bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1373: Identification of potential anti-tumor therapeutics targeting the Six1 transcriptional complex
Authors: Blevins Melanie , An Jianghong , Jones Steven , Swaroop Manju , Ferrer Marc , Ford Heide , Zhao Rui 
Published: June 2012

Abstract
Six1, a homeobox gene highly expressed during embryogenesis, is later down-regulated in most adult tissues. Six1 over-expression in adult tissues plays a causal role in the onset and progression of a significant proportion of breast and other cancers, as illustrated by its over-expression in 50% of primary breast tumors and 90% of metastatic sites. This selective over-expression establishes the Six1 gene as an attractive target for future anti-cancer therapeutics. To date, most breast cancer therapies do not specifically target cancerous cells and have considerable side effects. Therefore, it is important that new therapies are developed with specificity for cancerous cells and with fewer side effects. We hypothesize that molecules targeting the Six1 transcriptional complex can inhibit tumor cell proliferation and metastasis in breast cancer with limited side effects. Six1 requires the Eya family of co-activator proteins to activate transcription. Eya2 seems to be the most relevant Eya family member in breast tumorigenesis. Since single amino acid mutations have been shown to significantly reduce the Six1/Eya2 interaction, we hypothesize that this interaction can be disrupted by small molecules. We propose that disruption of the Six1/Eya2 interaction would greatly diminish the effects of Six1 activation in cancerous cells. Therefore, we developed a HTS assay to identify small molecule inhibitors of the Six1/Eya2 interaction. Additionally, screening of 33 compounds identified through an in silico screen in collaboration with the Michael Smith Genomics Center identified a promising lead compound that inhibits the Six1/Eya2 interaction. The lead compound is presently being evaluated for its efficacy, specificity, and mechanism of action using structural, biochemical, and cell-based assays. In addition, we have begun structure activity relationship studies to further optimize our lead compound.
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 1373. doi:10.1158/1538-7445.AM2011-1373
Abstract 1389: Cyr61 increases cell migration in human oral cancer cells through FAK, ERK and NF-κB pathways
Authors: Yu Nuo-Yi , Chuang Jing-Yuan , Hsieh Chin Hsuan , Tang Chih-Hsin 
Published: June 2012

Abstract
Cysteine-rich 61 (Cyr61), from the CCN gene family, is a secreted and matrix-associated protein, which is involved in many cellular activities such as growth and differentiation. Most of CCN family can regulate the cell motility, division and adhesion. However, the effect of Cyr61 on migration activity in human oral squamous carcinoma cells is mostly unknown. Here, we found that Cyr61 increased the migration in human oral squamous carcinoma cells (SCC-4 cells). Activations of focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK) and NF-κB pathways after Cyr61 treatment was demonstrated, and Cyr61-induced migration activity was inhibited by specific inhibitor of ERK and NF-κB cascades. Transfection of cells with FAK, ERK, IKKα(IkappaB kinase alpha) and IKKβ mutant also reduced Cyr61-mediated cancer migration. Taken together, our results suggest that Cyr61 acts through FAK/ERK, which in turn activates NF-κB, contributing to the migration of human oral squamous carcinoma 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 1389. doi:10.1158/1538-7445.AM2011-1389
Abstract 1390: Endothelin-1/ETBR axis promote COX-2 production and migration in human chondrosarcoma cells through MAPK and AP-1 pathways
Authors: Wu Min Huan , Lin James A , Huang Chih-Yang , Tang Chih-Hsin 
Published: June 2012

Abstract
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Endothelin-1 (ET-1) the most potent vasoconstrictor, plays a crucial role in migration and metastasis of human cancer cells. Cyclooxygenase (COX)-2 has been implicated in tumor metastasis. However, the effects of ET-1 in migration and COX-2 expression in chondrosarcoma cells are largely unknown. The aim of this study was to investigate whether ET-1 is associated with the motility of human chondrosarcoma cell. We found that treatment of human chondrosarcoma cells (JJ012 cells) with ET-1 increased migration and expression of COX-2. Activations of MAPK (p38, JNK and ERK) and activator protein-1 (AP-1) pathways after ET-1 treatment were demonstrated, and ET-1-induced expression of COX-2 and migration activity was inhibited by the specific inhibitor and mutant of Endothelin B receptor (ETBR), MAPK and AP-1 cascades. Moreover, ET-1 increased the binding of c-Jun to the AP-1 element on the COX-2 promoter. ETBR and MAPK inhibitor reduced ET-1 mediated binding activity and AP-1 luciferase activity. Taken together, our results indicated that ET-1 enhances the migration of chondrosarcoma cells by increasing COX-2 expression through the ETBR axis, MAPK and AP-1 signal transduction pathways.
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 1390. doi:10.1158/1538-7445.AM2011-1390
Abstract 1410: TIP-1 regulates Glioma invasion through small GTPases
Authors: Wang Hailun , Han Miaojun , Hallahan Dennis E. , Han Zhaozhong 
Published: June 2012

