bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibuprofen Inhibits Survival of Bladder Cancer Cells by Induced Expression of the p75NTR Tumor Suppressor Protein
Authors: Khwaja Fatima , Allen Jeff , Lynch John , Andrews Peter , Djakiew Daniel 
Published: September 2005

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to reduce inflammation and as analgesics by inhibition of cyclooxygenase-2. At higher concentrations, some NSAIDs inhibit proliferation and induce apoptosis of cancer cells. Although several molecular mechanisms have been postulated to explain the anticancer effects of NSAIDs, they do not involve merely the inhibition of cyclooxygenase-2, and a more proximate initiator molecule may be regulated by NSAIDs to inhibit growth. The p75 neurotrophin receptor (p75NTR) is a proximate cell membrane receptor glycoprotein that has been identified as a tumor and metastasis suppressor. We observed that NSAID treatment of cell lines from bladder and other organs induced expression of the p75NTR protein. Of the different types of NSAIDs examined, ibuprofen was more efficacious than aspirin and acetaminophen and comparable with (R)-flurbiprofen and indomethacin in induction of p75NTR protein expression. This rank order NSAID induction of the p75NTR protein correlated with the ability of these NSAIDs to reduce cancer cell survival. To examine a mechanistic relationship between ibuprofen induction of p75NTR protein and inhibition of survival, bladder cancer cells were transfected with ponasterone A-inducible vectors that expressed a death domain-deleted (ΔDD) or intracellular domain-deleted (ΔICD) p75NTR product that acts as a dominant negative antagonist of the intact p75NTR protein. Expression of ΔDD and ΔICD rescued cells from ibuprofen inhibition of growth. These observations suggest that p75NTR is an important upstream modulator of the anticancer effects of NSAIDs and that ibuprofen induction of the p75NTR protein establishes an alternate mechanism by which ibuprofen may exert an anticancer effect.
Expression of a Novel Human Gene,
Human Wings Apart-Like (hWAPL)
, Is Associated with Cervical Carcinogenesis and Tumor Progression
Authors: Oikawa Kosuke , Ohbayashi Tetsuya , Kiyono Tohru , Nishi Hirotaka , Isaka Keiichi , Umezawa Akihiro , Kuroda Masahiko , Mukai Kiyoshi 
Published: September 2005

Abstract
In Drosophila melanogaster, the wings apart-like (wapl) gene encodes a protein that regulates heterochromatin structure. Here, we characterize a novel human homologue of wapl (termed human WAPL; hWAPL). The hWAPL mRNA was predominantly expressed in uterine cervical cancer, with weak expression in all other normal and tumor tissues examined. hWAPL expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse hWAPL expression was found in all invasive squamous cell carcinomas examined. In addition, NIH3T3 cells overexpressing hWAPL developed into tumors on injection into nude mice. Furthermore, repression of hWAPL expression by RNA interference induced cell death in SiHa cells. These results demonstrate that hWAPL is associated with cell growth, and the hWAPL expression may play a significant role in cervical carcinogenesis and tumor progression.
Molecular Causes of the Aberrant Choline Phospholipid Metabolism in Breast Cancer
Authors: Glunde Kristine , Jie Chunfa , Bhujwalla Zaver M. 
Published: September 2005

Abstract
Proton magnetic resonance spectroscopy (1H MRS) consistently detects significant differences in choline phospholipid metabolites of malignant versus benign breast lesions. It is critically important to understand the molecular causes underlying these metabolic differences, because this may identify novel targets for attack in cancer cells. In this study, differences in choline membrane metabolism were characterized in breast cancer cells and normal human mammary epithelial cells (HMECs) labeled with [1,2-13C]choline, using 1H and 13C magnetic resonance spectroscopy. Metabolic fluxes between membrane and water-soluble pool of choline-containing metabolites were assessed by exposing cells to [1,2-13C]choline for long and short periods of time to distinguish between catabolic and anabolic pathways in choline metabolism. Gene expression analysis using microarrays was performed to understand the molecular mechanisms underlying these changes. Breast cancer cells exhibited increased phosphocholine (PC; P &lt; 0.001), total choline-containing metabolites (P &lt; 0.01), and significantly decreased glycerophosphocholine (P &lt; 0.05) compared with normal HMECs. Decreased 13C-enrichment was detected in choline (P &lt; 0.001) and phosphocholine (P &lt; 0.05, P &lt; 0.001) of breast cancer cells compared with HMECs, indicating a higher metabolic flux from membrane phosphatidylcholine to choline and phosphocholine in breast cancer cells. Choline kinase and phospholipase C were significantly overexpressed, and lysophospholipase 1, phospholipase A2, and phospholipase D were significantly underexpressed, in breast cancer cells compared with HMECs. The magnetic resonance spectroscopy data indicated that elevated phosphocholine in breast cancer cells was primarily attributable to increased choline kinase activity and increased catabolism mediated by increased phospholipase C activity. These observations were consistent with the overexpression of choline kinase and phospholipase C detected in the microarray analyses.
Deficiencies in Mouse
Myh
and
Ogg1
Result in Tumor Predisposition and G to T Mutations in Codon 12 of the
K-Ras
Oncogene in Lung Tumors
Authors: Xie Yali , Yang Hanjing , Cunanan Cristina , Okamoto Kimberly , Shibata Darryl , Pan Janet , Barnes Deborah E. , Lindahl Tomas , McIlhatton Michael , Fishel Richard , Miller Jeffrey H. 
Published: September 2005

