bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib Inhibits PKR-Like Endoplasmic Reticulum (ER) Kinase and Induces Apoptosis via ER Stress in Human Pancreatic Cancer Cells
Authors: Nawrocki Steffan T. , Carew Jennifer S. , Dunner Kenneth , Boise Lawrence H. , Chiao Paul J. , Huang Peng , Abbruzzese James L. , McConkey David J. 
Published: December 2005

Abstract
Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We hypothesized that proteasome inhibition would lead to an accumulation of misfolded proteins in the cell resulting in endoplasmic reticulum (ER) stress. The ability of bortezomib to induce ER stress and the unfolded protein response was investigated in a human pancreatic cancer cell line, L3.6pl. Bortezomib increased expression of ER stress markers, CHOP and BiP, but inhibited PKR-like ER kinase and subsequent phosphorylation of eukaryotic initiation factor 2α (eif2α), both of which are key events in translational suppression. These effects resulted in an accumulation of ubiquitylated proteins leading to protein aggregation and proteotoxicity. Peptide inhibitor or small interfering RNA targeting ER-resident caspase-4 blocked DNA fragmentation, establishing a central role for caspase-4 in bortezomib-induced cell death. The translation inhibitor cycloheximide abrogated bortezomib-induced protein aggregation, caspase-4 processing, and all other characteristics of apoptosis. Because malignant cells have higher protein synthesis rates than normal cells, they may be more prone to protein aggregation and proteotoxicity and possess increased sensitivity to bortezomib-induced apoptosis. Taken together, the results show that bortezomib induces a unique type of ER stress compared with other ER stress agents characterized by an absence of eif2α phosphorylation, ubiquitylated protein accumulation, and proteotoxicity. (Cancer Res 2005; 65(24): 11510-9)
Tumor Cell Plasticity in Ewing Sarcoma, an Alternative Circulatory System Stimulated by Hypoxia
Authors: van der Schaft Daisy W.J. , Hillen Femke , Pauwels Patrick , Kirschmann Dawn A. , Castermans Karolien , oude Egbrink Mirjam G.A. , Tran Maxine G.B. , Sciot Rafael , Hauben Esther , Hogendoorn Pancras C.W. , Delattre Olivier , Maxwell Patrick H. , Hendrix Mary J.C. , Griffioen Arjan W. 
Published: December 2005

AbstractA striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis. (Cancer Res 2005; 65(24): 11520-8)
Identification of GATA3 as a Breast Cancer Prognostic Marker by Global Gene Expression Meta-analysis
Authors: Mehra Rohit , Varambally Sooryanarayana , Ding Lei , Shen Ronglai , Sabel Michael S. , Ghosh Debashis , Chinnaiyan Arul M. , Kleer Celina G. 
Published: December 2005

Abstract
GATA binding protein 3 (GATA3) is a transcriptional activator highly expressed by the luminal epithelial cells in the breast. Here we did a meta-analysis of the available breast cancer cDNA data sets on a cohort of 305 patients and found that GATA3 was one of the top genes with low expression in invasive carcinomas with poor clinical outcome. To validate its prognostic utility, we did a tissue microarray analysis on a cohort of 139 consecutive invasive carcinomas (n = 417 tissue samples) immunostained with a monoclonal antibody against GATA3. Low GATA3 expression was associated with higher histologic grade (P &lt; 0.001), positive nodes (P = 0.002), larger tumor size (P = 0.03), negative estrogen receptor and progesterone receptor (P &lt; 0.001 for both), and HER2-neu overexpression (P = 0.03). Patients whose tumors expressed low GATA3 had significantly shorter overall and disease-free survival when compared with those whose tumors had high GATA3 levels. The hazard ratio of metastasis or recurrence according to the GATA3 status was 0.31 (95% confidence interval, 0.13-0.74; P = 0.009). Cox multivariate analysis showed that GATA3 had independent prognostic significance above and beyond conventional variables. Our data suggest that immunohistochemical analysis of GATA3 may be the basis for a new clinically applicable test to predict tumor recurrence early in the progression of breast cancer. (Cancer Res 2005; 65(24): 11259-64)
CDC4 Mutations Occur in a Subset of Colorectal Cancers but Are Not Predicted to Cause Loss of Function and Are Not Associated with Chromosomal Instability
Authors: Kemp Zoe , Rowan Andrew , Chambers William , Wortham Noel , Halford Sarah , Sieber Oliver , Mortensen Neil , von Herbay Axel , Gunther Thomas , Ilyas Mohammad , Tomlinson Ian 
Published: December 2005

