. We knocked down p32 in brain homing variants of the MDA-MB-231 and MDA-MB-435 metastasis cell models. Following luciferase tagged tumor cells by non-invasive bioluminescence imaging revealed that stable p32 knockdown greatly reduced metastatic activity in both MDA-MB-231 brain specific variant and the MDA-MB 435 cell line. Furthermore, our genomic profiling of p32 knock-down and control cells identified candidate genes in the respiration chain involved in p32-dependent tumor cell survival and growth that may impact progression to brain metastasis. Thus, the expression and functionality of p32 in tumor cells capable of colonizing the brain appears associated with changes in crucial pathways that enable the tumor cells to proliferate and survive within the brain microenvironment.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5090.
Abstract 5094: Mutant specific mitochondrial localization of BRAFV600E: Clinically used BRAF kinase inhibitors are not able to block mitochondrial actions of BRAFV600E
Authors: Lee Min Hee , Kim Koon Soon , Lee Seong Eun , Ryu Min Jeong , Kim Soung Joong , Kim Yong Kyoung , Kweon Gi Ryang , Jo Young Suk , Shong Minho 
Published: February 2011

Abstract
Oncogenic mutation in BRAF kinase (BRAFV600E) results active structural conformation characterized with greatly elevated ERK activities. However, other cellular effects which are specifically influenced by mutation in BRAF kinase remains to be identified. We investigated differences in subcellular localizations of wild type and mutant BRAFV600E and observed the effects of the BRAF inhibitors on subcellular compartment-specific effects of BRAFV600E. We found that significant portion of endogenous and exogenous BRAFV600E, but not wild type BRAF, was detected in mitochondrial fraction. The other BRAF mutants, BRAFV600D, BRAFV600K and BRAFV600R which shows higher kinase activities were able to localize in mitochondria. The localization of BRAFV600E onto mitochondria provides anti-apoptotic activities against staurosporine and TNFα/cycloheximide. In addition, inducible expression of BRAFV600E increases glucose uptake rate, decreased O2 consumption, suggesting reduced mitochondrial oxidative phosphorylation which are signature features found in cancer cells. Interestingly, suppression of MEK activities using U0126 did not affect both mitochondrial localization and anti-apoptotic activities of BRAFV600E. The BRAF inhibitor such as Sorafenib was effective to inhibit MEK/ERK activation, however, they did not block the mitochondrial localization of BRAFV600E. Therefore, these inhibitors did not block the antiapoptotic activities and not reduce high glucose uptake rate and glycolytic activities induced by BRAFV600E. We found oncogenic BRAF mutants are able to localize in mitochondria and these actions might be related to altered responses to apoptotic stimuli and to characteristic metabolic phenotypes. In addition, currently BRAFV600E inhibitors were not sufficient to block mitochondrial localization of BRAFV600E and it may explain the limited efficacy of these drugs in clinically advanced BRAFV600E-positive tumors. These observations provide new mutation- specific roles of BRAFV600E which is potentially important for the development of therapeutics.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5094.