bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Base Excision DNA Repair Genes Is a Sensitive Biomarker for
in Vivo
Detection of Chemical-induced Chronic Oxidative Stress
Authors: Rusyn Ivan , Asakura Shoji , Pachkowski Brian , Bradford Blair U. , Denissenko Mikhail F. , Peters Jeffrey M. , Holland Steven M. , Reddy Janardan K. , Cunningham Michael L. , Swenberg James A. 
Published: September 2005

Abstract
Oxidative stress to DNA is recognized as one of the mechanisms for the carcinogenic effects of some environmental agents. Numerous studies have been conducted in an attempt to document the fact that chemical carcinogens that are thought to induce production of oxidants also cause the formation of oxidative DNA lesions. Although many DNA adducts continue to be useful biomarkers of dose/effect, changes in gene expression have been proposed to be a practical novel tool for studying the role of chemically induced oxidative DNA damage. Here, we hypothesized that expression of base excision DNA repair genes is a sensitive biomarker for in vivo detection of chemically induced chronic oxidative stress. To test this hypothesis, mice were treated with a known rodent carcinogen and peroxisome proliferator, WY-14,643 (500 ppm, 1 month). A number of end points that are commonly used to assess oxidative DNA damage were considered. Our data demonstrate that no difference in 8-oxoguanine, the number of abasic sites, or single strand breaks can be detected in genomic DNA from livers of control or WY-treated animals. However, a concordant marked induction of genes specific for the long-patch base excision DNA repair, a predominant pathway that removes oxidized DNA lesions in vivo, was observed in livers of WY-treated mice. Kupffer cell NADPH oxidase, and peroxisomes in parenchymal cells have been proposed as the potential sources of peroxisome proliferator-induced oxidants. The analysis of expression of base excision DNA repair genes was used to assess whether this biomarker of oxidative stress can be used to determine the source of oxidants. The data suggest that DNA-damaging oxidants are generated by enzymes that are induced after activation of peroxisome proliferator activator receptor α, such as those involved in lipid metabolism in peroxisomes, and are not the result of activation of NADPH oxidase in Kupffer cells. We conclude that expression of base excision DNA repair genes is a sensitive in vivo biomarker for chemically induced oxidative stress to DNA that can be successfully used for the identification of the molecular source of radicals responsible for DNA damage in vivo.
Retinoblastoma Protein and CCAAT/Enhancer-Binding Protein β Are Required for 1,25-Dihydroxyvitamin D3-Induced Monocytic Differentiation of HL60 Cells
Authors: Ji Yan , Studzinski George P. 
Published: September 2005

Abstract
Derivatives of vitamin D (deltanoids) are well known to have the ability to induce differentiation of a variety of malignant cells, including human leukemia cells, but the signaling pathways that lead to such an outcome are unclear. In this study we investigated the role of the retinoblastoma protein (pRb) and the CCAAT/enhancer-binding protein (C/EBP) β in 1,25-dihydroxyvitamin D3 (1,25D3)-induced monocytic differentiation of human leukemia HL60 cells. It was found that in this system, pRb is up-regulated within 12 h of exposure to the inducer, and the kinetics of its increase parallel the appearance of the early markers of differentiation, CD14 and monocyte-specific esterase. The increase in pRb expression was accompanied by a similar increase in C/EBPβ protein, and these two proteins coimmunoprecipitated, suggesting formation of a complex. Oligonucleotides antisense to pRb or C/EBPβ (but not to C/EBPα) or containing the C/EBP-binding sequence (“decoys”), all inhibited 1,25D3-induced differentiation. Inhibition of signaling by vitamin D receptor or by mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase pathways using pharmacological inhibitors ZK159222, PD98059, or SP600125, respectively, inhibited pRb and C/EBPβ expression and differentiation in a coordinate manner. In contrast, inhibition of the p38MAPK pathway by SB202190 potentiated differentiation and the up-regulation of pRb and C/EBPβ. We suggest that 1,25D3 may signal monocytic differentiation of HL60 cells in a vitamin D receptor-dependent manner that includes activation of extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase MAPK pathways, which then up-regulate pRb and C/EBPβ expression and in turn initiate the differentiation process.
Progestin-Dependent Induction of Vascular Endothelial Growth Factor in Human Breast Cancer Cells
Authors: Wu Jianbo , Richer Jennifer , Horwitz Kathryn B. , Hyder Salman M. 
Published: September 2005