Abstract
Therapy resistance and invasion are two common features of malignant glioma. Our previous studies showed that TIP-1 regulates sensitivity of glioma cells to ionizing radiation. It was also found that TIP-1 protein level was elevated in human malignant glioma compared to the normal brain tissue counterparts, and correlated with the malignancy of gliomas. This observation was supported with a survival study within animal models, in which TIP-1 knockdown within glioma cell lines significantly retarded progression of the intracranially implanted tumors and extended survival time of the mice. In vitro and in vivo studies indicated that it is the reduced migration and invasion capability, but not the cell proliferation rate, that contributed to the retarded tumor progression of gliomas with TIP-1 knockdown. The glioma cells with TIP-1 knockdown also showed morphological changes with reorganized cytoskeleton and reduced efficiency of reorientation in directional migration. TIP-1 was reported to associate to beta-catenin and Rhotekin, two proteins that are involved in the cell skeleton reorganization and cell migration. Their interactions are through the single PDZ domain within TIP-1 and the classic Type I PDZ-binding motifs located at the carboxyl terminus of beta-catenin and Rhotekin respectively. It was found that TIP-1 knockdown altered intracellular location of Rhotekin. Mislocalization of Rhotekin at the cell migration leading edge resulted in irregular activation of RhoA, which generally regulates cell rear body retraction. Further, we identified that beta-PIX shares a similar PDZ-binding motif and associates to TIP-1 in vitro and in vivo. Beta-PIX is recruited to the leading edge by Scribble for Rac1 or Cdc42 activation and thus regulates cell front protrusion. Knockdown of TIP-1 within the invasive glioma cells disrupted the association of beta-PIX and Scribble, resulted in mislocalization of beta-PIX and reduced Rac1 activation. Taken together, these data illustrated that TIP-1 is one critical modulator in migration of the invasive glioma through regulating two small GTPases (RhoA and Rac1), and targeting TIP-1 might represent one novel approach to treat the highly invasive and mortal glioma tumors.
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 1410. doi:10.1158/1538-7445.AM2011-1410
Abstract 142: Novel tumor suppressor role of microRNA-205 in melanoma via regulation of E2F1
Authors: Dar Altaf A. , Majid Shahana , Nosrati Mehdi , de Semir David , Bezrookove Vladimir , Kashani-Sabet Mohammed 
Published: June 2012

Abstract
MicroRNAs (miRNAs) regulate gene expression by repressing translation or directing sequence-specific degradation of complementary mRNA. Altered miRNA expression has been demonstrated in several human cancers. Limited information is available concerning the expression and role of miRNAs in melanoma. Here, we report that expression of miR-205 is significantly suppressed in melanoma tumor samples when compared with nevi, and is correlated inversely with melanoma progression. miR-205 expression was also significantly downregulated in a panel of melanoma cell lines when compared to a normal melanocyte line. miRNA target databases predicted a conserved target site for miRNA-205 in the 3’ untranslated region (UTR) of E2F1 and E2F5. The expression levels of E2F1 and E2F5 were inversely correlated with that of miR-205 in melanoma cell lines. miR-205 significantly suppressed the luciferase activity of reporter plasmids containing the 3’UTR sequences complementary to either E2F1 or E2F5, which was abolished by mutations in these 3’UTR regions. Overexpression of miR-205 in melanoma cells reduced E2F1 and E2F5 protein levels without alteration of mRNA expression. The proliferative ability of melanoma cells was suppressed by miR-205, mediated by E2F-regulated AKT phosphorylation. Transient overexpression of miR-205 in melanoma cells resulted in induction of apoptosis, as indicated by increases in cleaved caspase-3, poly-(ADP-ribose) polymerase (PARP) and release of cytochrome-c. Stable overexpression of miR-205 suppressed cell proliferation and colony formation, and resulted in inhibition of tumor cell growth in vivo and induction of a senescence phenotype accompanied by elevated p16INK4A expression and other markers for senescence. These results demonstrate a novel role for miR-205 as a tumor suppressor in melanoma.
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 142. doi:10.1158/1538-7445.AM2011-142
Abstract 1434: Invasion of melanoma cells resistant to BRAF inhibition involves RHO-family GTPases
Authors: Klein Richard M. , Higgins Paul J. 
Published: June 2012