Abstract
CDC4/FBXW7 is part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction. CDC4 mutations occur in several cancer types and are best described in colorectal tumors. Knockout of CDC4 in vitro in colorectal cancer cells causes changes suggestive of chromosomal instability (CIN). In p53+/− mice, radiation-induced lymphomas show deletion or mutation of one copy of CDC4 and knockdown of CDC4 leads to increased aneuploidy in mouse fibroblasts. We screened 244 colorectal tumors and 40 cell lines for CDC4 mutations and allelic loss. Six percent (18 of 284) of tumors, including near-diploid (CIN−) lesions, harbored CDC4 mutations and there was no association between mutation and CIN (polyploidy). The CDC4 mutation spectrum in colorectal tumors was heavily biased towards C:G&gt;T:A changes, either missense mutations at critical arginine residues or nonsense changes in the 5′ half of the gene. The reasons for this odd mutation spectrum were unclear but C:G&gt;T:A changes were not found more often than expected at APC, K-ras, or p53 in the same tumors and we found no specific defects in DNA repair to account for the observations. No colorectal tumor was found to carry two CDC4 mutations predicted to abolish protein function; partial loss of CDC4 function may therefore cause tumorigenesis. The in vitro studies, therefore, did not assess the functional effects of mutant alleles which are found in vivo. CDC4 mutations may be selected primarily to drive progression through the cell cycle although CIN might be an important secondary effect in some cancers. (Cancer Res 2005; 65(24): 11361-6)
The Shed Ectodomain of Nr-CAM Stimulates Cell Proliferation and Motility, and Confers Cell Transformation
Authors: Conacci-Sorrell Maralice , Kaplan Anna , Raveh Shani , Gavert Nancy , Sakurai Takeshi , Ben-Ze'ev Avri 
Published: December 2005

Abstract
Nr-CAM, a cell-cell adhesion molecule of the immunoglobulin-like cell adhesion molecule family, known for its function in neuronal outgrowth and guidance, was recently identified as a target gene of β-catenin signaling in human melanoma and colon carcinoma cells and tissue. Retrovirally mediated transduction of Nr-CAM into fibroblasts induces cell motility and tumorigenesis. We investigated the mechanisms by which Nr-CAM can confer properties related to tumor cell behavior and found that Nr-CAM expression in NIH3T3 cells protects cells from apoptosis in the absence of serum by constitutively activating the extracellular signal-regulated kinase and AKT signaling pathways. We detected a metalloprotease-mediated shedding of Nr-CAM into the culture medium of cells transfected with Nr-CAM, and of endogenous Nr-CAM in B16 melanoma cells. Conditioned medium and purified Nr-CAM-Fc fusion protein both enhanced cell motility, proliferation, and extracellular signal-regulated kinase and AKT activation. Moreover, Nr-CAM was found in complex with α4β1 integrins in melanoma cells, indicating that it can mediate, in addition to homophilic cell-cell adhesion, heterophilic adhesion with extracellular matrix receptors. Suppression of Nr-CAM levels by small interfering RNA in B16 melanoma inhibited the adhesive and tumorigenic capacities of these cells. Stable expression of the Nr-CAM ectodomain in NIH3T3 cells conferred cell transformation and tumorigenesis in mice, suggesting that the metalloprotease-mediated shedding of Nr-CAM is a principal route for promoting oncogenesis by Nr-CAM. (Cancer Res 2005; 65(24): 11605-12)
Papillomavirus E2 Protein Induces Expression of the Matrix Metalloproteinase-9 via the Extracellular Signal-Regulated Kinase/Activator Protein-1 Signaling Pathway
Authors: Behren Andreas , Simon Christian , Schwab Roxana Michaela , Loetzsch Ekaterina , Brodbeck Stephan , Huber Evamaria , Stubenrauch Frank , Zenner Hans Peter , Iftner Thomas 
Published: December 2005

