bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased Replication Ability of E1-Deleted Adenoviruses Correlates with Increased Brain Tumor Malignancy
Authors: Ghosh Subrata , Duigou Gregory J. 
Published: October 2005

Abstract
E1 region replacement adenoviruses are replication defective and are propagated in cells providing adenovirus E1A and E1B proteins. Although they are being developed for antitumor therapies, the proliferative behaviors of these viruses in normal brain tissues or in brain tumors are unknown. To address this, freshly cultured cells from normal human brain and common brain tumors (astrocytomas and meningiomas) were infected using wild-type species C adenoviruses and adenoviruses missing E1A (H5dl312) or E1A plus E1B (H5dl434). Viral DNA replication, late viral protein expression, and production of infectious progeny were characterized. Wild-type adenoviruses grew efficiently in normal brain and brain tumor cells. In comparison, E1-deleted adenovirus DNA replication was delayed and lower in cells derived from normal brain tissues, meningiomas, and low-grade astrocytomas. However, in contrast, E1-deleted adenovirus DNA replication did not occur or was extremely low in cells derived from malignancy grade III and IV astrocytic tumors. Because wild-type adenoviruses infected and replicated in all cells, the malignancy grade-based differential E1-deleted adenovirus DNA replication was not explained by differential virus uptake. Infectious H5dl312 and H5dl434 production correlated with viral DNA replication. Compared with a 5-day average for wild-type infections, advanced cytopathology was noted ∼4 weeks after H5dl312 or H5dl434 infection of meningioma, astrocytoma, and normal brain cells. Cytopathology was not observed after H5dl312 or H5dl434 infection of glioblastoma, anaplastic astrocytoma, and gliosarcoma cells. Because of this tumor grade–based differential growth, the E1-deleted adenoviruses may represent novel tools for studies of brain tumor malignancy.
E-Cadherin Regulates the Association between β-Catenin and Actinin-4
Authors: Hayashida Yasuharu , Honda Kazufumi , Idogawa Masashi , Ino Yoshinori , Ono Masaya , Tsuchida Akihiko , Aoki Tatsuya , Hirohashi Setsuo , Yamada Tesshi 
Published: October 2005

Abstract
The E-cadherin/catenin system acts as an invasion suppressor of epithelial malignancies. This invasion suppressive activity seems be mediated not only by the cell adhesive activity of E-cadherin but by other undetermined signaling pathways elicited by β-catenin. In fact, cancer cells that have infiltrated the stroma reduce the expression of E-cadherin and accumulate β-catenin. We attempted to identify the alternative partner proteins that make complexes with β-catenin in the absence of E-cadherin. An ∼100-kDa protein was constantly coimmunoprecipitated with β-catenin from SW480 colorectal cancer cells, which lack the expression of E-cadherin, and was identified as actinin-4 by mass spectrometry. Transfection of E-cadherin cDNA suppressed the association between β-catenin and actinin-4. Inhibition of E-cadherin by RNA interference transferred the β-catenin and actinin-4 proteins into the membrane protrusions of DLD-1 cells. Immunofluorescence histochemistry of clinical colorectal cancer specimens showed that the β-catenin and actinin-4 proteins were colocalized in colorectal cancer cells infiltrating the stroma. We reported previously that overexpression of actinin-4 induces cell motility and specifically promotes lymph node metastasis by colorectal cancer. The association between β-catenin and actinin-4 and its regulation by E-cadherin may represent a novel molecular link connecting cell adhesion and motility. Shutting down the signals mediating this association may be worth considering as a therapeutic approach to cancer invasion and metastasis.
Contributions by MutL Homologues Mlh3 and Pms2 to DNA Mismatch Repair and Tumor Suppression in the Mouse
Authors: Chen Peng-Chieh , Dudley Sandra , Hagen Wayne , Dizon Diana , Paxton Leslie , Reichow Denise , Yoon Song-Ro , Yang Kan , Arnheim Norman , Liskay R. Michael , Lipkin Steven M. 
Published: October 2005