Abstract
Resistance to targeted therapies constitutes a major clinical obstacle that likely contributes to cancer recurrence following initial successful treatment. This study focused on the cellular responses associated with resistance to BRAF inhibition in an invasive melanoma cell line harboring a BRAFV600E mutation. Pharmacologic inhibitors targeting total or mutant-specific BRAF resulted in a dose-dependent reduction in phospho-MEK1/2 levels. Despite reduced ERK1/2 activation, viable melanoma cell subpopulations were present in cultures treated with BRAF inhibitors. Drug resistant cells were elongated and displayed prominent actin stress fibers. Melanoma cells resistant to BRAF inhibition were identified in both 2-D and 3-D cell cultures. Cells resistant to BRAF inhibition displayed reduced expression of RND3, an antagonist of RHOA activation. Restoration of RND3 expression or RHOA knockdown prevented actin cytoskeletal reorganization and attenuated the migratory ability of drug-insensitive cells without affecting cell survival. Additionally, the invasive ability of BRAF inhibitor resistance cells embedded in 3-D collagen gels was diminished following RND3 re-expression or RHOA depletion. Overall, these results describe previously uncharacterized roles for RND3 and RHOA in the ability of melanoma cells, treated with pharmaceutical BRAF inhibitors, to invade a dermal-like microenvironment. The molecular mechanisms learned from this information may assist in the development of strategies to improve overall therapeutic efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1434. doi:10.1158/1538-7445.AM2011-1434
Abstract 1436: The Cdk5 activator p39 specifically links muskelin to myosin and regulates stress fiber organization and contraction
Authors: Tripathi Brajendra K. , Lowy Douglas R. , Zelenka Peggy S. 
Published: June 2012

Abstract
Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine protein kinase, regulates signaling pathways implicated in the adhesion and migration of various cell types. Activation of Cdk5 requires its association with its activators p35 or p39. We have recently shown, in lens epithelial cells, that Cdk5 kinase activity regulates rho-dependent myosin phosphorylation, cytoskeletal contraction, and cell migration by controlling Src-p190RhoGAP signaling. In a separate line of investigation, we demonstrated that the N-terminus of p39 binds myosin essential light chain (MLC), while the C-terminus of p39 binds muskelin, a multi-domain scaffolding protein. As both muskelin and MLC have been associated with cytoskeletal organization, the present study seeks to determine whether p39 might serve as an adaptor that links muskelin to myosin and to investigate the possible biological relevance of such an interaction. Immunoprecipitation studies demonstrated that muskelin forms a protein complex with p39, MLC, myosin regulatory light chain (MRLC), and myosin heavy chain II (MHC II). Suppressing expression of p39 abrogated the interaction between muskelin and the myosin subunits, demonstrating that p39 is required to link muskelin to myosin. Immunofluorescence staining showed that muskelin colocalized with MRLC and actin-containing stress fibers. Suppressing muskelin expression with either of two different siRNAs significantly reduced MRLC phosphorylation and disrupted stress fiber organization. Similar effects were observed when Cdk5 activity was inhibited or suppressed. Moreover, suppressing muskelin expression prevented any further reduction of MRLC phosphorylation when Cdk5 activity was blocked, indicating that muskelin plays an important role in Cdk5-dependent regulation of MRLC phosphorylation. The Cdk5 activating protein p39 was necessary and sufficient for Cdk5-dependent regulation of myosin phosphorylation, as suppression of p39, but not p35, significantly reduced MRLC phosphorylation. Together, these results demonstrate that the Cdk5 activating protein p39 specifically links muskelin to myosin and thus, to stress fibers. Therefore, p39 has a dual role in cytoskeletal regulation: on one hand, it is an integral subunit of Cdk5 kinase; on the other, it acts as an adaptor protein to recruit muskelin to stress fibers. Each of these p39 functions is required for myosin phosphorylation, cytoskeletal contraction, and efficient cell migration.
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 1436. doi:10.1158/1538-7445.AM2011-1436
Abstract 1438: Breast cancer metastasis suppressor 1 (BRMS1) suppresses attachment and spreading of breast cancer cells on 2D and 3D extracellular matrix components by altering focal adhesion-associated signaling
Authors: Khotskaya Yekaterina B. , Beck Benjamin H. , Hurst Douglas R. , Hung Mien-Chie , Welch Danny R. 
Published: June 2012

