bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Antiapoptotic Role for Gastrin and the Gastrin/CCK-2 Receptor in Barrett’s Esophagus
Authors: Harris Joseph C. , Clarke Philip A. , Awan Altaf , Jankowski Janusz , Watson Susan A. 
Published: September 2005

Abstract
Mechanisms by which premalignant Barrett’s metaplasia (BM) progresses to esophageal adenocarcinoma are currently being sought. This study investigated the role played by the polypeptide hormone gastrin, specifically its antiapoptotic effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell lines with low basal levels of activated PKB/Akt, phosphorylation could be induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt were linked to endogenous gastrin expression and were reduced by treatment with a cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a constitutively active splice variant of the CCK-2R additionally increased basal activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may aid progression of BM through amplification of antiapoptotic pathways. Evidence for this proposal was provided through the observed specific up-regulation of PKB/Akt in BM samples.
Hypoxia Increases Heparanase-Dependent Tumor Cell Invasion, Which Can Be Inhibited by Antiheparanase Antibodies
Authors: He Xiaotong , Brenchley Paul E. C. , Jayson Gordon C. , Hampson Lynne , Davies John , Hampson Ian N. 
Published: September 2005

Abstract
The β-endoglucuronidase heparanase plays an important role in tumor invasion, a process that is significantly enhanced by hypoxia. We have used a strategy of stable transfection with antisense to derive ovarian carcinoma cell lines that express different levels of heparanase and used these to demonstrate that invasion correlates with heparanase activity. Secreted heparanase activity was increased by reduction, hypoxia, and growth of cells under reduced oxygen (1%) augmented heparanase activity and invasion, both of which are inhibited by treatment with antiheparanase antibodies. This is the first demonstration that heparanase activity may be regulated by microenvironmental redox conditions, which influence invasion, and that invasion can be blocked with specific heparanase-neutralizing antibodies.
The Tumor Invasion Inhibitor Dihydromotuporamine C Activates RHO, Remodels Stress Fibers and Focal Adhesions, and Stimulates Sodium–Proton Exchange
Authors: McHardy Lianne M. , Sinotte Ryan , Troussard Armelle , Sheldon Claire , Church John , Williams David E. , Andersen Raymond J. , Dedhar Shoukat , Roberge Michel , Roskelley Calvin D. 
Published: September 2005

Abstract
The motuporamines are macrocyclic alkaloids that inhibit tumor cell invasion by an, as yet, unknown mechanism. A structure–activity study recently identified dihydromotuporamine C (dhMotC) as a highly active and readily synthesized analogue. Here, we show that dhMotC causes subtle cytoskeletal alterations in highly invasive MDA231 breast tumor cells that include an increase in the thickness and number of cytoplasmic actin stress fibers. Experiments with serum-starved Swiss 3T3 fibroblasts showed that micromolar concentrations of dhMotC that inhibit tumor cell invasion induce the formation of new stress fibers and large focal adhesion complexes that are dispersed around the entire cell periphery. dhMotC treatment of Swiss 3T3 cells also initiates a strong, long-lived activation of the small GTP-binding protein Rho, and it stimulates Rho kinase-dependent sodium–proton exchanger activity. Liposome-mediated cell loading of C3 exoenzyme prevents dhMotC-mediated Rho activation and stress fiber formation in 3T3 cells. C3 exoenzyme loading also reestablishes elongated MDA231 breast tumor cell invasion in the presence of dhMotC. Taken together, these results indicate that the ability to activate Rho is one important determinant of the anti-invasive activity of dhMotC.
The Role of Metastasis-Associated Protein 1 in Prostate Cancer Progression
Authors: Hofer Matthias D. , Kuefer Rainer , Varambally Sooryanarayana , Li Haojie , Ma Jing , Shapiro Geoffrey I. , Gschwend Juergen E. , Hautmann Richard E. , Sanda Martin G. , Giehl Klaudia , Menke Andre , Chinnaiyan Arul M. , Rubin Mark A. 
Published: September 2005