Abstract
Germ line DNA mismatch repair mutations in MLH1 and MSH2 underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of Escherichia coli MutL heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. Although MLH1/PMS2 is generally thought to have the major MutL activity, the precise contributions of each MutL heterodimer to mismatch repair functions are poorly understood. Here, we show that Mlh3 contributes to mechanisms of tumor suppression in the mouse. Mlh3 deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, Mlh3;Pms2 double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from Mlh1-deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between MLH3 and PMS2 orthologues for mutation avoidance and show a role for Mlh3 in gastrointestinal and extragastrointestinal tumor suppression. The data also suggest a mechanistic basis for the more severe mismatch repair–related phenotypes and cancer susceptibility in Mlh1- versus Mlh3- or Pms2-deficient mice. Contributions by both MLH1/MLH3 and MLH1/PMS2 complexes to mechanisms of mismatch repair–mediated tumor suppression, therefore, provide an explanation why, among MutL homologues, only germ line mutations in MLH1 are common in hereditary non-polyposis colon cancer.
Increased Susceptibility of Vault Poly(ADP-Ribose) Polymerase–Deficient Mice to Carcinogen-Induced Tumorigenesis
Authors: Raval-Fernandes Sujna , Kickhoefer Valerie A. , Kitchen Christina , Rome Leonard H. 
Published: October 2005

Abstract
Vault poly(ADP-ribose) polymerase (VPARP) and telomerase-associated protein 1 (TEP1) are components of the vault ribonucleoprotein complex. Vaults have been implicated in multidrug resistance of human tumors and are thought to be involved in macromolecular assembly and/or transport. Previous studies showed that VPARP-deficient mice were viable, fertile, and did not display any vault-related or telomerase-related phenotype, whereas disruption of telomerase-associated protein 1 in mice led to reduced stability of the vault RNA and affected its stable association with vaults, although there were no telomerase-related changes. In this study, we evaluated the susceptibility of Vparp−/− and Tep1−/− mice to dimethylhydrazine-induced colon tumorigenesis and urethane-induced lung tumorigenesis. Mice received i.p. injections of either 1 g/kg body weight of urethane twice a week for 2 weeks or 20 mg/kg body weight of dimethylhydrazine once a week for 10 weeks and were analyzed after 10 and 60 weeks, respectively. The colon tumor incidence and multiplicity were significantly higher and colon tumor latency was significantly shorter in Vparp−/− mice compared with wild-type mice. Increased colon tumor incidence, multiplicity, and reduced tumor latency were also seen in Tep1−/− mice, however, these results were statistically not significant. Lung tumor multiplicities were increased in both Vparp−/− and Tep1−/− mice but were not significant. The increase in carcinogen-induced tumors in VPARP-deficient mice is the only phenotype observed to date, and suggests a possible role for VPARP, directly or indirectly, in chemically induced neoplasia.
The In vitro and In vivo Effects of JNJ-7706621: A Dual Inhibitor of Cyclin-Dependent Kinases and Aurora Kinases
Authors: Emanuel Stuart , Rugg Catherine A. , Gruninger Robert H. , Lin Ronghui , Fuentes-Pesquera Angel , Connolly Peter J. , Wetter Steven K. , Hollister Beth , Kruger Walter W. , Napier Cheryl , Jolliffe Linda , Middleton Steven A. 
Published: October 2005

