bluuebunny/crossref_metadata_2025_split huggingface dataset:
Helicobacter pyloriInduces Plasminogen Activator Inhibitor 2 in Gastric Epithelial Cells through Nuclear Factor-κB and RhoA
Authors: Varro Andrea , Noble P-J. M. , Pritchard D. Mark , Kennedy Susan , Hart C. Anthony , Dimaline Rod , Dockray Graham J. 
Published: September 2005

AbstractThe gastric pathogen Helicobacter pylori is associated with a progression to gastric cancer. The specific targets of H. pylori that might influence this progression are still unclear. Previous studies indicated that the gastric hormone gastrin, which may be increased in H. pylori infection, stimulates gastric expression of plasminogen activator inhibitor (PAI)-2, which is an inhibitor of the urokinase plasminogen activator and has previously been shown to be increased in gastric adenocarcinoma. Here, we report that H. pylori also increases PAI-2 expression. In gastric biopsies of H. pylori-positive subjects there was increased PAI-2, including subjects with plasma gastrin concentrations in the normal range. PAI-2 was expressed mainly in chief and mucous cells. In a gastric cancer cell line (AGS), H. pylori increased PAI-2 expression, which was associated with inhibition of H. pylori-stimulated cell invasion and apoptosis. The induction of PAI-2 by H. pylori was mediated by release of interleukin-8 and activation of cyclooxygenase-2, and interestingly, gastrin stimulated PAI-2 expression by similar paracrine pathways. The activation of NFκB was required for interleukin-8 and cyclooxygenase-2 activation but did not occur in cells responding to these paracrine mediators. The data suggest that induction of PAI-2 is a specific target in H. pylori infection, mediated at least partly by paracrine factors; induction of PAI-2 inhibits cell invasion and apoptosis and is a candidate for influencing the progression to gastric cancer.
Resveratrol-induced Autophagocytosis in Ovarian Cancer Cells
Authors: Opipari Anthony W. , Tan Lijun , Boitano Anthony E. , Sorenson Dorothy R. , Aurora Anjili , Liu J. Rebecca 
Published: September 2005

Abstract
Resveratrol (3,5,4-trihydroxystilbene), a natural phytoalexin present in grapes, nuts, and red wine, has antineoplastic activities. Several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo. In the present study, the response of ovarian cancer cells to resveratrol is explored. Resveratrol inhibited growth and induced death in a panel of five human ovarian carcinoma cell lines. The response was associated with mitochondrial release of cytochrome c, formation of the apoptosome complex, and caspase activation. Surprisingly, even with these molecular features of apoptosis, analysis of resveratrol-treated cells by light and electron microscopy revealed morphology and ultrastructural changes indicative of autophagocytic, rather than apoptotic, death. This suggests that resveratrol can induce cell death through two distinct pathways. Consistent with resveratrol’s ability to kill cells via nonapoptotic processes, cells transfected to express high levels of the antiapoptotic proteins Bcl-xL and Bcl-2 are equally sensitive as control cells to resveratrol. Together, these findings show that resveratrol induces cell death in ovarian cancer cells through a mechanism distinct from apoptosis, therefore suggesting that it may provide leverage to treat ovarian cancer that is chemoresistant on the basis of ineffective apoptosis.
Overexpression of a Dominant-Negative Mutant Ubc9 Is Associated with Increased Sensitivity to Anticancer Drugs
Authors: Mo Yin-Yuan , Yu Yanni , Ee P. L. Rachel , Beck William T. 
Published: September 2005

Abstract
Ubc9 is an E2-conjugating enzyme required for sumoylation and has been implicated in regulating several critical cellular pathways. We have shown previously that Ubc9 is important for sumoylation and nucleolar delocalization of topoisomerase (topo) I in response to topo I inhibitors such as topotecan. However, the role for Ubc9 in tumor drug responsiveness is not clear. In this study, we found that although MCF7 cells expressing a Ubc9 dominant-negative mutant (Ubc9-DN) display decreased activity of topo I, these cells are more sensitive to the topo I inhibitor topotecan and other anticancer agents such as VM-26 and cisplatin. In addition, we found that alteration of Ubc9 expression correlates with drug responsiveness in tumor cell lines. To understand possible mechanisms of Ubc9-associated drug responsiveness, we examined several proteins that have been shown to interact with Ubc9 and that may be involved in drug responsiveness. One such protein is Daxx, which is a Fas-associated protein that plays a role in Fas-mediated apoptosis by participating in a caspase-independent pathway through activation of apoptosis signal-regulating kinase 1 and c-Jun NH2-terminal kinase. We found that cells expressing Ubc9-DN accumulate more cytoplasmic Daxx than the control cells. Because cytoplasmic Daxx is believed to participate in cellular apoptosis, we suggest that the interaction of Ubc9 with Daxx and subsequent alteration in the subcellular localization of Daxx may contribute to the increased sensitivity to anticancer drugs in the cells expressing Ubc9-DN. Finally, we found that overexpression of Daxx sensitizes cells to anticancer drugs possibly in part through alterations of the ratio of cytoplasmic and nuclear Daxx. Together, our results suggest a role for Ubc9 in tumor drug responsiveness.
Resveratrol Inhibits Drug-Induced Apoptosis in Human Leukemia Cells by Creating an Intracellular Milieu Nonpermissive for Death Execution
Authors: Ahmad Kashif Adil , Clement Marie-Veronique , Hanif Ismail Muhamad , Pervaiz Shazib 
Published: September 2005

