bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2883: Vimentin downregulation modulates p53 levels and apoptosis in cancer cells
Authors: Fortier Anne-Marie , Cadrin Monique , Asselin Eric 
Published: June 2012

Abstract
Vimentin, a mesenchymal-specific intermediate filament (IF) protein, is often express in epithelial cancers exhibiting a de-differentiated phenotype. Vimentin is associated with increased chemoresistance and metastatic potential. Chemoresistance is a multifactorial phenomenon which is a major cause of treatment failure in human cancer. Some IF proteins are known to promote resistance to stress-induced apoptosis, but the role of vimentin in this process is still unknown. In the present study, we investigate the role of vimentin in response to apoptosis-induced chemotherapeutic drugs in different epithelial carcinoma cell lines. Surprisingly, using siRNA, our results show that vimentin downregulation decreases caspase-3 and PARP cleavage induced by cisplatin, doxorubicin and TNFalpha. This unexpected result could be explained by the decrease of p53 protein levels in vimentin-downregulated cells. Indeed, we observed that vimentin knockdown decreases p53 levels in a proteasome-dependent manner and also modulates p53 ubiquitination. PI3K/Akt pathway is well known to promote chemoresistant phenotype in different cancers and Akt can also regulate p53 function. Our results show that vimentin-induced p53 decrease is associated with an increase of Akt phosphorylation. We propose that vimentin knockdown results in an increase of Akt activity which in turn regulates ubiquitination and proteasomal degradation of p53. We have recently showed that Akt isoforms regulates vimentin and keratins IF expression in epithelial cancer cells, suggesting that IF proteins are directly involved in PI3K/Akt signaling pathway. To our knowledge, these results represent the first indication that vimentin could regulate Akt activity and p53 levels in response to apoptosis-induced chemotherapeutic drugs. These results support the hypothesis that modulation of IF expression plays an active role in cancer progression and that vimentin could be a possible target for cancer therapy.
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 2883. doi:10.1158/1538-7445.AM2011-2883
Abstract 2889: NF-κB inducing kinase modulates melanoma tumorigenesis by regulating pro-survival factors through β-catenin
Authors: Thu Yee Mon , Su Yingjun , Yang Jinming , Splittgerber Ryan , Richmond Ann 
Published: June 2012

Abstract
Nuclear factor-κB (NF-κB) contributes to the progression of many cancers due to its role in regulating the transcription of genes important for inflammation, proliferation, apoptosis, and survival. In melanoma, high NF-κB activity results from constitutive elevation of IKKβ activity, a major kinase of this pathway. Targeted deletion of IKKβ prevents Ras induced melanoma tumor formation in INK4a/ARF-/- mice, underscoring the importance of NF-κB in melanoma. We have demonstrated that the NF-κB inducing kinase (NIK) is elevated in many melanoma cell lines. To determine the role of NIK overexpression in melanoma, we knocked down NIK using shRNA in WM115 and Hs294T human melanoma cell lines. NIK knock-down melanoma cells exhibited increased apoptosis and decreased proliferation. Similarly, NIK depletion substantially decreased tumor burden of WM115 cells in a xenograft model. Analysis of gene expression microarray data suggests that NIK modulates expression of c-Myc, c-Met, CCND2 and CXCR4, genes which are crucial for melanoma progression. Consistent with the apoptotic phenotype of NIK knock-down melanoma cells, expression of survival factors, such as Bcl2, cIAP1 and survivin, were attenuated in NIK knock-down melanoma cells. Intriguingly, Bcl2 and survivin expression levels (mRNA and protein) were also diminished in NIK knock-out mouse embryonic fibroblasts (MEFs), suggesting that these pro-survival genes are under the regulation of NIK. However, NF-κB activity is not reduced in NIK knock down cells, possibly due to the compensatory activation of IKKβ. Thus, we explored the possibility that NIK affects expression of survival factors in a NF-κB independent manner. Our data suggest that NIK regulates subcellular localization of β-catenin and modulates expression of survival genes such as survivin. Our findings reveal a novel mechanism by which NIK modulates pro-survival genes and suggest that NIK may be a promising therapeutic target for melanoma malignancy.
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 2889. doi:10.1158/1538-7445.AM2011-2889
Abstract 290: Use of serum and tissue biomarker analysis embedded in a phase II clinical trial of cytarabine in castration-refractory prostate cancer to investigate prostate cancer biology
Authors: Dhani Neesha , Emmeneger Urban , Sridhar Srikala , Knox Jennifer , Tannock Ian , Day John , Manthe Jonathon , Groskopf Jack , Joshua Anthony M. 
Published: June 2012