Abstract
Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, mutY and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.
The Tumor Microenvironment Controls Primary Effusion Lymphoma Growthin Vivo
Authors: Staudt Michelle R. , Kanan Yogita , Jeong Joseph H. , Papin James F. , Hines-Boykin Rebecca , Dittmer Dirk P. 
Published: September 2005

AbstractCertain lymphomas in AIDS patients, such as primary effusion lymphoma (PEL), are closely associated with the lymphotropic γ herpes virus Kaposi’s sarcoma-associated herpes virus (KSHV), also called human herpesvirus 8. The virus is thought to be essential for tumorigenesis, yet systems to investigate PEL in vivo are rare. Here we describe PEL tumorigenesis in a new xenograft model. Embedded in Matrigel, PEL cells formed rapid, well-organized, and angiogenic tumors after s.c. implantation of C.B.17 SCID mice. Without Matrigel we did not observe comparable tumors, which implies that extracellular support and/or signaling aids PEL. All of the tumors maintained the KSHV genome, and the KSHV latent protein LANA/orf73 was uniformly expressed. However, the expression profile for key lytic mRNAs, as well as LANA-2/vIRF3, differed between tissue culture and sites of implantation. We did not observe a net effect of ganciclovir on PEL growth in culture or as xenograft. These findings underscore the importance of the microenvironment for PEL tumorigenesis and simplify the preclinical evaluation of potential anticancer agents.
The HER-2-Targeting Antibodies Trastuzumab and Pertuzumab Synergistically Inhibit the Survival of Breast Cancer Cells
Authors: Nahta Rita , Hung Mien-Chie , Esteva Francisco J. 
Published: September 2005

Abstract
Trastuzumab (herceptin) and pertuzumab (Omnitarg, 2C4) are recombinant humanized monoclonal antibodies that target different extracellular regions of the HER-2 tyrosine kinase receptor. We explored combination effects of these agents in the HER-2-overexpressing BT474 breast cancer cell line. Trastuzumab and 2C4 synergistically inhibited the survival of BT474 cells, in part, because of increased apoptosis. Trastuzumab increased 2C4-mediated disruption of HER-2 dimerization with the epidermal growth factor receptor and HER-3. Combination drug treatment reduced levels of total and phosphorylated HER-2 protein and blocked receptor signaling through Akt but did not affect mitogen-activated protein kinase. These results suggest that combining HER-2-targeting agents may be a more effective therapeutic strategy in breast cancer rather than treating with a single HER-2 monoclonal antibody.
Reduction in Raf Kinase Inhibitor Protein Expression Is Associated with Increased Ras-Extracellular Signal-Regulated Kinase Signaling in Melanoma Cell Lines
Authors: Schuierer Marion M. , Bataille Frauke , Hagan Suzanne , Kolch Walter , Bosserhoff Anja-Katrin 
Published: September 2005

Abstract
Mutations in the Raf signaling pathway are known to play a pivotal role in the progression of malignant melanoma. In this study, we provide evidence that the Raf-1 kinase inhibitory protein (RKIP) and its effects on Raf-1-mediated activation of mitogen-activated protein/extracellular signal-regulated kinase kinase are important for the metastatic potential of malignant melanoma. Screening nine melanoma cell lines at mRNA and protein levels, we detected significant down-regulation of RKIP expression in comparison with normal melanocytes. Loss of RKIP expression in transformed cells in vivo was confirmed in immunohistochemical analyses demonstrating reduction of RKIP expression already in primary melanoma and even stronger down-regulation or complete loss in melanoma metastases. Stable transfection of the melanoma cell line Mel Im with an RKIP expression plasmid blocked the Raf kinase pathway, resulting in down-regulation of extracellular signal-regulated kinase 1/2 and activator protein 1 activity. In very good agreement with the in vivo finding that down-regulation of RKIP expression is most obvious in melanoma metastasis, overexpression of RKIP in the highly invasive Mel Im cell line leads to a significant inhibition of invasiveness in vitro. Taken together, our results suggest that loss of RKIP in malignant melanoma contributes to enhanced invasiveness of transformed cells and therefore to progression of the disease.
B-Raf Is Dispensable for K-Ras-Mediated Oncogenesis in Human Cancer Cells
Authors: Kim Jung-Sik , Lee Carolyn , Foxworth Aaron , Waldman Todd 
Published: September 2005

