bluuebunny/crossref_metadata_2025_split huggingface dataset:
7,12-Dimethylbenz(a)Anthracene Treatment of a c-rel Mouse Mammary Tumor Cell Line Induces Epithelial to Mesenchymal Transition via Activation of Nuclear Factor-κB
Authors: Shin Sangmin Ryan , Sánchez-Velar Nuria , Sherr David H. , Sonenshein Gail E. 
Published: March 2006

Abstract
The aberrant expression of the nuclear factor-κB (NF-κB) c-Rel subunit that occurs in many human breast cancers can play a causal role in tumorigenesis as judged by findings with a mouse mammary tumor virus (MMTV)-c-rel transgenic mouse model, in which 31.6% of mice developed one or more mammary tumors after a long latency. Interestingly, none of the cell lines established from the mammary tumors grew in soft agar. To begin to test the hypothesis that a prototypic carcinogen insult can promote a more invasive, mesenchymal phenotype, a cell line established from a MMTV-c-rel mammary tumor rel-3983 was treated in culture with the polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA; rel-3983D cells) or DMSO vehicle (rel-3983V cells). Rel-3983D cells displayed an increased rate of proliferation, displayed growth to a higher cell density, and acquired the ability to grow in soft agar and in Matrigel compared with the parental rel-3983 or vehicle-treated rel-3983V cells. Consistent with a more mesenchymal phenotype, rel-3983D cells showed loss of E-cadherin expression as judged by immunofluorescence microscopy. Compared with control cells, rel-3983D displayed increased NF-κB binding and higher levels of the NF-κB transactivating subunits c-Rel, RelA, and RelB, which seemed functional as judged by induction of c-Myc and vimentin, products of two NF-κB target genes. Ectopic expression of a super repressor mutant of IκB-α reduced rel-3983D cell growth and invasive morphology in Matrigel, confirming the role of NF-κB in epithelial to mesenchymal transition (EMT). Thus, DMBA treatment of c-Rel–transformed mammary tumor cells in culture is shown here for the first time to result in EMT via activation of NF-κB. The aberrant c-Rel expression present in most human breast cancers suggests that this mechanism may play an important role in carcinogenesis. (Cancer Res 2006; 66(5): 2570-5)
p44 Mitogen-Activated Protein Kinase (Extracellular Signal-Regulated Kinase 1)–Dependent Signaling Contributes to Epithelial Skin Carcinogenesis
Authors: Bourcier Christine , Jacquel Arnaud , Hess Jochen , Peyrottes Isabelle , Angel Peter , Hofman Paul , Auberger Patrick , Pouysségur Jacques , Pagès Gilles 
Published: March 2006

Abstract
Extracellular signal-regulated kinases (ERK) regulate cellular functions in response to a variety of external signals. However, the specific functions of individual ERK isoforms are largely unknown. Hence, we have investigated the specific function of ERK1 in skin homeostasis and tumorigenesis in ERK1 knockout mice. They spontaneously develop cutaneous lesions and hyperkeratosis with epidermis thickness. Skin hyperproliferation and inflammation induced by application of 12-O-tetradecanoylphorbol-13-acetate (TPA) is strongly reduced in mutant mice. ERK1−/− mice are resistant to development of skin papillomas induced by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by TPA. Tumor appearance was delayed, their formation was less frequent, and their number and size were reduced. Keratinocytes obtained from knockout mice showed reduced growth and resistance to apoptotic signals, accompanied by an impaired expression of genes implicated in growth control and invasiveness. These results highlight the importance of ERK1 in skin homeostasis and in the process of skin tumor development. (Cancer Res 2006; 66(5): 2700-7)
Phosphorylation of Ezrin by Cyclin-Dependent Kinase 5 Induces the Release of Rho GDP Dissociation Inhibitor to Inhibit Rac1 Activity in Senescent Cells
Authors: Yang Hi-Su , Hinds Philip W. 
Published: March 2006