Abstract
Efficient apoptotic signaling is a function of a permissive intracellular milieu created by a decrease in the ratio of superoxide to hydrogen peroxide and cytosolic acidification. Resveratrol (RSV) triggers apoptosis in some systems and inhibits the death signal in others. In this regard, the inhibitory effect on hydrogen peroxide-induced apoptosis is attributed to its antioxidant property. We provide evidence that exposure of human leukemia cells to low concentrations of RSV (4–8 μm) inhibits caspase activation, DNA fragmentation, and translocation of cytochrome c induced by hydrogen peroxide or anticancer drugs C2, vincristine, and daunorubicin. Interestingly, at these concentrations, RSV induces an increase in intracellular superoxide and inhibits drug-induced acidification. Blocking the activation of NADPH oxidase complex neutralized RSV-induced inhibition of apoptosis. Furthermore, our results implicate intracellular hydrogen peroxide as a common effector mechanism in drug-induced apoptosis that is inhibited by preincubation with RSV. Interestingly, decreasing intracellular superoxide with the NADPH oxidase inhibitor diphenyliodonium reversed the inhibitory effect of RSV on drug-induced hydrogen peroxide production. These data show that low concentrations of RSV inhibit death signaling in human leukemia cells via NADPH oxidase-dependent elevation of intracellular superoxide that blocks mitochondrial hydrogen peroxide production, thereby resulting in an intracellular environment nonconducive for death execution.
LynIs a Target Gene for Prostate Cancer
Authors: Goldenberg-Furmanov Mirela , Stein Ilan , Pikarsky Eli , Rubin Hila , Kasem Shafika , Wygoda Marc , Weinstein Irina , Reuveni Hadas , Ben-Sasson Shmuel A. 
Published: September 2005

AbstractThe Src-related protein kinase Lyn plays an important role in B-cell activation. However, several lines of evidence suggest that it is also involved in the control of cellular proliferation and the inhibition of apoptosis. We have discovered that Lyn is expressed in normal prostate epithelia, in 95% of primary human prostate cancer (PC) specimens examined, and in all of the PC cell lines that we assayed. Moreover, Lyn knockout mice display abnormal prostate gland morphogenesis, which suggests that Lyn plays an important role in prostate epithelium development and implies that Lyn is a candidate target for specific therapy for PC. Using a drug-design strategy to construct sequence-based peptide inhibitors, a Lyn-specific inhibitor, KRX-123, targeting a unique interaction site within Lyn, was synthesized. KRX-123 was found to inhibit cellular proliferation in three hormone-refractory PC cell lines, DU145, PC3, and TSU-Pr1 with IC50 values of 2–4 μm. In vivo, tumor volume of DU145 explants in nude mice was significantly reduced after once-a-week injections of KRX-123, at a dose of 10 mg/kg, for a period of 5 weeks. Histological analyses of the treated tumors indicated extensive apoptosis. Thus, we suggest that Lyn inhibition may serve as a prime target for the treatment of hormone-refractory PC.
In Vitro
Studies with Methylproamine
Authors: Martin Roger F. , Broadhurst Sam , Reum Monica E. , Squire Christopher J. , Clark George R. , Lobachevsky Pavel N. , White Jonathan M. , Clark Chris , Sy Denise , Spotheim-Maurizot Melanie , Kelly David P. 
Published: September 2005