Abstract
Oncogenic mutations in B-Raf and Kirsten-Ras (K-Ras) are mutually exclusive during human cancer pathogenesis. In an effort to study the biological basis of this epistasis, gene targeting was used to create isogenic sets of human cancer cells differing only in presence or absence of endogenous oncogenic K-Ras or wild-type B-Raf. Whereas cells lacking the K-Ras oncogene were unable to efficiently form xenograft tumors, isogenic cells retaining activated K-Ras but deleted for B-Raf remained highly tumorigenic. Deletion of oncogenic K-Ras failed to reduce the activation state of B-Raf or ERK1/2, despite the requirement of oncogenic K-Ras for tumorigenesis. Genechip analysis revealed numerous genes in which the regulation by oncogenic K-Ras did not require B-Raf. These studies suggest that despite the mutual exclusivity of K-Ras and B-Raf mutations in human cancer and the well-described role for Raf proteins as Ras effectors, B-Raf is dispensable for K-Ras-mediated oncogenesis in a human cancer cell line. Additional studies are required to demonstrate the generalizability of these unexpected findings.
Functional Characterization of the Candidate Tumor Suppressor Gene
NPRL2
/
G21
Located in 3p21.3C
Authors: Li Jingfeng , Wang Fuli , Haraldson Klas , Protopopov Alexey , Duh Fuh-Mei , Geil Laura , Kuzmin Igor , Minna John D. , Stanbridge Eric , Braga Eleonora , Kashuba Vladimir I. , Klein George , Lerman Michael I. , Zabarovsky Eugene R. 
Published: September 2005

Abstract
Initial analysis identified the NPRL2/G21 gene located in 3p21.3C, the lung cancer region, as a strong candidate tumor suppressor gene. Here we provide additional evidence of the tumor suppressor function of NPRL2/G21. The gene has highly conserved homologs/orthologs ranging from yeast to humans. The yeast ortholog, NPR2, shows three highly conserved regions with 32 to 36% identity over the whole length. By sequence analysis, the main product of NPRL2/G21 encodes a soluble protein that has a bipartite nuclear localization signal, a protein-binding domain, similarity to the MutS core domain, and a newly identified nitrogen permease regulator 2 domain with unknown function. The gene is highly expressed in many tissues.
We report inactivating mutations in a variety of tumors and cancer cell lines, growth suppression of tumor cells with tet-controlled NPRL2/G21 transgenes on plastic Petri dishes, and suppression of tumor formation in SCID mice. Screening of 7 renal, 5 lung, and 7 cervical carcinoma cell lines showed homozygous deletions in the 3′ end of NPRL2 in 2 renal, 3 lung, and 1 cervical (HeLa) cell line. Deletions in the 3′ part of NPRL2 could result in improper splicing, leading to the loss of the 1.8 kb functional NPRL2 mRNA. We speculate that the NPRL2/G21 nuclear protein may be involved in mismatch repair, cell cycle checkpoint signaling, and activation of apoptotic pathway(s). The yeast NPR2 was shown to be a target of cisplatin, suggesting that the human NPRL2/G21 may play a similar role. At least two homozygous deletions of NPRL2/G21 were detected in 6 tumor biopsies from various locations and with microsatellite instability. This study, together with previously obtained results, indicates that NPRL2 is a multiple tumor suppressor gene.
BN80927
Authors: Demarquay Danièle , Huchet Marion , Coulomb Helène , Lesueur-Ginot Laurence , Lavergne Olivier , Camara José , Kasprzyk Philip G. , Prévost Grégoire , Bigg Dennis C. H. 
Published: September 2005

AbstractBN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered β-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G0-G1 synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC50 values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927.
High-Throughput Retroviral Tagging for Identification of Genes Involved in Initiation and Progression of Mouse Splenic Marginal Zone Lymphomas
Authors: Shin Min Sun , Fredrickson Torgny N. , Hartley Janet W. , Suzuki Takeshi , Agaki Keiko , Morse Herbert C. 
Published: September 2005