Abstract
Metastatic dissemination of cancer cells from primary tumor to secondary sites is a multi-step process that depends heavily on the ability of cancer cells to respond to the microenvironmental cues, such as changes in composition of surrounding extracellular matrix (ECM), by adapting their adhesion abilities and undergoing cytoskeletal rearrangement. Many of these interactions between cancer cells and ECM are mediated by signaling cascades initiated at the cell surface through activation of integrins and growth factor receptors. BRMS1, or Breast cancer Metastasis Suppressor 1, belongs to a family of metastasis suppressor genes and has been shown to affect several steps of the metastatic cascade. BRMS1-expressing cells shed by the primary tumor can enter the circulation and reach secondary sites, where they remain largely as single cells. Moreover, ectopic expression of BRMS1 results in a significant decrease in survival of tumor cells within blood stream, increased susceptibility to anoikis and inability to form colonies at secondary organ sites, all events that could be attributed to failure of BRMS1 expressing cells to activate integrins and strongly adhere to ECM components. Here, we show that BRMS1 expression in MDA-MB-231 and MDA-MB-435 cells did not significantly alter expression levels of the integrin monomers tested. However, after short-term (15-30 minutes) plating of cells onto mixed ECM or individual ECM components (collagen I, collagen IV, or fibronectin) under 2D conditions, BRMS1-expressing cells exhibited reduced activation of β1 integrin, focal adhesion kinase (FAK), and scaffolding protein Talin1, as well as a decrease in their localization to focal adhesions. Furthermore, short-term plating of BRMS1-expressing cells on collagens I or IV or fibronectin resulted in marked inhibition of cytoskeletal rearrangement and failure to form cellular adhesion projections, as compared to cells vector-transfected cells. In addition, under 3D conditions, BRMS1-expressing cells remained rounded and failed to reorganize their cytoskeleton even after 24-hour stimulation with serum. Taken together, we believe that these findings demonstrate that BRMS1-expressing breast cancer cells are inherently unable to respond to microenvironment changes, which may explain why they exhibit reduced survival in circulation, increased susceptibility to anoikis, and decreased colonization of secondary sites.
YBK was supported in part by NIH T32 (AR047512-09) and DOD CDMRP BCRP Postdoctoral Fellowship (BC096855)
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 1438. doi:10.1158/1538-7445.AM2011-1438
Abstract 144: microRNA-107 regulates PKCepsilon and functions as a tumor suppressor miR in head and neck squamous cell carcinoma
Authors: Datta Jharna , Smith Ashley , Lang James , Islam Mozaffarul , Teknos Theodoros N. , Pan Quintin 
Published: June 2012

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. The 5-year survival rate of HNSCC has remained stagnant despite advances in the clinical management of this disease. Understanding the molecular pathways that lead to aggressive HNSCC is crucial to identify new “druggable” targets for anti-cancer drug development. Protein kinase Cepsilon (PKCε) is elevated in HNSCC and regulates cell invasion and motility thorough activation of Rho GTPases. Our laboratory and others provide evidence that PKCε is a transforming oncogene that phosphorylates and modulates a cascade of signal transduction pathways, including Akt, EGFR, Rho GTPases, and Stat3. Thus, targeting PKCε may be an attractive therapeutic approach to dampen multiple hyper-active signaling pathways in concert. At this time, the molecular mechanism of PKCε dysregulation in HNSCC remains to be elucidated. In silico analysis with TargetScan, MiRBase, and miRanda identified numerous putative microRNA (miR) binding sites in the 3’-UTR region of PKCε. We screened a panel of miRs using qPCR and miR-107 was identified to have an inverse association with PKCε in HNSCC cell lines with high endogenous PKCε. Ectopic expression of miR-107 in several HNSCC cell lines significantly reduced PKCε mRNA expression and protein levels. The expression of a luciferase reporter construct containing the 3’-UTR of PKCε was down-regulated by miR-107 and deletion/mutation of the three cognate miR-107 binding sites completely abolished the regulation by miR-107. These observations confirm PKCε as a validated target of miR-107. Ectopic expression of miR-107 in HNSCC cell lines significantly inhibited cell proliferation, DNA replication, clonogenic survival, invasion and migration. Tumor take and tumor growth of HNSCC cells was suppressed by miR-107 in a pre-clinical nude mouse model of HNSCC. Lastly, miR-107 was significantly reduced and showed an inverse expression relationship with PKCε in human primary HNSCC tumors. These results indicate that miR-107 regulates PKCε levels to control the tumorigenicity of HNSCC cells. Taken together, our data substantiate the potential application of miR-107 as a novel anti-cancer therapeutic for HNSCC.
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 144. doi:10.1158/1538-7445.AM2011-144