Abstract
Normal somatic cells enter a state of irreversible proliferation arrest-designated cellular senescence, which is characterized by biochemical changes and a distinctive morphology. Cellular stresses, including oncogene activation, can lead to senescence. Consistent with an antioncogenic role in this process, the tumor suppressor pRb plays a critical role in senescence. Reexpression of pRb in human tumor cells results in senescence-like changes, including cell cycle exit and cell shape alteration. Here, we show that pRb-induced senescent SAOS-2 cells and senescent human diploid fibroblasts are accompanied by increased phosphorylation of ezrin at T235 by cyclin-dependent kinase 5 and consequent dissociation of Rho GDP dissociation inhibitor (Rho-GDI) from an ezrin/Rho-GDI complex. The release of Rho-GDI results in increased interaction with Rac1 GTPase and inhibition of Rac1 GTPase activity. In addition, reduction of Rho-GDI by small interfering RNA in pRb-transfected cells prevented senescence-associated flat cell formation, suggesting that Rho-GDI plays an important role in contributing to cellular morphology in the process of senescence. (Cancer Res 2006; 66(5): 2708-15)
Oxidative Damage and Aging: Spotlight on Mitochondria
Authors: Linford Nancy J. , Schriner Samuel E. , Rabinovitch Peter S. 
Published: March 2006

Abstract
Whereas free radical damage has been proposed as a key component in the tissue degeneration associated with aging, there has been little evidence that free radical damage limits life span in mammals. The current research shows that overexpression of the antioxidant enzyme catalase in mitochondria can extend mouse life span. These results highlight the importance of mitochondrial damage in aging and suggest that when targeted appropriately, boosting antioxidant defenses can increase mammalian life span. (Cancer Res 2006; 66(5): 2497-9)
Chemopreventive Properties of Black Raspberries in N-Nitrosomethylbenzylamine-Induced Rat Esophageal Tumorigenesis: Down-regulation of Cyclooxygenase-2, Inducible Nitric Oxide Synthase, and c-Jun
Authors: Chen Tong , Hwang Hyejeong , Rose Miranda E. , Nines Ronald G. , Stoner Gary D. 
Published: March 2006

Abstract
Our laboratory has used a rodent model of human esophageal squamous cell carcinoma to identify putative chemopreventive agents for this disease and to determine their mechanisms of action. In the present study, we treated F344 rats with the esophageal carcinogen, N-nitrosomethylbenzylamine (NMBA), thrice per week for 5 weeks. Beginning 1 week later, they were fed a synthetic diet containing 5% black raspberries (BRB) for the duration of the bioassay (25 weeks). Rats were sacrificed at weeks 9, 15, and 25. Esophageal tissues were collected, and tumor data were recorded. The expression and enzymatic activities of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as the expression of c-Jun in the esophagi, were evaluated to investigate the mechanism(s) by which black raspberries modulate tumorigenesis. At week 25, BRB inhibited tumor multiplicity, the standard end point in this tumor model, from 3.78 ± 0.41 tumors per rat in NMBA-treated animals to 2.23 ± 0.21 tumors per rat in animals treated with NMBA plus BRB (P &lt; 0.005). BRB reduced mRNA and protein expression levels of COX-2, iNOS, and c-Jun as well as the level of prostaglandin E2 in preneoplastic lesions of the esophagus at week 25. The berries inhibited mRNA expression of iNOS and c-Jun, but not COX-2, in papillomatous lesions of the esophagus. Prostaglandin E2 and total nitrite levels were also decreased by BRB in papillomas. These results suggest a novel tumor suppressive role of BRB through inhibition of COX-2, iNOS, and c-Jun. (Cancer Res 2006; 66(5): 2853-9)
Large-Scale Molecular Comparison of Human Schwann Cells to Malignant Peripheral Nerve Sheath Tumor Cell Lines and Tissues
Authors: Miller Shyra J. , Rangwala Fatima , Williams Jon , Ackerman Peter , Kong Sue , Jegga Anil G. , Kaiser Sergio , Aronow Bruce J. , Frahm Silke , Kluwe Lan , Mautner Victor , Upadhyaya Meena , Muir David , Wallace Margaret , Hagen Jussara , Quelle Dawn E. , Watson Mark A. , Perry Arie , Gutmann David H. , Ratner Nancy 
Published: March 2006

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14Arf, and p16INK4a proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100β protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool. (Cancer Res 2006; 66(5): 2584-91)
Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen
Authors: Stribinskis Vilius , Ramos Kenneth S. 
Published: March 2006