Abstract
New analogues of the minor groove binding ligand Hoechst 33342 have been investigated in an attempt to improve radioprotective activity. The synthesis, DNA binding, and in vitro radioprotective properties of methylproamine, the most potent derivative, are reported. Experiments with V79 cells have shown that methylproamine is ∼100-fold more potent than the classical aminothiol radioprotector WR1065. The crystal structures of methylproamine and proamine complexes with the dodecamer d(CGCGAATTCGCG)2 confirm that the new analogues also are minor groove binders. It is proposed that the DNA-bound methylproamine ligand acts as a reducing agent by an electron transfer mechanism, repairing transient radiation-induced oxidizing species on DNA.
Antibodies Directed against Lewis-Y Antigen Inhibit Signaling of Lewis-Y Modified ErbB Receptors
Authors: Klinger Markus , Farhan Hesso , Just Herwig , Drobny Helmut , Himmler Gottfried , Loibner Hans , Mudde Geert C. , Freissmuth Michael , Sexl Veronika 
Published: September 2005

AbstractThe majority of cancer cells derived from epithelial tissue express Lewis-Y (LeY) type difucosylated oligosaccharides on their plasma membrane. This results in the modification of cell surface receptors by the LeY antigen. We used the epidermal growth factor (EGF) receptor family members ErbB1 and ErbB2 as model systems to investigate whether the sugar moiety can be exploited to block signaling by growth factor receptors in human tumor cells (i.e., SKBR-3 and A431, derived from a breast cancer and a vulval carcinoma, respectively). The monoclonal anti-LeY antibody ABL364 and its humanized version IGN311 immunoprecipitated ErbB1 and ErbB2 from detergent lysates of A431 and SKBR-3, respectively. ABL364 and IGN311 blocked EGF- and heregulin-stimulated phosphorylation of mitogen-activated protein kinase [MAPK = extracellular signal-regulated kinase 1/2] in SKBR-3 and A431 cells. The effect was comparable in magnitude with that of trastuzumab (Herceptin) and apparently noncompetitive with respect to EGF. Stimulation of MAPK by ErbB was dynamin dependent and contingent on receptor internalization. ABL364 and IGN311 changed the intracellular localization of fluorescent EGF-containing endosomes and accelerated recycling of intracellular [125I]EGF to the plasma membrane. Taken together, these observations show that antibodies directed against carbohydrate side chains of ErbB receptors are capable of inhibiting ErbB-mediated signaling. The ability of these antibodies to reroute receptor trafficking provides a mechanistic explanation for their inhibitory action.
Transcriptional Regulation of the Melanoma Prognostic Marker Melastatin (TRPM1) by MITF in Melanocytes and Melanoma
Authors: Miller Arlo J. , Du Jinyan , Rowan Sheldon , Hershey Christine L. , Widlund Hans R. , Fisher David E. 
Published: September 2005

Abstract
Determining the metastatic potential of intermediate thickness lesions remains a major challenge in the management of melanoma. Clinical studies have demonstrated that expression of melastatin/TRPM1 strongly predicts nonmetastatic propensity and correlates with improved outcome, leading to a national cooperative prospective study, which is ongoing currently. Similarly, the melanocytic markers MLANA/MART1 and MITF also have been shown to lose relative expression during melanoma progression. Recent studies have revealed that MITF, an essential transcription factor for melanocyte development, directly regulates expression of MLANA. This prompted examination of whether MITF also might transcriptionally regulate TRPM1 expression. The TRPM1 promoter contains multiple MITF consensus binding elements that were seen by chromatin immunoprecipitation to be occupied by endogenous MITF within melanoma cells. Endogenous TRPM1 expression responded strongly to MITF up- or down-regulation, as did TRPM1 promoter-driven reporters. In addition, MITF and TRPM1 mRNA levels were correlated tightly across a series of human melanoma cell lines. Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation. These studies identify MITF as a major transcriptional regulator of TRPM1 and suggest that its prognostic value may be linked to MITF-mediated regulation of cellular differentiation.
TIMP-1 Alters Susceptibility to Carcinogenesis
Authors: Rhee Jin-Sae , Diaz Robert , Korets Lidiya , Hodgson J. Graeme , Coussens Lisa M. 
Published: September 2005