Abstract
Background: Other than the androgen receptor, the TMPRSS2-ERG genomic aberrations in prostate cancer provide the first recent opportunity to target therapy in castration refractory prostate cancer (CRPC). We initiated a phase 2 clinical trial of cytarabine in docetaxel refractory CRPC on the basis of microarray, in vitro and case report evidence that cytarabine may be particularly effective in men harbouring abnormalities of the ERG oncogenes. Embedded in this clinical trial was the first use of blood mRNA levels of prostate cancer related genes as biomarkers of response and prognosis. Methods: Patients with docetaxel refractory progressive CRPC received intravenous cytarabine at doses between 1g/m2- 0.25 g/m2 q3 weekly. Responses were defined according to PCWG2C. 10 patients were enrolled between June 2007 and January 2010. TMPRSS2:ERG, PSA and PCA3 mRNA copies in whole blood collected with PAXgene tubes at the beginning of each cycle and at trial termination were quantified using transcription-mediated amplification assays. The prototype TMPRSS2:ERG assay detects the gene fusion isoform TMPRSS2 exon1 to ERG exon4. Results: No patients demonstrated a serum PSA response (PCWG2C). The average number of cycles administered was 2.6. Significant toxicities including grade 3-4 thrombocytopenia (2) and grade 3-4 neutropenia (3). These toxicities necessitated several dose reductions in the protocol, however most patients were removed from trial for serum PSA progression alone. PCA3 and PSA mRNAs were detectable in 8/10 and 9/10 cases, respectively; there was no correlation between serum PSA and PCA3 or PSA mRNA copy levels in blood. Testing for TMPRSS2:ERG in blood was able to predict the presence or absence of the TMPRSS2-ERG rearrangement in 9/10 cases when compared to 3 colour FISH carried out on baseline biopsies/ prostatectomies (2/10 positive for Exon 4:Exon 1 deletion). Conclusions: Cytarabine administation is ineffective in docetaxel refractory CRPC. Blood mRNA levels of prostate cancer genes reveal novel aspects of prostate cancer biology and have implications for the understanding of circulating tumour 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 290. doi:10.1158/1538-7445.AM2011-290
Abstract 2904: Docking-based virtual screening of Chk1 inhibitors
Authors: Li Yan , Kim Dong Joon , Bode Ann M. , Dong Zigang 
Published: June 2012