Abstract
Papillomaviruses are involved in the development of cancers of the female cervix, head and neck, and skin. An excellent model to study papillomavirus-induced tumor induction and progression is the New Zealand White rabbit, where the skin is infected with the cottontail rabbit papillomavirus (CRPV). This leads to the formation of benign tumors that progress into invasive and metastasizing carcinomas without the need for cofactors. We have shown previously that specific mutations in the transactivation domain of the transcription/replication factor E2 cause a dramatic loss in the tumor induction efficiency of the viral genome and a major deficiency in tumor progression as we show now. By comparing wild-type (WT) and mutant E2-induced skin tumors, we found high levels of matrix metalloproteinase-9 (MMP-9) protein and transcripts in WT CRPV-E2–induced tumors in contrast to certain mutant CRPV-E2–induced papillomas and normal uninfected skin. Stable cell lines and reporter assays revealed that E2 from different papillomavirus types is able to transactivate the MMP-9 promoter via the promoter-proximal activator protein-1 (AP-1) site as shown in reporter gene assays with mutant MMP-9 promoter constructs. Furthermore, WT E2 but not mutant E2 strongly transactivated a minimal promoter reporter construct with multiple AP-1 sites. The MMP-9 protein induced in cells expressing E2 degrades collagen matrices as measured in Matrigel-based invasion/mobility assays. E2-induced MMP-9 expression can be blocked by a chemical inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase 1 (PD 098059), suggesting that E2 activates the MAPK/ERK signaling pathway, which is further supported by the induction of ERK1 in CRPV-E2–transfected cells. (Cancer Res 2005; 65(24): 11613-21)
Sphingosine Kinase-1 as a Chemotherapy Sensor in Prostate Adenocarcinoma Cell and Mouse Models
Authors: Pchejetski Dimitri , Golzio Muriel , Bonhoure Elisabeth , Calvet Cyril , Doumerc Nicolas , Garcia Virginie , Mazerolles Catherine , Rischmann Pascal , Teissié Justin , Malavaud Bernard , Cuvillier Olivier 
Published: December 2005

Abstract
Systemic chemotherapy was considered of modest efficacy in prostate cancer until the recent introduction of taxanes. We took advantage of the known differential effect of camptothecin and docetaxel on human PC-3 and LNCaP prostate cancer cells to determine their effect on sphingosine kinase-1 (SphK1) activity and subsequent ceramide/sphingosine 1-phosphate (S1P) balance in relation with cell survival. In vitro, docetaxel and camptothecin induced strong inhibition of SphK1 and elevation of the ceramide/S1P ratio only in cell lines sensitive to these drugs. SphK1 overexpression in both cell lines impaired the efficacy of chemotherapy by decreasing the ceramide/S1P ratio. Alternatively, silencing SphK1 by RNA interference or pharmacologic inhibition induced apoptosis coupled with ceramide elevation and loss of S1P. The differential effect of both chemotherapeutics was confirmed in an orthotopic PC-3/green fluorescent protein model established in nude mice. Docetaxel induced a stronger SphK1 inhibition and ceramide/S1P ratio elevation than camptothecin. This was accompanied by a smaller tumor volume and the reduced occurrence and number of metastases. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to docetaxel treatment. These results provide the first in vivo demonstration of SphK1 as a sensor of chemotherapy. (Cancer Res 2005; 65(24): 11667-75)
Modeling Human Cancer: Report on the Eighth Beatson International Cancer Conference
Authors: Olson Michael F. 
Published: December 2005