Abstract
Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, as current therapy requires over treating men with prostate cancer to prevent the progression of a few cases. Expression of the metastasis-associated protein 1 (MTA1) has previously been found to be associated with progression to the metastatic state in various cancers. Analyzing DNA microarray data, we found MTA1 to be selectively overexpressed in metastatic prostate cancer compared with clinically localized prostate cancer and benign prostate tissue. These results were validated by demonstrating overexpression of MTA1 in metastatic prostate cancer by immunoblot analysis. MTA1 protein expression was evaluated by immunohistochemistry in a broad spectrum of prostate tumors with tissue microarrays containing 1940 tissue cores from 300 cases. Metastatic prostate cancer demonstrated significantly higher mean MTA1 protein expression intensity (score = 3.4/4) and percentage of tissue cores staining positive for MTA1 (83%) compared with clinically localized prostate cancer (score = 2.8/4, 63% positive cores) or benign prostate tissue (score = 1.5/4, 25% positive cores) with a mean difference of 0.54 and 1.84, respectively (P &lt; 0.00001 for both). Paradoxically, for localized disease, higher MTA1 protein expression was associated with lower rates of prostate specific antigen recurrence after radical prostatectomy for localized disease. In summary, this study identified an association of MTA1 expression and prostate cancer progression.
Prostate Specific Antigen Expression Is Down-Regulated by Selenium through Disruption of Androgen Receptor Signaling
Authors: Dong Yan , Lee Soo Ok , Zhang Haitao , Marshall James , Gao Allen C. , Ip Clement 
Published: September 2005

Abstract
A previous controlled intervention trial showed that selenium supplementation was effective in reducing the incidence of prostate cancer. Physiological concentrations of selenium have also been reported to inhibit the growth of human prostate cancer cells in vitro. The present study describes the observation that selenium was able to significantly down-regulate the expression of prostate-specific antigen (PSA) transcript and protein within hours in the androgen-responsive LNCaP cells. Decreases in androgen receptor (AR) transcript and protein followed a similar dose and time response pattern upon exposure to selenium. The reduction of AR and PSA expression by selenium occurred well before any significant change in cell number. With the use of a luciferase reporter construct linked to either the PSA promoter or the androgen responsive element, it was found that selenium inhibited the trans-activating activity of AR in cells transfected with the wild-type AR expression vector. Selenium also suppressed the binding of AR to the androgen responsive element site, as evidenced by electrophoretic mobility shift assay of the AR-androgen responsive element complex. In view of the fact that PSA is a well-accepted prognostic indicator of prostate cancer, an important implication of this study is that a selenium intervention strategy aimed at toning down the amplitude of androgen signaling could be helpful in controlling morbidity of this disease.
Induction of Apoptosis and Down-Regulation of Bcl-XL in Cancer Cells by a Novel Small Molecule, 2[ [3-(2,3-Dichlorophenoxy)propyl]amino]ethanol
Authors: Wu Shuhong , Zhu Hongbo , Gu Jian , Zhang Lidong , Teraishi Fuminori , Davis John J. , Jacob Dietmar A. , Fang Bingliang 
Published: September 2005

Abstract
In a search for new anticancer agents, we identified that 2[[3-(2,3-dichlorophenoxy) propyl]amino]ethanol (2,3-DCPE) induced apoptosis more effectively in various cancer cells than in normal human fibroblasts. We further evaluated the cell-killing effects of this compound in vitro in several human cancer cell lines and normal human fibroblasts. A cell viability assay showed that IC50s for human colon cancer cell lines LoVo and DLD-1, for human lung cancer cell lines H1299 and A549, and for normal human fibroblasts were 0.89, 1.95, 2.24, 2.69, and 12.6 μm, respectively. Subsequent studies revealed that 2,3-DCPE could cause cleavage of caspase-8, caspase-3, caspase-9, and poly(ADP-ribose) polymerase and release of cytochrome c in cancer cells but not in normal human fibroblasts. Our data also showed that 2,3-DCPE attenuated the protein level of Bcl-XL and that apoptosis induction by 2,3-DCPE could be blocked by enforced overexpression of Bcl-XL. Our results suggest that 2,3-DCPE might be a potential new anticancer agent.
Significant Differences in the Effects of Magnetic Field Exposure on 7,12-Dimethylbenz(a)anthracene-Induced Mammary Carcinogenesis in Two Substrains of Sprague-Dawley Rats
Authors: Fedrowitz Maren , Kamino Kenji , Löscher Wolfgang 
Published: September 2005