Abstract
Checkpoint 1 (Chk1), which is required for checkpoint arrest, is activated in response to DNA damage through the ATM/ATR pathway, and plays an essential role in the regulation of the G2/M checkpoint. Inhibition of Chk1 should abrogate this checkpoint in a manner relevant to the treatment of cancer, and may also induce apoptosis. Selective Chk1 inhibitors should also prove useful to study the regulation of the G2/M checkpoint. Several Chk1 inhibitors are already known, including natural products. UCN-01, a Chk1 inhibitor and staurosporine derivative, is undergoing clinical trials as an anticancer agent. A limited number of additional Chk1 inhibitors have been reported; however, a need to identify more drug-like Chk1 inhibitors is clear. This should be facilitated by the structural information available for the Chk1 kinase domain. The first crystal structure of the kinase domain of human Chk1 has been reported at 1.7Å resolution in 2000. After that, 46 co-crystal structures of Chk1 and inhibitors have also been solved. This puts docking-based virtual screening of Chk1 inhibitors on firm footing. Molecular docking is a very popular method employed to investigate molecular associations and is particularly useful in the drug discovery arena to study the binding of small molecules (ligands) to macromolecules (receptors). To deal with the binding event in a realistic manner, we took into account the conformational flexibility of the ligand and the flexibility of the receptor. In this work, a large collection of crystallographic structures of Chk1 was employed to determine if multiple-structure docking performs better than single-structure docking. Known ligands were used to test the success of docking in binding mode prediction and virtual screening enrichment factors. A chemical library with more than 60,000 compounds was docked into the selected Chk1 structures, and the top-ranked compounds were then tested in experiments.
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 2904. doi:10.1158/1538-7445.AM2011-2904
Abstract 2905: The HMGA1-MMP-2 pathway in poorly differentiated uterine tumors
Authors: Hillion Joelle , Cello Francescopaolo Di , Huso David , Resar Linda 
Published: June 2012

Abstract
Uterine cancer is the most common cancer of the female genital tract and the fourth most frequent cause for cancer death in women in the United States. Thus, further study has the potential to significantly benefit women's health worldwide. Despite the high prevalence of this disease, the molecular events that lead to uterine cancers are poorly understood. We are studying the role of the high mobility group A1 (HMGA1) gene in the pathogenesis of uterine cancer. The HMGA1 gene encodes the HMGA1a and HMGA1b chromatin remodeling proteins, which function in modulating gene expression. In a previously published pilot study, we showed that HMGA1 is overexpressed in poorly differentiated uterine cancers, but not in normal uterine tissue, benign tumors, or most low-grade neoplasms of the uterus. We also engineered HMGA1 transgenic mice and found that all females develop uterine sarcomas by 9 months of age. In lung cancer, we reported that HMGA1 induces expression of the matrix metalloproteinase-2 (MMP-2) gene, but only in poorly differentiated tumors, suggesting that this pathway could drive tumor progression and a poorly differentiated state. Here, we investigated the role of the HMGA1-MMP-2 pathway in the pathogenesis of uterine tumorigenesis. Using a genetic approach, we crossed our HMGA1 transgenic mice with mice that are null for the MMP-2 gene. We found that the uterine tumors were significantly smaller in the HMGA1 transgenic mice that are also null for MMP-2. To determine if this pathway is involved in human uterine tumorigenesis, we assessed expression of the HMGA1 and MMP-2 genes in primary, human uterine tumors. We studied: 1.) endometrioid tumors, which are derived from the endometrial epithelium and tend to be low-grade (well-differentiated), 2.) serous tumors, which are also derived from the endometrial epithelium, but tend to be high-grade (poorly differentiated), and, 3.) carcinosarcomas (or mixed malignant, mullerian tumors), which are derived from the endometrial epithelium and stroma and tend to by high-grade. We found that HMGA1 expression was highest in the high-grade serous tumors and carcinosarcomas, with lower levels in the endometrioid tumors. Moreover, we found that there was a significant correlation between HMGA1 and MMP-2, but only in the high-grade carcinosarcomas and serous tumors. Taken together, our studies demonstrate that HMGA1 induces expression of MMP-2 during uterine tumorigenesis and suggest that this pathway is important in aggressive, poorly differentiated tumors. Although further studies are needed, our findings also suggest that the HMGA1-MMP-2 pathway could serve as a rational therapeutic target in poorly differentiated uterine cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2905. doi:10.1158/1538-7445.AM2011-2905
Abstract 2910: Oncogenic role of MUC1 in context of TGF-β production and signaling
Authors: Nath Sritama , Rao Shanti , Tinder Teresa L. , Gendler Sandra , Mukherjee Pinku 
Published: June 2012