Abstract
Long interspersed nuclear elements [LINE-1 (L1)] are abundant retrotransposons in mammalian genomes that remain silent under most conditions. Cellular stress signals activate L1, but the molecular mechanisms controlling L1 activation remain unclear. Evidence is presented here that benzo(a)pyrene (BaP), an environmental hydrocarbon metabolized by mammalian cytochrome P450s to reactive carcinogenic intermediates, increases L1 retrotransposition in HeLa cells. Increased retrotransposition is mediated by up-regulation of L1 RNA levels, increased L1 cDNA synthesis, and stable genomic integration. Activation of L1 is dependent on the ability of BaP to cause DNA damage because it is absent in HeLa cells challenged with nongenotoxic hydrocarbon carcinogens. Thus, the mutations and genomic instability observed in human populations exposed to genotoxic environmental hydrocarbons may involve epigenetic activation of mobile elements dispersed throughout the human genome. (Cancer Res 2006; 66(5): 2616-20)
Novel Nanoliposomal CPT-11 Infused by Convection-Enhanced Delivery in Intracranial Tumors: Pharmacology and Efficacy
Authors: Noble Charles O. , Krauze Michal T. , Drummond Daryl C. , Yamashita Yoji , Saito Ryuta , Berger Mitchel S. , Kirpotin Dmitri B. , Bankiewicz Krystof S. , Park John W. 
Published: March 2006

Abstract
We hypothesized that combining convection-enhanced delivery (CED) with a novel, highly stable nanoparticle/liposome containing CPT-11 (nanoliposomal CPT-11) would provide a dual drug delivery strategy for brain tumor treatment. Following CED in rat brains, tissue retention of nanoliposomal CPT-11 was greatly prolonged, with &gt;20% injected dose remaining at 12 days for all doses. Tissue residence was dose dependent, with doses of 60 μg (3 mg/mL), 0.8 mg (40 mg/mL), and 1.6 mg (80 mg/mL) resulting in tissue half-life (t1/2) of 6.7, 10.7, and 19.7 days, respectively. In contrast, CED of free CPT-11 resulted in rapid drug clearance (tissue t1/2 = 0.3 day). At equivalent CED doses, nanoliposomal CPT-11 increased area under the time-concentration curve by 25-fold and tissue t1/2 by 22-fold over free CPT-11; CED in intracranial U87 glioma xenografts showed even longer tumor retention (tissue t1/2 = 43 days). Plasma levels were undetectable following CED of nanoliposomal CPT-11. Importantly, prolonged exposure to nanoliposomal CPT-11 resulted in no measurable central nervous system (CNS) toxicity at any dose tested (0.06-1.6 mg/rat), whereas CED of free CPT-11 induced severe CNS toxicity at 0.4 mg/rat. In the intracranial U87 glioma xenograft model, a single CED infusion of nanoliposomal CPT-11 at 1.6 mg resulted in significantly improved median survival (&gt;100 days) compared with CED of control liposomes (19.5 days; P = 4.9 × 10−5) or free drug (28.5 days; P = 0.011). We conclude that CED of nanoliposomal CPT-11 greatly prolonged tissue residence while also substantially reducing toxicity, resulting in a highly effective treatment strategy in preclinical brain tumor models. (Cancer Res 2006; 66(5): 2801-6)
Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate
Authors: Jones Dylan T. , Trowbridge Ian S. , Harris Adrian L. 
Published: March 2006

Abstract
Cellular iron is needed for cell survival and hydroxylation of hypoxia-inducible factor-1α (HIF-α) by prolyl hydroxylases (PHD). One mechanism of iron uptake is mediated by the cell surface transferrin receptor (TfR). Because iron is required for cell growth and suppression of HIF-α levels, we tested the effects of the two anti-TfR monoclonal antibodies (mAb) E2.3 and A27.15 on growth of breast cancer cells and induction of HIF-α and hypoxia-regulated genes. Treatment with both mAbs together synergistically inhibited cell proliferation in a dose-responsive manner by up to 80% following 8 days of exposure, up-regulated HIF-1α and HIF transcription targets, down-regulated TfR expression, and down-regulated cellular labile iron pool by 60%. Because combined treatment with anti-TfR mAbs resulted in the up-regulation of the hypoxia pathway, which may increase tumor angiogenesis, we analyzed the effects of ascorbate on cell viability and HIF-1α levels in cells treated with both anti-TfR mAbs together, as ascorbate has been shown to be required by PHD enzymes for full catalytic activity. Ascorbate at physiologic concentrations (25 μmol/L) suppressed HIF-1α protein levels and HIF transcriptional targets in anti-TfR mAb-treated cells but did not suppress the antiproliferative effect of the mAbs. These results indicate that the addition of ascorbate increased the activity of the PHD enzymes in down-regulating HIF but not the proliferation of iron-starved anti-TfR mAb-treated cells. The use of anti-TfR mAbs and ascorbate in inhibiting both cell proliferation and HIF-1α and angiogenesis under normoxic conditions may be of therapeutic use. (Cancer Res 2006; 66(5): 2749-56)
Physicochemical and Pharmacokinetic Characterization of Highly Potent Recombinant l-Methionine γ-Lyase Conjugated with Polyethylene Glycol as an Antitumor Agent
Authors: Takakura Tomoaki , Takimoto Akio , Notsu Yoshihide , Yoshida Hiroshi , Ito Takaomi , Nagatome Hirofumi , Ohno Masahiro , Kobayashi Yoshinao , Yoshioka Takayuki , Inagaki Kenji , Yagi Shigeo , Hoffman Robert M. , Esaki Nobuyoshi 
Published: March 2006