Abstract
Modulation of aberrant cell cycle regulation is a potential therapeutic strategy applicable to a wide range of tumor types. JNJ-7706621 is a novel cell cycle inhibitor that showed potent inhibition of several cyclin-dependent kinases (CDK) and Aurora kinases and selectively blocked proliferation of tumor cells of various origins but was about 10-fold less effective at inhibiting normal human cell growth in vitro. In human cancer cells, treatment with JNJ-7706621 inhibited cell growth independent of p53, retinoblastoma, or P-glycoprotein status; activated apoptosis; and reduced colony formation. At low concentrations, JNJ-7706621 slowed the growth of cells and at higher concentrations induced cytotoxicity. Inhibition of CDK1 kinase activity, altered CDK1 phosphorylation status, and interference with downstream substrates such as retinoblastoma were also shown in human tumor cells following drug treatment. Flow cytometric analysis of DNA content showed that JNJ-7706621 delayed progression through G1 and arrested the cell cycle at the G2-M phase. Additional cellular effects due to inhibition of Aurora kinases included endoreduplication and inhibition of histone H3 phosphorylation. In a human tumor xenograft model, several intermittent dosing schedules were identified that produced significant antitumor activity. There was a direct correlation between total cumulative dose given and antitumor effect regardless of the dosing schedule. These results show the therapeutic potential of this novel cell cycle inhibitor and support clinical evaluation of JNJ-7706621.
The Transcription Factor Pokemon: A New Key Player in Cancer Pathogenesis
Authors: Maeda Takahiro , Hobbs Robin M. , Pandolfi Pier Paolo 
Published: October 2005

Abstract
Learning how critical cell regulatory pathways are controlled may lead to new opportunities for cancer treatment. We recently identified the transcription factor Pokemon as a central regulator of the important tumor suppressor ARF. Pokemon is overexpressed in multiple human cancers and cells lacking Pokemon are refractory to oncogenic transformation. These findings suggest that Pokemon may offer an effective new target for cancer therapeutics.
Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas
Authors: Bredel Markus , Bredel Claudia , Juric Dejan , Harsh Griffith R. , Vogel Hannes , Recht Lawrence D. , Sikic Branimir I. 
Published: October 2005

Abstract
Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.
Stable RNA Interference–Mediated Suppression of Cyclophilin A Diminishes Non–Small-Cell Lung Tumor Growth In vivo
Authors: Howard Brandon A. , Furumai Ryohei , Campa Michael J. , Rabbani Zahid N. , Vujaskovic Zeljko , Wang Xiao-Fan , Patz Edward F. 
Published: October 2005

Abstract
Cyclophilin A (CypA) was recently reported to be overexpressed in non–small-cell lung cancer, and represents a potentially novel therapeutic target. To determine the role of CypA in oncogenesis, stable RNA interference (RNAi)–mediated knockdown of CypA was established in two non–small-cell lung cancer cell lines (ADLC-5M2 and LC-103H), and these cells were grown as xenografts in severe combined immunodeficient mice. Tumor cell proliferation, apoptosis, and angiogenesis were measured by Ki67, terminal deoxyribonucleotidyl transferase–mediated dUTP nick-end labeling, and CD31 immunohistochemistry, respectively. Tumor glucose metabolism was assessed by fluorodeoxyglucose positron emission tomography imaging. Knockdown of CypA correlated in vivo with slower growth, less fluorodeoxyglucose uptake, decreased proliferation, and a greater degree of apoptosis in the tumors. These results establish the relevance of CypA to tumor growth in vivo, specifically to proliferation and apoptosis. Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for lung cancer.
Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity
Authors: Kong Dehe , Park Eun Jung , Stephen Andrew G. , Calvani Maura , Cardellina John H. , Monks Anne , Fisher Robert J. , Shoemaker Robert H. , Melillo Giovanni 
Published: October 2005

AbstractThe identification of small molecules that inhibit the sequence-specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1α and HIF-1β proteins containing the basic-helix-loop-helix and PAS domains. Expressed recombinant HIF-1α and HIF-1β proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compounds previously identified in a HIF-1–targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compounds identified, echinomycin (NSC-13502), a small-molecule known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1α and HIF-1β proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-κB (NF-κB) consensus sequences. Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-κB to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters.
Targeted Virus Replication Plus Immunotherapy Eradicates Primary and Distant Pancreatic Tumors in Nude Mice
Authors: Sarkar Devanand , Su Zao-zhong , Vozhilla Nicolaq , Park Eun Sook , Randolph Aaron , Valerie Kristoffer , Fisher Paul B. 
Published: October 2005