Abstract
The progesterone receptor (PR) is a ligand-dependent transcription factor that promotes progestin-stimulated expression of target genes. Two functional PR isoforms, PRA and PRB, are expressed in progestin-responsive cells. PRA and PRB have distinct roles in gene expression and in mammary gland development. One role of PRs in T47-D cells is regulating expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor. This study explores the isoform specificity of this PR function using parental T47-Dco cells that express both PRA and PRB and clonal derivatives that express either PRA (YA cells) or PRB (YB cells) or lack PR (Y cells). Treatment with progesterone induces VEGF mRNA and protein ∼2-fold in T47-Dco and YA cells and 3–7-fold in YB cells, suggesting that PRA inhibits PRB-dependent induction of VEGF. This is consistent with the observation that clinically relevant progestins induce a much higher level of VEGF in YB cells than in YA cells. Another novel finding in this report is that estradiol (10−8 m) induces VEGF production from YB cells. However, this induction is not blocked by 100-fold excess tamoxifen or ICI-182,780. Moreover, both tamoxifen (10−6 m) and ICI-182,780 (10−6 m) function as agonists for VEGF in YB cells. Small interfering RNA against PR or estrogen receptor abrogated estradiol and tamoxifen induction, indicating that the agonist-like response of these compounds in YB cells is estrogen receptor and PR dependent. Estradiol, tamoxifen, and ICI-182780 also induce VEGF in BT-474 cells when their PRB levels were elevated by transfecting an expression plasmid for PRB, but not when the cells were transfected with vector alone. These results indicate that (a) PRB preferentially regulates VEGF expression in breast cancer cells and (b) PRB-enriched tumor cells may produce more VEGF, have a better developed vasculature, and potentially are more resistant to tamoxifen and ICI-182,780 than cells that express an equivalent or higher level of PRA than PRB. These results imply that PRB-enriched breast tumors may respond well to anticancer therapies that include inhibitors of angiogenesis.
A Potential Oncogenic Activity of Platelet-Derived Growth Factor D in Prostate Cancer Progression
Authors: Ustach Carolyn V. , Taube Marcus E. , Hurst Newton J. , Bhagat Sunita , Bonfil R. Daniel , Cher Michael L. , Schuger Lucia , Kim Hyeong-Reh Choi 
Published: September 2005

Abstract
The platelet-derived growth factor (PDGF) proteins are potent stimulators of cell proliferation/transformation and play a major role in cell-cell communication. For over two decades, PDGFs were thought to exist as three dimeric polypeptides (the homodimers AA and BB and the heterodimer AB). Recently, however, the PDGF C and D chains were discovered in a BLAST search of the expressed sequence tag databases. The PDGF CC and DD dimers have a unique two-domain structure with an NH2-terminal CUB (compliment subcomponents C1r/C1s, Uegf, and Bmp1) domain and a COOH-terminal PDGF/vascular endothelial growth factor domain. Whereas secreted PDGF AA, BB, and AB readily activate their cell surface receptors, it was suggested that extracellular proteolytic removal of the CUB domain is required for the PDGF/vascular endothelial growth factor domain of PDGF CC and DD to activate PDGF receptors. In the present study, we examined the processing of latent PDGF D into its active form and the effects of PDGF D expression on prostate cancer progression. We show that LNCaP cells auto-activate latent PDGF DD into the active PDGF domain, which can induce phosphorylation of the β-PDGF receptor and stimulates LNCaP cell proliferation in an autocrine manner. Additionally, LNCaP-PDGF D-conditioned medium induces migration of the prostate fibroblast cell line 1532-FTX, indicating LNCaP-processed PDGF DD is active in a paracrine manner as well. In a severe combined immunodeficient mouse model, PDGF DD expression accelerates early onset of prostate tumor growth and drastically enhances prostate carcinoma cell interaction with surrounding stromal cells. These demonstrate a potential oncogenic activity of PDGF DD in the development and/or progression of prostate cancer.
Optimization of the Tet-on System To Regulate Interleukin 12 Expression in the Liver for the Treatment of Hepatic Tumors
Authors: Zabala Maider , Wang Lin , Hernandez-Alcoceba Ruben , Hillen Wolfgang , Qian Cheng , Prieto Jesus , Kramer M. Gabriela 
Published: September 2005