Abstract
A highly potent recombinant l-methionine γ-lyase (METase) conjugated with polyethylene glycol (PEG) was characterized physicochemically and pharmacokinetically in vivo and in vitro. Pegylated METase (PEG-METase), which contains pyridoxal 5′-phosphate (PLP) as a cofactor in the molecule, is a potent anticancer agent that can deplete l-methionine from plasma. Although pegylation decreased its specific activity, dithiothreitol (DTT) treatment increased it over three times with the detachment of one PEG moiety modified with a cysteine residue. We can produce DTT-treated PEG-METase on a large scale in sufficient quality for therapeutic use. The superiority of DTT-treated PEG-METase was confirmed by the enhancement of l-methionine depletion and amelioration of pharmacokinetics in mice. The holoenzyme of DTT-treated PEG-METase gave a several times larger area under the plasma concentration curve than that of DTT-untreated PEG-METase, not because of an increase of the half-life but because of high specific activity. Conversely, simultaneous PLP infusion led to a greatly increased half-life of the holoenzyme. DTT-treated PEG-METase administration with PLP infusion was the most useful combination for maximizing the potency of the enzyme. We showed that serum albumin interfered with holoenzyme activity in vitro. The decrease of holoenzyme activity was dependent on the type of serum albumin. We concluded that PLP was released from PEG-METase by serum albumin in vivo and in vitro. The deleterious effect of PLP dissociation from PEG-METase could be improved by supplementing PLP and oleic acid. Their synergistic effect in preventing a decrease of the holoenzyme activity was also observed. (Cancer Res 2006; 66(5): 2807-14)
Cyclooxygenase-1 Is Overexpressed in Multiple Genetically Engineered Mouse Models of Epithelial Ovarian Cancer
Authors: Daikoku Takiko , Tranguch Susanne , Trofimova Irina N. , Dinulescu Daniela M. , Jacks Tyler , Nikitin Alexander Yu. , Connolly Denise C. , Dey Sudhansu K. 
Published: March 2006

Abstract
Cyclooxygenases-1 and -2 (Cox-1 and Cox-2) are two distinct isoforms that catalyze the conversion of arachidonic acid to prostaglandins. The role of Cox-2 in a variety of cancers is well recognized, but the contribution of Cox-1 remains much less explored. We have previously shown that human epithelial ovarian tumors have increased levels of Cox-1, but not Cox-2. We also observed that Cox-1 is highly expressed in a mouse model of epithelial ovarian cancer (EOC), which lacks p53 but overexpresses c-myc and K-ras or c-myc and Akt. More importantly, a Cox-1-selective inhibitor, SC-560, attenuates EOC growth. In the present investigation, we used various genetically engineered mouse models of EOC to determine whether Cox-1 overexpression is unique to specific genetic and oncogenic alterations or is widespread. These models include: (a) deletion of both p53 and Rb, (b) induction of the transforming region of SV40 under the control of Mullerian inhibitory substance type II receptor, or (c) activation of K-Ras in the absence of Pten locally in the ovarian surface epithelium. We found that these three models, which produce spontaneous EOC, also show up-regulated expression of Cox-1, but not Cox-2. The results provide further evidence that Cox-1 overexpression is common in various models of EOC. Thus, Cox-1 serves as a potential marker of EOC and is a possible target for the prevention and/or treatment of this deadly disease. (Cancer Res 2006; 66(5): 2527-31)
Down-regulation of Notch-1 Inhibits Invasion by Inactivation of Nuclear Factor-κB, Vascular Endothelial Growth Factor, and Matrix Metalloproteinase-9 in Pancreatic Cancer Cells
Authors: Wang Zhiwei , Banerjee Sanjeev , Li Yiwei , Rahman K.M. Wahidur , Zhang Yuxiang , Sarkar Fazlul H. 
Published: March 2006