AbstractTissue inhibitors of metalloproteinases (TIMPs) are a family of multifunctional proteins known to possess a broad range of biological activities, including inhibition of metalloproteinase activity, regulation of proliferation and apoptosis of a variety of cell types, and, depending on the context, differential regulation of angiogenic and inflammatory responses. Elevated mRNA expression of TIMP family members correlates with malignancy and clinical outcome in many human cancer types; however, a protective role for TIMPs also has been observed in various mouse models of human cancer. In the current study, we found distinct spatial-temporal expression patterns for the mRNA of TIMP family members in a mouse model of epithelial carcinogenesis [i.e., keratin 14-human papillomavirus 16 (K14-HPV16) transgenic mice]. To test the hypothesis that elevated expression of TIMP-1 functionally regulates epithelial carcinogenesis, we introduced a human TIMP-1 transgene into K14-HPV16 transgenic mice and assessed neoplastic progression. Results from these studies suggest that TIMP-1 enhances tumorgenicity by potentiating keratinocyte hyperproliferation and appearance of chromosomal aberrations in premalignant cells, thereby increasing their risk to undergo malignant conversion. In addition, TIMP-1 inhibits tissue gelatinolytic activity in tumor stroma, affects stabilization of collagen fibrils, but does not inhibit malignant conversion of dysplasias into carcinomas or development of metastases. The combined implications of these studies suggest that TIMP-1 is an important contributor to epithelial neoplastic progression and supports the concept that TIMP-1 exerts differential regulation on tissues in a stage-dependent manner.
Improved Grading of Breast Adenocarcinomas Based on Genomic Instability
Authors: Kronenwett Ulrike , Huwendiek Sören , Östring Carin , Portwood Neil , Roblick Uwe J. , Pawitan Yudi , Alaiya Ayodele , Sennerstam Roland , Zetterberg Anders , Auer Gert 
Published: September 2005

Abstract
Numerous investigations have shown that in primary breast adenocarcinomas DNA aneuploidy in contrast to DNA diploidy indicates high malignancy potential. On the basis of the study of 104 breast carcinomas, we describe a subtype of aneuploidy, which demonstrates a low degree of malignancy. In image cytometric DNA histograms, this subtype possessed a low percentage (≤8.8%) of nonmodal DNA values as measured by the stemline scatter index (SSI), which is defined as sum of the percentage of cells in the S-phase region, the G2 exceeding rate and the coefficient of variation of the tumor stemline. The cut point of SSI = 8.8% (P = 0.03) enabled us to also subdivide diploid and tetraploid tumors into clinically low and high malignant variants. One possible reason for aneuploidy is impaired distribution of chromosomes at mitosis caused by numerical or structural centrosome aberrations. Cyclins A and E seem to be involved in centrosome duplication. Real-time quantitative PCR measurements of cyclin A and E transcript levels and immunohistochemical determination of cyclin A protein expression showed statistically significantly increased values in the tumors with a high SSI (&gt;8.8%), compared with those with a low SSI. A pilot study demonstrated centrosomal aberrations in an average of 9.6% of the measured cells in four aneuploid carcinomas with high SSI values and in an average of 2.5% of the cells in three aneuploid and three diploid tumors with low SSI. Our data indicate that the SSI, most likely reflecting the degree of genomic instability, allows additional classifying of the known aneuploid, diploid, and tetraploid categories of primary breast adenocarcinomas into low and high malignant subtypes.
The Role of Cytidine Deaminase and GATA1 Mutations in the Increased Cytosine Arabinoside Sensitivity of Down Syndrome Myeloblasts and Leukemia Cell Lines
Authors: Ge Yubin , Jensen Tanya L. , Stout Mark L. , Flatley Robin M. , Grohar Patrick J. , Ravindranath Yaddanapudi , Matherly Larry H. , Taub Jeffrey W. 
Published: September 2005

Abstract
Myeloblasts from Down syndrome (DS) children with acute myeloid leukemia (AML) are significantly more sensitive in vitro to 1-β-d-arabinofuranosylcytosine (ara-C) and generate higher 1-β-d-arabinofuranosylcytosine 5′-triphosphate (ara-CTP) than non-DS AML myeloblasts. Semiquantitative reverse transcription-PCR analyses demonstrated that transcripts for cytidine deaminase (CDA) were 2.7-fold lower in DS than for non-DS myeloblasts. In contrast, transcripts of cystathionine-β-synthase and deoxycytidine kinase were a median 12.5- and 2.6-fold higher in DS compared with non-DS myeloblasts. The ratio of deoxycytidine kinase/CDA transcripts significantly correlated with ara-C sensitivities and ara-CTP generation. In clinically relevant AML cell line models, high cystathionine-β-synthase transcripts in DS CMK cells were accompanied by 10-fold greater ara-C sensitivity and 2.4-fold higher levels of ara-CTP compared with non-DS CMS cells. Overexpression of CDA in non-DS THP-1 cells was associated with a 100-fold decreased ara-C sensitivity and 40-fold decreased ara-CTP generation. THP-1 cells secreted CDA into the incubation media and converted extracellular ara-C completely to 1-β-d-arabinofuranosyluracil within 30 min. Rapid amplification of 5′-cDNA ends (5′-RACE) and reverse transcription-PCR assays identified short- (sf) and long-form (lf) CDA transcripts in THP-1 cells with different 5′ untranslated regions and translational start sites; however, only the latter resulted in the active CDA. Although 5′ flanking sequences for both CDA transcripts exhibited promoter activity in reporter gene assays, activity for the CDAlf was low. The presence of several GATA1 binding sites in the CDAsf promoter and the uniform detection of GATA1 mutations in DS megakaryocytic leukemia suggested the potential role of GATA1 in regulating CDA transcription and the CDAsf promoter acting as an enhancer. Transfection of GATA1 into Drosophila Mel-2 cells stimulated the CDAlf promoter in a dose-dependent fashion. Additional identification of the mechanisms of differential expression of genes encoding enzymes involved in ara-C metabolism between DS and non-DS myeloblasts may lead to improvements in AML therapy.
Basal Cell Carcinoma and Its Development
Authors: Mancuso Mariateresa , Pazzaglia Simonetta , Tanori Mirella , Hahn Heidi , Merola Paola , Rebessi Simonetta , Atkinson Michael J. , Di Majo Vincenzo , Covelli Vincenzo , Saran Anna 
Published: September 2005