AbstractInterleukin 12 (IL-12) is a potent antitumoral cytokine, but it can be toxic at high doses. Therapy of liver tumors might benefit from the use of vectors enabling tight control of IL-12 expression in hepatic tissue for long periods of time. To this aim, we have improved the Tet-on system by modifying the minimal region of the inducible promoter and adjusting the level of the trans-activator using liver-specific promoters with graded activities. The resulting vectors allowed hepato-specific gene regulation with lower basal activity and higher inducibility compared with the original system in the absence of repressor molecules. The basal and final protein levels depend on the strength of the promoter that directs the transcripcional activator as well as the relative orientation of the two genes in the same plasmid. We have selected the construct combining minimal leakage with higher level of induced gene expression to regulate IL-12 after DNA transfer to mouse liver. Administration of doxycycline (Dox) enhanced IL-12 expression in a dose-dependent manner, whereas it was undetectable in serum in the noninduced state. Gene activation could be repeated several times, and sustained levels of IL-12 were achieved by daily administration of Dox. The antitumor effect of IL-12 was evaluated in a mouse model of metastatic colon cancer to the liver. Complete eradication of liver metastasis and prolonged survival was observed in all mice receiving Dox for 10 days. These data demonstrate the potential of a naked DNA gene therapy strategy to achieve tight control of IL-12 within the liver for the treatment of cancer.
Pol ι Is a Candidate for the Mouse Pulmonary Adenoma Resistance 2 Locus, a Major Modifier of Chemically Induced Lung Neoplasia
Authors: Wang Min , Devereux Theodora R. , Vikis Haris G. , McCulloch Scott D. , Holliday Wanda , Anna Colleen , Wang Yian , Bebenek Katarzyna , Kunkel Thomas A. , Guan Kunliang , You Ming 
Published: September 2005

Abstract
In this study, we performed systematic candidate gene analyses of the Pulmonary adenoma resistance 2 locus. Differential gene expression in lung tissues and nucleotide polymorphisms in coding regions between A/J and BALB/cJ mice were examined using reverse transcription-PCR and direct sequencing. Although not all genes in the interval were analyzed at this moment due to the recent database updating, we have found that the Pol ι gene, encoding the DNA polymerase ι, contains 25 nucleotide polymorphisms in its coding region between A/J and BALB/cJ mice, resulting in a total of ten amino acid changes. Primer extension assays with purified BALB/cJ and A/J proteins in vitro demonstrate that both forms of Pol ι are active but that they may differ in substrate discrimination, which may affect the formation of Kras2 mutations in mouse lung tumors. Altered expression of POL ι protein and an amino acid-changing nucleotide polymorphism were observed in human lung cancer cells, suggesting a possible role in the development of lung cancer. Thus, our data support the Pol ι gene as a modifier of lung tumorigenesis by altering DNA polymerase activity.
Inhibition of Akt/Protein Kinase B Signaling by Naltrindole in Small Cell Lung Cancer Cells
Authors: Chen Yulong L. , Law P. Y. , Loh Horace H. 
Published: September 2005