Abstract
Notch signaling plays a critical role in the pathogenesis and progression of human malignancies but the precise role and mechanism of Notch-1 for tumor invasion remains unclear. In our earlier report, we showed that down-regulation of Notch-1 reduced nuclear factor-κB (NF-κB) DNA-binding activity and matrix metalloproteinase-9 (MMP-9) expression. Because NF-κB, VEGF, and MMPs are critically involved in the processes of tumor cell invasion and metastasis, we investigated the role and mechanism(s) by which Notch-1 down-regulation (using molecular approaches) may lead to the down-regulation of NF-κB, vascular endothelial growth factor (VEGF), and MMP-9, thereby inhibiting invasion of pancreatic cancer cells through Matrigel. We found that the down-regulation of Notch-1 by small interfering RNA decreased cell invasion, whereas Notch-1 overexpression by cDNA transfection led to increased tumor cell invasion. Consistent with these results, we found that the down-regulation of Notch-1 reduced NF-κB DNA-binding activity and VEGF expression. Down-regulation of Notch-1 also decreased not only MMP-9 mRNA and its protein expression but also inactivated the pro-MMP-9 protein to its active form. Taken together, we conclude that the down-regulation of Notch-1 could be an effective approach for the down-regulation and inactivation of NF-κB and its target genes, such as MMP-9 and VEGF expression, resulting in the inhibition of invasion and metastasis. (Cancer Res 2006; 66(5): 2778-84)
From Integrated Genomics to Tumor Lineage Dependency
Authors: Garraway Levi A. , Sellers William R. 
Published: March 2006

Abstract
In principle, genomic information derived from tumors should illuminate critical cellular dependencies that are tractable to therapeutic targeting; however, realizing this ideal remains difficult. Using an integrated analysis of high-resolution single nucleotide polymorphism maps and gene expression databases associated with the NCI60 collection cancer cell lines, we identified the transcription factor MITF as an amplified oncogene in melanoma that is critical for anchoring lineage dependence and malignant character. Similar combined genomic approaches may be useful in other cancer types to learn how critical regulators of tumor lineage are linked to genomic alterations in cancer cells. (Cancer Res 2006; 66(5): 2506-8)
'Do You Want To Receive A Missionary At Home?': Conversion And The Religious Market
Authors: Sengers Erik 
Published: March 2006

AbstractThis paper offers an introduction in religious market theory on the basis of the theme of conversion. Conversions have everything to do with the religious market. Where people are looking for religious satisfaction, they will turn themselves to religious organisations that are willing to give that on certain conditions. Starting from the assumption of the rational actor, the theory makes some strong hypotheses on religious organisations and the religious market. What does the religious market look like, what are the basic characteristics of this market, and how can religious organisations interact with that market? However, when we discuss social-scientific research on conversion in Europe, the limits of religious market theory come to the fore. In the conclusion, the main questions that arise from religious market theory for the project Conversion Careers and Culture Politics in Pentecostalism are being discussed.
Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells
Authors: Obeng Esther A. , Carlson Louise M. , Gutman Delia M. , Harrington William J. , Lee Kelvin P. , Boise Lawrence H. 
Published: March 2006

AbstractMultiple myeloma (MM) is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in MM cells; however, the nature of its selectivity remains unknown. Here we demonstrate that 5 different MM cell lines display similar patterns of sensitivity to 3 proteasome inhibitors (PIs) but respond differently to specific NF-κB inhibition. We further show that PIs initiate the unfolded protein response (UPR), a signaling pathway activated by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). Consistent with reports that prosurvival/physiologic UPR components are required for B-cell differentiation into antibody-secreting cells, we found that MM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96. However, bortezomib rapidly induced components of the proapoptotic/terminal UPR, including PERK, the ER stress–specific eIF-2α kinase; ATF4, an ER stress–induced transcription factor; and its proapoptotic target, CHOP/GADD153. Consistent with our hypothesis that PIs induce the accumulation of misfolded ER-processed proteins, we found that the amount of immunoglobulin subunits retained within MM cells correlated with their sensitivity to PIs. These findings suggest that MM cells have a lower threshold for PI-induced UPR induction and ER stress–induced apoptosis because they constitutively express ER stress survival factors to function as secretory cells.