Abstract
Human B-cell lymphomas are frequently associated with specific genetic changes caused by chromosomal translocations that activate proto-oncogenes. For lymphomas of mice expressing murine leukemia virus, mutagenic proviral insertions are thought to play a similar role. Here we report studies designed to determine whether specific retroviral integration sites might be associated with a specific subset of mouse B-cell lymphomas and if the genes associated with these sites are regularly altered in expression. We studied splenic marginal zone lymphomas (MZL) of NFS.V+ mice that are unusual in exhibiting frequent progression from low to high grade, potentially allowing assignment of cancer genes to processes of initiation and progression. We used inverse PCR to clone and analyze 212 retroviral integration sites from 43 MZL at different stages of progression. Sixty-two marked common integration sites and included 31 that had been marked previously. Among the new common integration sites, seven were unique to MZL. Using microarrays and real-time quantitative PCR analysis, we defined differential patterns of gene expression in association with disease progression for Gfi1, Sox4, Brca2, Snf1lk, Nfkb1, Pou2af1, Prdm1, Stat6, and Blnk. Heightened expression of Gfi1 distinguishes MZL from other lymphoma types. The combined use of proviral tagging and analyses of gene expression thus provides a powerful approach to understanding of genes that collaborate in tumorigenesis.
Cripto
Authors: Xing Pei Xiang , Hu Xiu Feng , Pietersz Geoffrey A. , Hosick Howard L. , McKenzie Ian F. C. 
Published: September 2005

Abstract
Cripto, a member of the epidermal growth factor-Cripto-FRL-Criptic (EGF-CFC) family, has been described recently as a potential target for immunotherapy (Adkins et al., J Clin Invest 2003;112:575–87). We have produced rat monoclonal antibodies (mAbs) to a Cripto 17-mer peptide, corresponding to the “EGF-like” motif of Cripto. The mAbs react with most cancers of the breast, colon, lung, stomach, and pancreas but do not react or react weakly with normal tissues. The mAbs inhibit cancer cell growth in vitro, and this effect was greater with cytotoxic drugs such as 5-fluorouracil, epirubicin, and cisplatin. The anti-Cripto mAbs prevent tumor development in vivo and inhibit the growth of established tumors of LS174T colon xenografts in Scid mice. The growth inhibitory effects with these mAbs may be greater than those described elsewhere, possibly because of IgM giving more effective cross-linking or binding to a different epitope (EGF-like region versus CFC region). The mechanism of inhibitory effects of the Cripto mAbs includes both cancer cell apoptosis, activation of c-Jun-NH2-terminal kinase and p38 kinase signaling pathways and blocking of Akt phosphorylation. Thus, Cripto is a unique target, and mAbs to Cripto could be of therapeutic value for human cancers.
Efflux Kinetics and Intracellular Distribution of Daunorubicin Are Not Affected by Major Vault Protein/Lung Resistance-Related Protein (Vault) Expression
Authors: van Zon Arend , Mossink Marieke H. , Schoester Martijn , Scheper Rik J. , Sonneveld Pieter , Wiemer Erik A. C. 
Published: September 2005

Abstract
Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent protein (GFP)-tagged major vault protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 μm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP−/− cells results in the formation of vault particles but did not give rise an altered daunorubicin handling compared with MVP−/− cells expressing GFP. Our results indicate that vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.
Overexpression of Histone Deacetylase 1 Confers Resistance to Sodium Butyrate–Mediated Apoptosis in Melanoma Cells through a p53-Mediated Pathway
Authors: Bandyopadhyay Debdutta , Mishra Anupam , Medrano Estela E. 
Published: September 2005

Abstract
Melanoma cells typically express wild-type p53, yet they are notoriously resistant to DNA-damaging agents. Here, we show that sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor, induced apoptosis in human melanoma cells in a dose- and time-dependent manner. Apoptosis was associated with HDAC1-dependent induction of Bax and acetylation of p53. Down-regulation of HDAC1 by an antisense vector sensitized the cells to NaB-induced apoptosis, whereas its overexpression conferred resistance to this agent. Increased HDAC1 levels and activity impaired NaB-mediated activation of Bax promoter and Bax protein levels. Finally, using p53-null melanoma cell line and RNA interference in cells expressing wild-type p53 protein, we show that Bax induction and NaB-mediated apoptosis is p53 dependent.
Proteasome-Mediated Destruction of the Cyclin A/Cyclin-Dependent Kinase 2 Complex Suppresses Tumor Cell Growth
in Vitro
and
in Vivo
Authors: Chen Wei , Lee Jeongwu , Cho Steve Y. , Fine Howard A. 
Published: September 2005

Abstract
Cyclin-dependent kinases (cdks) represent potentially promising molecular targets for cancer therapeutic strategies. To evaluate the antitumor activity of selective cyclin/cdk inhibition, we constructed a chimeric protein composed of a F-box protein (TrCP) fused to a peptide comprising the cyclin/cdk2 binding motif in p21-like cdk inhibitors (TrCP-LFG). We now demonstrate that endogenous cyclin A and its binding substrate, cdk2, can be tethered to β-TrCP, ubiquitinated, and effectively degraded. Degradation of cdk2 and cyclin A together, but not cdk2 alone, results in massive tumor cell apoptosis in vitro and in vivo in a proteasome-dependent manner with no toxicity to normal tissue. These data demonstrate that cyclin A and/or the cyclin A/cdk2 complex is a promising anticancer target with a high therapeutic index.