Abstract
The phosphatidylinositol 3-kinase-Akt/protein kinase B (PKB) survival signaling is very important for cancer cell survival and growth. Constitutively active phosphatidylinositol 3-kinase-Akt/PKB signaling in small cell lung cancer (SCLC) is a major factor for the survival of SCLC cells. Inhibitors of this signaling pathway would be potential antitumor agents, particularly for SCLC. Here we report that naltrindole, which has been used as a classic δ opioid antagonist, inhibited growth and induced apoptosis in the three characteristic SCLC cell lines, NCI-H69, NCI-H345, and NCI-H510. Naltrindole treatment reduced constitutive phosphorylation of Akt/PKB on serine 473 and threonine 308 in cells. We found that the levels of constitutive phosphorylation of Akt/PKB on serine 473 correlate with the sensitivity of the three cell lines to naltrindole treatment. Furthermore, naltrindole treatment not only reduced the phosphorylation of the Akt/PKB upstream kinase phosphoinositide-dependent kinase-1, but also its downstream effectors glycogen synthase kinase-3β and the Forkhead transcription factors AFX and FKHR. DNA array analysis of 205 apoptosis-related genes indicated that some Akt/PKB-dependent genes were either up- or down-regulated by naltrindole. Flow cytometric and microscopic analyses clearly showed that naltrindole induced apoptosis in SCLC cells. RNA interference experiments confirmed that naltrindole-induced cell death was associated with the Akt/PKB survival pathway. Together, these results show that naltrindole is a new inhibitor of the Akt/PKB signaling pathway, suggesting that naltrindole could be a potential lead for the development of a new type of inhibitors that target the constitutively active Akt/PKB signaling-dependent SCLC cells.
Analysis of the Drug Resistance Profile of Multidrug Resistance Protein 7 (ABCC10)
Authors: Hopper-Borge Elizabeth , Chen Zhe-Sheng , Shchaveleva Irina , Belinsky Martin G. , Kruh Gary D. 
Published: September 2005

AbstractThe multidrug resistance protein (MRP) family consists of nine members that can be categorized according to whether or not a third (NH2-terminal) membrane-spanning domain is present. Three (MRP1, MRP2, and MRP3) of the four members that have this structural feature are able to confer resistance to natural product anticancer agents. We previously established that MRP7, the remaining family member that has three membrane-spanning domains, possesses the cardinal biochemical activity of MRPs in that it is able to transport amphipathic anions such as 17β-estradiol 17-(β-d-glucuronide). However, the drug resistance profile of the pump has not been determined. In this study, the drug resistance capabilities of MRP7 are evaluated by analyzing the resistance profiles of two clones of HEK293 cells in which the pump was ectopically expressed. MRP7-transfected HEK293 cells exhibited the highest levels of resistance toward docetaxel (9–13-fold). In addition, lower levels of resistance were observed for paclitaxel (3-fold), vincristine (3-fold), and vinblastine (3–4-fold). Consistent with the operation of an ATP-dependent efflux pump, MRP7-transfected cells exhibited reduced accumulation of radiolabeled paclitaxel compared with HEK293 cells transfected with parental plasmid. These results indicate that MRP7, unlike other MRPs, is a resistance factor for taxanes.
NE-10 Neuroendocrine Cancer Promotes the LNCaP Xenograft Growth in Castrated Mice
Authors: Jin Ren Jie , Wang Yongqing , Masumori Naoya , Ishii Kenichiro , Tsukamoto Taiji , Shappell Scott B. , Hayward Simon W. , Kasper Susan , Matusik Robert J. 
Published: September 2005