AbstractWe have shown previously (S. Thun-Battersby et al., Cancer Res., 59: 3627–3633, 1999) that power-line frequency (50-Hz) magnetic fields (MFs) at μT-flux densities enhance mammary gland tumor development and growth in the 7,12-dimethylbenz(a)anthracene (DMBA) model of breast cancer in female Sprague-Dawley (SD) rats. We also demonstrated that MF exposure results in an enhanced proliferative activity of the mammary epithelium of SD rats (M. Fedrowitz et al., Cancer Res., 62: 1356–1363, 2002), which is a likely explanation for the cocarcinogenic or tumor-promoting effects of MF exposure in the DMBA model. However, in contrast with our data, in a similar study conducted by Battelle in the United States, no evidence for a cocarcinogenic or tumor-promoting effect of MF exposure was found in the DMBA model in SD rats (L. E. Anderson et al., Carcinogenesis, 20: 1615–1620, 1999). Probably the most important difference between our and the Battelle studies was the use of different substrains of SD rats; the United States rats were much more susceptible to DMBA than the rats used in our studies. This prompted us to compare different substrains of SD outbred rats in our laboratory in respect to MF effects on cell proliferation in the mammary gland, susceptibility to DMBA-induced mammary cancer, and MF effects on mammary tumor development and growth in the DMBA model. The SD substrain (termed “SD1”) used in all of our previous studies was considered MF-sensitive and used for comparison with another substrain (“SD2”) obtained from the same breeder. In contrast with SD1 rats, no enhanced cell proliferation was determined after MF exposure in SD2 rats. MF exposure significantly increased mammary tumor development and growth in SD1 but not SD2 rats. These data indicate that the genetic background plays a pivotal role in effects of MF exposure. Different strains or substrains of rats may serve to evaluate the genetic factors underlying sensitivity to cocarcinogenic or tumor-promoting effects of MF exposure.
Emmprin Promotes Anchorage-Independent Growth in Human Mammary Carcinoma Cells by Stimulating Hyaluronan Production
Authors: Marieb Erica A. , Zoltan-Jones Alexandra , Li Rongsong , Misra Suniti , Ghatak Shibnath , Cao Jian , Zucker Stanley , Toole Bryan P. 
Published: September 2005

Abstract
Emmprin (CD147; basigin) is a plasma membrane glycoprotein, enriched on the surface of many cancer cells, which induces matrix metalloproteinase synthesis via cell-cell interactions. Elevated emmprin production causes increased growth in vivo of human mammary carcinoma cells. In this study, we show that elevation of emmprin expression in less aggressive human carcinoma cells, which normally express low emmprin levels, induces the ability to grow under anchorage-independent conditions. We also found that elevated emmprin expression stimulates hyaluronan production and that the effect of emmprin on anchorage-independent growth is dependent on hyaluronan. Furthermore, emmprin stimulates cell survival pathway signaling in a hyaluronan-dependent manner. From these and other studies we conclude that emmprin enhances several malignant properties of cancer cells, including anchorage-independent growth, invasiveness, and chemoresistance.
Antitumor Activity of 3-Ingenyl Angelate
Authors: Ogbourne Steven M. , Suhrbier Andreas , Jones Brad , Cozzi Sarah-Jane , Boyle Glen M. , Morris Melanie , McAlpine Devi , Johns Jenny , Scott Tania M. , Sutherland Kirsty P. , Gardner Joy M. , Le Thuy T. T. , Lenarczyk Aleksandra , Aylward James H. , Parsons Peter G. 
Published: September 2005

Abstract
Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodessication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 μg) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; n = &gt;14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; n = &gt;4 tumors/group) previously established (5–10 mm3) on C57BL/6 or Foxn1nu mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD90 for PEP005 for a panel of tumor cell lines was 180–220 μm. Electron microscopy showed that treatment with PEP005 both in vitro (230 μm) and in vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. 51Cr release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 μm) treatment of tumor cells in vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.
Association of Homozygous Wild-Type Glutathione S-Transferase M1 Genotype with Increased Breast Cancer Risk
Authors: Roodi Nady , Dupont William D. , Moore Jason H. , Parl Fritz F. 
Published: September 2005