Abstract
Loss-of-function mutations in Patched (Ptch1) are implicated in constitutive activation of the Sonic hedgehog pathway in human basal cell carcinomas (BCCs), and inherited Ptch1 mutations underlie basal cell nevus syndrome in which a typical feature is multiple BCC occurring with greater incidence in portals of radiotherapy. Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with basal cell nevus syndrome. We therefore examined BCC development in control and irradiated Ptch1neo67/+ mice. We show that unirradiated mice develop putative BCC precursor lesions, i.e., basaloid hyperproliferation areas arising from both follicular and interfollicular epithelium, and that these lesions progress to nodular and infiltrative BCCs only in irradiated mice. Data of BCC incidence, multiplicity, and latency support the notion of epidermal hyperproliferations, nodular and infiltrative BCC-like tumors representing different stages of tumor development. This is additionally supported by the pattern of p53 protein expression observed in BCC subtypes and by the finding of retention of the normal remaining Ptch1 allele in all nodular, circumscribed BCCs analyzed compared with its constant loss in infiltrative BCCs. Our data suggest chronological tumor progression from basaloid hyperproliferations to nodular and then infiltrative BCC occurring in a stepwise fashion through the accumulation of sequential genetic alterations.
Selective Potentiation of the Hypoxic Cytotoxicity of Tirapazamine by Its 1-
N
-Oxide Metabolite SR 4317
Authors: Siim Bronwyn G. , Pruijn Frederik B. , Sturman Joanna R. , Hogg Alison , Hay Michael P. , Brown J. Martin , Wilson William R. 
Published: September 2005

Abstract
Tirapazamine (TPZ), a bioreductive drug with selective toxicity for hypoxic cells in tumors, is currently in Phase III clinical trials. It has been suggested to have a dual mechanism of action, both generating DNA radicals and oxidizing these radicals to form DNA breaks; whether the second (radical oxidation) step is rate-limiting in cells is not known. In this study we exploit the DNA radical oxidizing ability of the 1-N-oxide metabolite of TPZ, SR 4317, to address this question. SR 4317 at high, but nontoxic, concentrations potentiated the hypoxic (but not aerobic) cytotoxicity of TPZ in all four of the human tumor cell lines tested (HT29, SiHa, FaDu, and A549), thus providing a 2–3-fold increase in the hypoxic cytotoxicity ratio. In potentiating TPZ, SR 4317 was 20-fold more potent than the hypoxic cell radiosensitizers misonidazole and metronidazole but was less potent than misonidazole as a radiosensitizer, suggesting that the initial DNA radicals from TPZ and radiation are different. SR 4317 had favorable pharmacokinetic properties in CD-1 nude mice; coadministration with TPZ provided a large increase in the SR 4317 plasma concentrations relative to that for endogenous SR 4317 from TPZ. It also showed excellent extravascular transport properties in oxic and anoxic HT29 multicellular layers (diffusion coefficient 3 × 10−6 cm2s−1, with no metabolic consumption). Coadministration of SR 4317 (1 mmol/kg) with TPZ at a subtherapeutic dose (0.133 mmol/kg) significantly enhanced hypoxic cell killing in HT29 tumor xenografts without causing oxic cell killing, and the combination at its maximum tolerated dose was less toxic to hypoxic cells in the retina than was TPZ alone at its maximum tolerated dose. This study demonstrates that benzotriazine mono-N-oxides have potential use for improving the therapeutic utility of TPZ as a hypoxic cytotoxin in cancer treatment.