Abstract
Introduction: Pancreatic cancer is the fourth leading cause of cancer-related death in United States. Most human pancreatic cancers overexpress MUC1, which is associated with high metastasis and poor prognosis of the disease. We have recently shown that MUC1 initiates the process of epithelial to mesenchymal transition (EMT) and promotes metastasis in pancreatic cancer cells via signaling through the seven tyrosines present in its cytoplasmic tail (CT) motif. When the 7 tyrosines were mutated to phenylalanine, EMT was completely abrogated. Since TGF-β has been extensively studied as a mediator of EMT and invasion in pancreatic cancer, we hypothesized that MUC1 may be inducing its effect through regulating TGF-β production and signaling. We also aimed at identifying the specific tyrosine residue(s) responsible for MUC1 induced EMT. Method: We made the following plasmids containing a) full length MUC1 (MUC1), b) all 7 tyrosine residues of MUC1 CT were mutated to Phenylalanine (Y0), c) Y6 (Tyrosine 6 present, the rest replaced by Phenylalanine), d) Y7 (Tyrosine 7 present, the rest replaced by Phenylalanine), e) Y2,5 (Tyrosine 2 and 5 present, the rest replaced by Phenylalanine), f) Y3,6,7 (Tyrosine3, 6 and 7 present, the rest replaced by Phenylalanine) and g) empty vector (Neo). These plasmids were stably expressed in human pancreatic cancer cell lines, BxPC3 and Su86.86 that express low levels of endogenous MUC1. We first assessed the levels of functional TGF-β secreted by BxPC3 Neo, MUC1 and Y0 cells as well as the levels of TGF-βI and II receptors. We then treated these cells with exogenous human recombinant TGF-β and assessed both, the process of EMT and the capacity to invade through growth-reduced matrigel. Results: We found that BxPC3.MUC1 cells produced strikingly larger amounts of TGF-β compared to BxPC3 Neo and Y0 cells. We also found that MUC1-expressing cells became more invasive in response to exogenous TGF-β while the Y0 cells did not respond to exogenous TGF-β although the receptor levels were similar in all three cell lines. However, none of the mutants of MUC1 CT could rescue the function of full length MUC1, in the context of induction of EMT. Conclusion: 1) We believe that TGF-β mediated EMT and TGF-β signal propagation requires the tyrosine residue of MUC1, which is evident from the data that mutating the tyrosine residues in MUC1CT abrogates TGF-β mediated EMT in these cells. 2) Induction of EMT by MUC1 is a complex process, which involves a particular combination of tyrosine residues of MUC1.
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 2910. doi:10.1158/1538-7445.AM2011-2910
Abstract 2912: Protein pathway activation mapping of leukemia-associated JAK1 mutants
Authors: Fodale Valentina , Flex Elisabetta , Stellacci Emilia , Policicchio Eleonora , Deng Jianghong , Calvert Valerie S. , Liotta Lance A. , Petricoin Emanuel F. , Tartaglia Marco 
Published: June 2012

Abstract
The Janus kinase 1 (JAK1) is a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival and differentiation. We documented that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL) (Flex et al. 2008, J Exp Med 205:751-8). JAK1 mutations were more prevalent among adult subjects with T-cell precursor ALL, where they accounted for approximately 20% of cases, and were associated with poor response to therapy and overall prognosis. In order to understand the molecular and cellular mechanisms by which aberrant JAK1 function contribute to leukemogenesis we analysed the signaling architecture of BaF3 cell lines stably expressing a series of leukemia-associated JAK1 gene mutations by Reverse Phase Protein Microarray (RPMA). We utilized BaF3 cell lines, stably expressing human wild type JAK1 and five ALL-associated mutants bearing missense mutations in different domains of the kinase. Cells were serum starved for 16 hours and lysed before and after induction with IL-3 for 20 minutes. RPMA analysis was performed to determine the phosphorylation/activation state of 102 different key signalling proteins involved in the major intracellular signal transduction pathways. Results showed that intacellular signaling downstream JAK/STAT is differentially modulated between cell lines expressing the different ALL-associated JAK1 mutants. Statistical analysis revealed that mutations affecting the pseudo-kinase and in the kinase domains resulted in a different phosphorylation pathway network compared to mutations involving the FERM and SH2 domains.
Our results support a model in which mutations affecting distinct domains of JAK1 have a differential perturbing effect on JAK1 function and signalling. Characterization of the consequences of leukemia-associated JAK1 mutants on the protein signalling network may help to identify new therapeutic targets for ALL. The present findings further document that functional protein pathway activation mapping using RPMA represents a powerful approach to uncovering mutation-driven events, and elucidating the specific events associated with different mutations within a single protein.
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 2912. doi:10.1158/1538-7445.AM2011-2912
Abstract 2919: Unexpected role of CRAF in tumor cell mitosis revealed by an allosteric inhibitor
Authors: Mielgo Ainhoa , Murphy Eric , Huang Miller , Seguin Laetitia , Weis Sara , Cheresh David 
Published: June 2012