Abstract
More than 500 studies have examined the association of the glutathione S-transferase M1 (GSTM1) genotype with various malignancies yielding inconsistent results. The genotyping was based on a PCR assay that identified the GSTM1 null (−/−) genotype but did not distinguish homozygous wild-type (+/+) and heterozygous (+/−) individuals. We developed an assay that allowed the definition of +/+, +/−, and −/− genotypes by separate identification of wild-type and null alleles, which were found with frequencies of 0.225 and 0.775, respectively, in Caucasian women. We applied the new assay to a breast cancer case-control study and identified the +/+ genotype in 14 (6.9%) of 202 control subjects compared with 37 (18.2%) of 203 patients. Compared with women with the −/− genotype, the relative risk of breast cancer for the +/+ genotype was 2.83 (95% confidence interval, 1.45–5.59; P = 0.002), suggesting a protective effect of the GSTM1 deletion.
Rituximab-Dependent Cytotoxicity by Natural Killer Cells
Authors: Dall’Ozzo Sébastien , Tartas Sophie , Paintaud Gilles , Cartron Guillaume , Colombat Philippe , Bardos Pierre , Watier Hervé , Thibault Gilles 
Published: September 2005

AbstractThe FCGR3A gene dimorphism generates two allotypes: FcγRIIIa-158V and FcγRIIIa-158F. The genotype homozygous for FcγRIIIa-158V (VV) is associated with higher clinical response to rituximab, a chimeric anti-CD20 IgG1 used in the treatment of B lymphoproliferative malignancies. Our objective was to determine whether this genetic association relates to rituximab-dependent cytotoxicity mediated by FcγRIIIa/CD16a+ cells. The number of CD16+ circulating monocytes, T cells, and natural killer (NK) cells in 54 donors was first shown to be unrelated to FCGR3A polymorphism. We then demonstrated that FcγRIIIa-158V displays higher affinity for rituximab than FcγRIIIa-158F by comparing rituximab concentrations inhibiting the binding of 3G8 mAb (anti-CD16) with VV NK cells and NK cells homozygous for FcγRIIIa-158F (FF). VV and FF NK cells killed Daudi cells similarly after FcγRIIIa engagement by saturating concentrations of rituximab or 3G8. However, the rituximab concentration resulting in 50% lysis (EC50) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors (on average 0.00096 and 0.00402 μg/ml, respectively, P = 0.0043). Finally, the functional difference between VV and FF NK cells was restricted to rituximab concentrations weakly sensitizing CD20. This study supports the conclusion that FCGR3A genotype is associated with response to rituximab because it affects the relationship between rituximab concentration and NK cell-mediated lysis of CD20+ cells. Rituximab administration could therefore be adjusted according to FCGR3A genotype.
Insulin-Like Growth Factor Binding Protein-3 Interacts with Autocrine Motility Factor/Phosphoglucose Isomerase (AMF/PGI) and Inhibits the AMF/PGI Function
Authors: Mishra Suresh , Raz Avrahram , Murphy Liam J. 
Published: September 2005

Abstract
Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) was identified as a binding partner for insulin-like growth factor binding protein-3 (IGFBP-3) in solubilized T47D and MCF-7 human breast cancer cell membranes. The interaction between AMF/PGI and IGFBP-3 was verified by cross-linking biotinylated IGFBP-3 to intact cells. After solubilization of the membranes, the biotinylated complexes were precipitated with streptavidin-agarose conjugate and analyzed by SDS-PAGE. A Mr ∼80,000 complex was identified when the nitrocellulose membranes were probed either with streptavidin-horseradish peroxidase conjugate or AMF/PGI antiserum confirming the cross-linking of IGFBP-3 to AMF/PGI. The interaction between IGFBP-3 and AMF/PGI was also further confirmed by ligand blotting of purified AMF/PGI using biotinylated IGFBP-3. Both glycosylated and nonglycosylated IGFBP-3 inhibited the catalytic activity of AMF/PGI in a dose-dependent fashion. In addition, IGFBP-3 inhibited the binding of AMF/PGI to breast cancer cells and AMF/PGI-induced migration of both T47D and MCF-7 human breast cancer cells. IGFBP-3 also decreased the phosphorylation of AMF/PGI and reduced the translocation of AMF/PGI to the cell membrane and AMF/PGI. AMF/PGI resulted in a dose-dependent inhibition of IGFBP-3 induced apoptosis in T47D and MCF-7 cells. In summary, we have identified AMF/PGI as a membrane-associated binding partner for IGFBP-3 in breast cancer cells. The ability of IGFBP-3 to bind and inhibit the actions of AMF/PGI may have some role in the antiproliferative proapoptotic effects of IGFBP-3.
Role of the Grb2-Associated Binder 1/SHP-2 Interaction in Cell Growth and Transformation
Authors: Holgado-Madruga Marina , Wong Albert J. 
Published: September 2005