Abstract
Pancreatic cancer is an aggressive neoplasm with no current viable, effective treatment options. In the majority of cases, at first diagnosis, pancreatic cancer has already become metastatic so that conventional treatment regimens provide minimal, if any, clinical benefit in prolonging life or ameliorating the negative prognosis of this disease. These harsh realities underscore the need for developing improved treatment paradigms for this cancer, with gene therapy and immunotherapy currently being evaluated as potential therapeutic options. We currently describe an adenovirus-based therapy for successfully managing pancreatic cancer, the cancer terminator virus (CTV), which is founded on targeted induction of viral replication from a cancer-specific progression elevated gene-3 (PEG-3) promoter (PEG-Prom) and immune modulation by IFN-γ. The PEG-Prom functions selectively in cancer cells of diverse lineages compared with their normal cellular counterparts. In the CTV, the PEG-Prom drives expression of the adenoviral early region 1A (E1A) gene, necessary for virus replication, with IFN-γ simultaneously being expressed from the E3 region. Infection of normal cells and pancreatic cancer cells with the CTV confirmed cancer cell–selective adenoviral replication, robust IFN-γ production coupled with virus replication, growth inhibition, and apoptosis induction. Infection of established pancreatic tumors in nude mice with the CTV promoted viral replication, IFN-γ production, and activation of antitumor immunity resulting in complete eradication of both primary and distant tumors, curing animals of disease. The CTV provides a novel reagent for treating pancreatic and other human cancers with potential for eliminating both primary tumors and metastatic disease.
Rho GTPase-Activating Protein Deleted in Liver Cancer Suppresses Cell Proliferation and Invasion in Hepatocellular Carcinoma
Authors: Wong Chun-Ming , Yam Judy Wai-Ping , Ching Yick-Pang , Yau Tai-On , Leung Thomas Ho-Yin , Jin Dong-Yan , Ng Irene Oi-Lin 
Published: October 2005

Abstract
Deleted in liver cancer (DLC1) is a candidate tumor suppressor gene recently isolated from human hepatocellular carcinoma. Structurally, DLC1 protein contains a conserved GTPase-activating protein for Rho family protein (RhoGAP) domain, which has been thought to regulate the activity of Rho family proteins. Previous studies indicated that DLC1 was frequently inactivated in cancer cells. In the present study, we aimed to characterize the tumor suppressor roles of DLC1 in hepatocellular carcinoma. We showed that DLC1 significantly inhibited cell proliferation, anchorage-independent growth, and in vivo tumorigenicity when stably expressed in hepatocellular carcinoma cells. Moreover, DLC1 expression greatly reduced the motility and invasiveness of hepatocellular carcinoma cells. With RhoGAP-deficient DLC1 mutant (DLC1-K714E), we showed that the RhoGAP activity was essential for DLC1-mediated tumor suppressor function. Furthermore, the 292– to 648–amino acid region and the steroidogenic acute regulatory related lipid transfer domain played an auxiliary role to RhoGAP and tumor suppressor function of DLC1. Taken together, our findings showed that DLC1 functions as a tumor suppressor in hepatocellular carcinoma and provide the first evidence to support the hypothesis that DLC1 suppresses cancer cell growth by negatively regulating the activity of Rho proteins.
Molecular Evidence for Increased Antitumor Activity of Gemcitabine by Genistein In vitro and In vivo Using an Orthotopic Model of Pancreatic Cancer
Authors: Banerjee Sanjeev , Zhang Yuxiang , Ali Shadan , Bhuiyan Mohammad , Wang Zhiwei , Chiao Paul J. , Philip Philip A. , Abbruzzese James , Sarkar Fazlul H. 
Published: October 2005