Abstract
RAF kinases regulate fundamental cellular processes such as proliferation and survival and can be mutated or dysregulated in tumors. Although, RAF inhibitors show clinical activity in some cancer patients, recent reports have shown that ATP-competitive RAF inhibitors can enhance the proliferation of RAS driven tumors by promoting B- and CRAF dimerization and phosphorylation of CRAF on serine 338. Recently, we characterized an allosteric inhibitor of RAF that disrupts RAF dimerization, CRAF serine 338 phosphorylation and tumor growth in mice. Here, we report the surprising finding that phospho-S338 CRAF localizes to the mitotic spindle of proliferating tumor cells in vitro and in biopsies from cancer patients. Importantly, treatment of these cells with an allosteric, but not an ATP-competitive inhibitor of RAF, prevents CRAF localization to the mitotic spindle and causes cell cycle arrest at pro-metaphase in a MAPK-independent manner. Mechanistically, phospho-S338 CRAF interacts and co-localizes with active Polo-like kinase 1 (Plk1) at the mitotic spindle of proliferating cells. In fact, allosteric or genetic inhibition of CRAF inhibits Plk1 activity and its accumulation at the kinetochores causing pro-metaphase arrest. These findings define an unexpected role for RAF in mitosis, revealing a novel mechanism for RAF as a therapeutic target in oncology.
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 2919. doi:10.1158/1538-7445.AM2011-2919
Abstract 2925: Protein pathway activation mapping of the NCI60 cell line series: Discovery of lineage-independent protein biomarkers for drug sensitivity/resistance prediction
Authors: Federici Giulia , Fodale Valentina , Deng Jianghong , De Maria Ruggero , Liotta Lance A. , Petricoin Emanuel F. , Wulfkuhle Julia D. 
Published: June 2012

Abstract
The NCI-60 cell lines are a set of human tumor cell lines derived from different organ sites including brain, blood and bone marrow, breast, colon, kidney, lung, ovary, prostate and skin. These cell lines have been characterized through genetic screening, such as chromosome karyotyping, gene expression analysis, protein expression and sequencing and are likely the most well-characterized cell lines in the world. Through the use of Reverse-Phase Protein Microarrays (RPMA) we performed an in-depth analysis of signal pathway activation, measuring the activation state of nearly 200 key signaling proteins representative of pathways involved in proliferation, survival, inflammation, adhesion, and migration. This broad-based screening allowed the characterization of activated intracellular signaling pathways and identified 11 clear subclasses based on molecular architectures which transcended cell line lineage. Statistical analysis of signaling architecture of the most drug-resistant and sensitive lines, defined by publicly available GI50 data was performed for a number of molecularly targeted-therapeutics. We identified novel and previously known protein biomarkers that correlated with resistance and sensitivity to these inhibitors, which indicated the potential for functional signaling analysis of the cell lines to produce biomarkers that could be useful in vivo if extensively validated. Our goal is to be able to assign a specific protein signaling architecture for each specific drug sensitivity profile such that predictive markers can emerge in a biochemically-driven fashion.
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 2925. doi:10.1158/1538-7445.AM2011-2925