Abstract
Grb2-associated binder 1 (Gab1) is a docking protein that is tyrosine phosphorylated following the activation of multiple cytokine receptors and receptor tyrosine kinases. Its function then is to recruit and activate multiple signaling molecules. In our previous work, we showed that Gab1 enhances cell growth and induces the transformed phenotype in NIH3T3 cells downstream of the epidermal growth factor (EGF) receptor. In this report, we analyze how it produces these effects. Because SHP-2 is the major binding partner of Gab1, we mutated its binding site in the Gab1 cDNA (Gab1/ΔSHP-2). This construct was stably overexpressed in NIH3T3 cells (3T3-Gab1/ΔSHP-2) and in the wild-type Gab1 cDNA (3T3-Gab1) or an empty expression vector (3T3-CTR). Our findings show that after EGF stimulation, Gab1/ΔSHP-2 has a higher level of tyrosine phosphorylation at early time points than Gab1. Gab1/ΔSHP-2 recruits more phosphatidylinositol 3′-kinase than Gab1 after EGF triggering, which accounts for a higher and more sustained AKT activation in 3T3-Gab1/ΔSHP-2 cells relative to 3T3-Gab1 fibroblasts. Moreover, 3T3-Gab1/ΔSHP-2 cells demonstrate a higher level of extracellular-regulated kinase 1 activation at early time points of EGF stimulation. However, there was an unexpected decrease in c-fos promoter induction in 3T3-Gab1/ΔSHP-2 cells when compared with 3T3-Gab1 cells. Additionally, the 3T3-Gab1/ΔSHP-2 cells show a reversion of the transformed phenotype, including fewer morphologic changes, an increase in stress fiber cytoskeletal organization, and a decrease in cell proliferation and anchorage independent growth. These results reveal that the Gab1/SHP-2 interaction is essential for cell growth and transformation but that this must occur through a novel pathway that is independent of extracellular-regulated kinase or AKT. On the basis of its role in growth and transformation, the Gab1/SHP-2 interaction may become an attractive target for the pharmacologic intervention of malignant cell growth.
Caspase-8-Dependent HER-2 Cleavage in Response to Tumor Necrosis Factor α Stimulation Is Counteracted by Nuclear Factor κB through c-FLIP-L Expression
Authors: Benoit Valérie , Chariot Alain , Delacroix Laurence , Deregowski Valérie , Jacobs Nathalie , Merville Marie-Paule , Bours Vincent 
Published: September 2005

AbstractThe oncoprotein HER-2/neu is a prosurvival factor, and its overexpression has been correlated with poor prognosis in patients with breast cancer. We report that HER-2 is a new substrate for caspase-8 and that tumor necrosis factor α (TNF-α) stimulation leads to an early caspase-8-dependent HER-2 cleavage in MCF7 A/Z breast adenocarcinoma cells defective for nuclear factor κB (NFκB) activation. We show that the antiapoptotic transcription factor NFκB counteracts this cleavage through induction of the caspase-8 inhibitor c-FLIP. Our results also demonstrate that this HER-2 cleavage contributes to the TNF-α-induced apoptosis pathway because ectopic expression of an uncleavable HER-2 protects NFκB-defective cells against TNF-α-mediated cell death. Therefore, we propose an original model in which NFκB exerts a new antiapoptotic function by counteracting TNF-α-triggered cleavage of the HER-2 survival factor.