Abstract
Soy isoflavone genistein exhibits growth inhibitory activity against human pancreatic cancer cell lines. We previously reported the potential of genistein to augment chemotherapeutic response of pancreatic cancer cells in vitro. In the present study, we investigated whether genistein pretreatment could be used as a novel strategy for gemcitabine-induced killing in vitro and enhanced antitumor activity in vivo using an orthotopic tumor model. We conducted our studies using paired isogenic human pancreatic cancer cell line with differences in metastatic behavior (COLO 357 and L3.6pl). In vitro studies were done to measure growth inhibition and degree of apoptotic cell death induced by either genistein alone, gemcitabine alone, or genistein followed by gemcitabine. Our results show that pretreatment of cells with genistein for 24 hours followed by gemcitabine resulted in 60% to 80% growth inhibition compared with 25% to 30% when gemcitabine was used alone. The overall growth inhibition was directly correlated with apoptotic cell death irrespective of the metastatic potential of cells. Several genes that are known to inhibit apoptosis and contribute to chemoresistance such as nuclear factor-κB (NF-κB) and Akt were assessed to investigate the basis for the observed chemosensitizing effects of genistein. Genistein potentiated the gemcitabine-induced killing by down-regulation of NF-κB and Akt. In contrast, Akt and NF-κB were found to be up-regulated when pancreatic cancer cells were exposed to gemcitabine alone, suggesting the potential mechanism of acquired chemoresistance. In addition to in vitro results, we show here for the first time, that genistein in combination with gemcitabine is much more effective as an antitumor agent compared with either agent alone in our orthotopic tumor model. But most importantly, our data also showed that a specific target, such as NF-κB, was inactivated in genistein-treated animal tumors and that gemcitabine-induced activation of NF-κB was completely inhibited in animal tumors treated with genistein and gemcitabine. These results provide strong molecular in vivo evidence in support of our hypothesis that inactivation of NF-κB signaling pathway by genistein could also abrogate gemcitabine-induced activation of NF-κB resulting in the chemosensitization of pancreatic tumors to gemcitabine, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.
Proficient Global Nucleotide Excision Repair in Human Keratinocytes but not in Fibroblasts Deficient in p53
Authors: Ferguson Bridget E. , Oh Dennis H. 
Published: October 2005

Abstract
The p53 tumor suppressor protein is important for many cellular responses to DNA damage in mammalian cells, but its role in regulating DNA repair in human keratinocytes is undefined. We compared the nucleotide excision repair (NER) response of human fibroblasts and keratinocytes deficient in p53. Fibroblasts expressing human papillomavirus 16 E6 oncoprotein had impaired repair of UV radiation–induced cyclobutane pyrimidine dimers in association with reduced levels of p53 and XPC, which is involved in DNA damage recognition. In contrast, keratinocytes expressing E6 alone or concurrently with the E7 oncoprotein, while possessing reduced levels of p53 but normal levels of XPC, continued to repair pyrimidine dimers as efficiently as control cells with normal p53 levels. Despite preservation of DNA repair, E6 and E6/E7 keratinocytes were hypersensitive to UV radiation. E6 fibroblasts exhibited markedly reduced basal and induced levels of mRNA encoding DDB2, another protein implicated in early events in global NER. In contrast, E6 or E6/E7 keratinocytes possessed basal DDB2 mRNA levels that were not significantly altered relative to control cells, although little induction occurred following UV radiation. Intact global NER was also confirmed in SCC25 cells possessing inactivating mutations in p53 as well as in cells treated with pifithrin-α, a chemical inhibitor of p53 that decreased sensitivity of cells to UV radiation. Collectively, these results indicate that human keratinocytes, unlike fibroblasts, do not require p53 to maintain basal global NER activity, but p53 may still be important in mediating inducible responses following DNA damage.