Abstract
One of the major challenges facing cancer researchers is the necessity to adequately model the human disease. This need is driven by goals, including validating/determining the contribution of a gene to cancer, establishing systems for drug discovery and validation, and discovering additional factors that modify the oncogenic process. Recent advances in cancer modeling were discussed at the Eighth Beatson International Cancer Conference on June 19 to 22, 2005 in Glasgow, United Kingdom. The conference was attended by 250 scientists with &gt;130 oral and poster presentations. The research presented made use of systems ranging from two-dimensional and three-dimensional cell culture to nonmammalian and mammalian in vivo models. In addition to basic research on the fundamental processes involved in cancer, novel developments in cancer treatment were presented. (Cancer Res 2005; 65(24): 11247-50)
Apoptotic Cells Initiate Endothelial Cell Sprouting via Electrostatic Signaling
Authors: Weihua Zhang , Tsan Rachel , Schroit Alan J. , Fidler Isaiah J. 
Published: December 2005

AbstractAngiogenesis, the development of new blood vessels from preexisting vessels, is crucial to tissue growth, repair, and maintenance. This process begins with the formation of endothelial cell sprouts followed by the proliferation and migration of neighboring endothelial cells along the preformed extensions. The initiating event and mechanism of sprouting is not known. We show that the phenotypic expression of negatively charged membrane surface in apoptotic cells initiates the formation of directional endothelial cell sprouts that extend toward the dying cells by a mechanism that involves endothelial cell membrane hyperpolarization and cytoskeleton reorganization but is independent of diffusible molecules. (Cancer Res 2005; 65(24): 11529-35)
Aromatase Inhibitors in Human Lung Cancer Therapy
Authors: Weinberg Olga K. , Marquez-Garban Diana C. , Fishbein Michael C. , Goodglick Lee , Garban Hermes J. , Dubinett Steven M. , Pietras Richard J. 
Published: December 2005

Abstract
Lung cancer is the most common cancer in the world. It is a highly lethal disease in women and men, and new treatments are urgently needed. Previous studies implicated a role of estrogens and estrogen receptors in lung cancer progression, and this steroidal growth-stimulatory pathway may be promoted by tumor expression and activity of aromatase, an estrogen synthase. We found expression of aromatase transcripts and protein in human non–small cell lung cancer (NSCLC) cells using reverse transcription-PCR and Western immunoblots, respectively. Aromatase staining by immunohistochemistry was detected in 86% of archival NSCLC tumor specimens from the clinic. Further, biological activity of aromatase was determined in NSCLC tumors using radiolabeled substrate assays as well as measure of estradiol product using ELISA. Significant activity of aromatase occurred in human NSCLC tumors, with enhanced levels in tumor cells compared with that in nearby normal cells. Lung tumor aromatase activity was inhibited by anastrozole, an aromatase inhibitor, and treatment of tumor cells in vitro with anastrozole led to significant suppression of tumor cell growth. Similarly, among ovariectomized nude mice with A549 lung tumor xenografts, administration of anastrozole by p.o. gavage for 21 days elicited pronounced inhibition of tumor growth in vivo. These findings show that aromatase is present and biologically active in human NSCLCs and that tumor growth can be down-regulated by specific inhibition of aromatase. This work may lead to development of new treatment options for patients afflicted with NSCLC. (Cancer Res 2005; 65(24): 11287-91)
Motexafin Gadolinium and Zinc Induce Oxidative Stress Responses and Apoptosis in B-Cell Lymphoma Lines
Authors: Lecane Philip S. , Karaman Mazen W. , Sirisawad Mint , Naumovski Louie , Miller Richard A. , Hacia Joseph G. , Magda Darren 
Published: December 2005

AbstractThere is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element–binding transcription factor-1 (MTF-1)–regulated and hypoxia-inducible transcription factor-1 (HIF-1)–regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1– and HIF-1–regulated transcripts as well as additional transcripts regulated by NF-E2–related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies. (Cancer Res 2005; 65(24): 11676-88)
Anoikis and Survival Connections in the Tumor Microenvironment: Is There a Role in Prostate Cancer Metastasis?
Authors: Rennebeck Gabriela , Martelli Matthew , Kyprianou Natasha 
Published: December 2005

Abstract
Overcoming the androgen independence of prostate tumors is considered the most critical therapeutic end point for improving survival in patients with metastatic prostate cancer. Normal epithelial and endothelial cells can undergo apoptosis when detached from the extracellular matrix (ECM), via the anoikis phenomenon. In contrast, tumor cells upon detachment from the ECM are capable of evading anoikis and metastasizing to different distant organs. Is the biological repertoire of the epithelial and endothelial cells sufficient to account for the events associated with the process of anoikis during prostate cancer metastasis? Although there is no clear answer to this question, what has become increasingly evident from the existing evidence is that molecules that induce anoikis in tumor epithelial and endothelial cells provide exciting new leads into effective therapeutic targeting as well as markers of prostate cancer progression and prediction of therapeutic resistance. This review analyzes recent findings on anoikis regulators and discusses the relevance of this unique apoptosis mode in the development of metastatic prostate cancer and identification of molecular signatures for treatment of advanced disease. (Cancer Res 2005; 65(24): 11230-5)
Coactivation of Liver Receptor Homologue-1 by Peroxisome Proliferator-Activated Receptor γ Coactivator-1α on Aromatase Promoter II and Its Inhibition by Activated Retinoid X Receptor Suggest a Novel Target for Breast-Specific Antiestrogen Therapy
Authors: Safi Rachid , Kovacic Agnes , Gaillard Stéphanie , Murata Yoko , Simpson Evan R. , McDonnell Donald P. , Clyne Colin D. 
Published: December 2005

AbstractAromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinically useful to selectively inhibit aromatase production in breast. In this regard, we have determined that the orphan nuclear receptor liver receptor homologue-1 (LRH-1) is a specific transcriptional activator of aromatase gene expression in human breast preadipocytes but not in other tissues of postmenopausal women. In this study, we show that the coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a physiologically relevant modulator of LRH-1, and that its transcriptional activity can be inhibited effectively using receptor-interacting peptide antagonists that prevent PGC-1α recruitment. Interestingly, we note that all of these peptides also interact in an agonist-dependent manner with retinoid X receptor α (RXRα), suggesting that these two receptors may compete for limiting cofactors within target cells. In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1α–induced transcriptional activity of LRH-1. The importance of this finding was confirmed by showing that LRH-1–dependent, PGC-1α–stimulated regulation of aromatase gene expression in primary human breast preadipocytes was effectively suppressed by RXR agonists. We infer from these data that LRH-1 is a bona fide target whose inhibition would selectively block aromatase expression in breast, while sparing other sites of expression. (Cancer Res 2005; 65(24): 11762-70)
Para to Ortho Repositioning of the Arsenical Moiety of the Angiogenesis Inhibitor 4-(N-(S-Glutathionylacetyl)Amino)Phenylarsenoxide Results in a Markedly Increased Cellular Accumulation and Antiproliferative Activity
Authors: Dilda Pierre J. , Decollogne Stephanie , Rossiter-Thornton Michael , Hogg Philip J. 
Published: December 2005

Abstract
The synthetic tripeptide arsenical 4-(N-(S-glutathionylacetyl)amino)p-phenylarsenoxide (p-GSAO) is an angiogenesis inhibitor that inactivates mitochondrial adenine nucleotide translocase (ANT) by cross-linking a pair of matrix-facing cysteine residues. This causes an increase in superoxide levels and proliferation arrest of endothelial cells followed by mitochondrial depolarization and apoptosis. p-GSAO induces proliferation arrest in endothelial cells and is a selective inhibitor of endothelial cells compared with tumor cells. An analogue of p-GSAO has been made in which the arsenical moiety is at the ortho instead of the para position on the phenyl ring. o-GSAO, like p-GSAO, bound to ANT in a dithiol-dependent manner but was ∼8-fold more efficient than p-GSAO at triggering the mitochondria permeability transition in isolated mitochondria. o-GSAO was an ∼50-fold more potent inhibitor of endothelial and tumor cell proliferation than p-GSAO. The mechanism of this effect was a consequence of ∼300-fold faster rate of accumulation of o-GSAO in the cells, which is due, at least in part, to impaired export by the multidrug resistance–associated protein 1. Administration of o-GSAO to tumor-bearing mice delayed tumor growth by inhibiting tumor angiogenesis but there were side effects not observed with p-GSAO administration. (Cancer Res 2005; 65(24): 11729-34)