Abstract
Increases in neuroendocrine (NE) cells and their secretory products are closely correlated with tumor progression and androgen-independent prostate cancer. However, the mechanisms by which NE cells influence prostate cancer growth and progression, especially after androgen ablation therapy, are poorly understood. To investigate the role of NE cells on prostate cancer growth, LNCaP xenograft tumors were implanted into nude mice. After the LNCaP tumors were established, the NE mouse prostate allograft (NE-10) was implanted on the opposite flank of these nude mice to test whether NE tumor-derived systemic factors can influence LNCaP growth. Mice bearing LNCaP tumors with or without NE allografts were castrated 2 weeks after NE tumor inoculation, and changes in LNCaP tumor growth rate and gene expression were investigated. After castration, LNCaP tumor growth decreased in mice bearing LNCaP tumors alone, and this was accompanied by a loss of nuclear androgen receptor (AR) localization. In contrast, in castrated mice bearing both LNCaP and NE-10 tumors, LNCaP tumors continued to grow, had increased levels of nuclear AR, and secreted prostate-specific antigen. Therefore, in the absence of testicular androgens, NE secretions were sufficient to maintain LNCaP cell growth and androgen-regulated gene expression in vivo. Furthermore, in vitro experiments showed that NE secretions combined with low levels of androgens activated the AR, an effect that was blocked by the antiandrogen bicalutamide. Because an increase in AR level has been reported to be sufficient to account for hormone refractory prostate cancers, the NE cell population ability to increase AR level/activity can be another mechanism that allows prostate cancer to escape androgen ablation therapy.
Bone Marrow Stroma Influences Transforming Growth Factor-β Production in Breast Cancer Cells to Regulate c-myc Activation of the Preprotachykinin-I Gene in Breast Cancer Cells
Authors: Oh Hyun S. , Moharita Anabella , Potian Joseph G. , Whitehead Ian P. , Livingston Jason C. , Castro Tammy A. , Patel Prem S. , Rameshwar Pranela 
Published: September 2005

AbstractBreast cancer cells (BCCs) have preference for the bone marrow (BM). This study used an in vitro coculture of BCCs and BM stroma to represent a model of early breast cancer metastasis to the BM. The overarching hypothesis states that once BCCs are in the BM, microenvironmental factors induce changes in the expression of genes for cytokines and preprotachykinin-I (PPT-I) in both BCCs and stromal cells. Consequently, the expression of both PPT-I and cytokines are altered to facilitate BCC integration within BM stroma. Cytokine and transcription factor arrays strongly suggested that transforming growth factor-β (TGF-β) and c-myc regulate the expression of PPT-I so as to facilitate BCC integration among stroma. Northern analyses and TGF-β bioassays showed that stromal cells and BCCs influence the level of PPT-I and TGF-β in each other. In cocultures, PPT-I and TGF-β expressions were significantly (P &lt; 0.05) increased and decreased, respectively. TGF-β and PPT-I were undetectable in separate stromal cultures but were expressed as cocultures. Two consensus sequences for c-myc in the 5′ flanking region of the PPT-I gene were shown to be functional using gel shift and reporter gene assays. Mutagenesis of c-myc sites, neutralization studies with anti-TGF-β, and transient tranfections all showed that c-myc is required for TGF-β-mediated induction of PPT-I in BCCs. TGF-β was less efficient as a mediator of BCC integration within stroma for c-myc-BCCs. Because the model used in this study represents BCC integration within BM stroma, these studies suggest that TGF-β is important to the regulation of PPT-I in the early events of bone invasion by BCCs.
Thrombospondin-1 Associated with Tumor Microenvironment Contributes to Low-Dose Cyclophosphamide-Mediated Endothelial Cell Apoptosis and Tumor Growth Suppression
Authors: Hamano Yuki , Sugimoto Hikaru , Soubasakos Mary A. , Kieran Mark , Olsen Bjorn R. , Lawler Jack , Sudhakar Akulapalli , Kalluri Raghu 
Published: September 2005

Abstract
Low-dose cyclophosphamide (LDC) induces selective apoptosis of endothelial cells within the vascular bed of tumors. Here, we investigated a hypothesis that the effect of LDC is mediated by the pro-apoptotic action of endogenous inhibitors of angiogenesis. Tumors treated with LDC demonstrate similar expression of matrix metalloproteinases and also basement membrane-derived angiogenesis inhibitors when compared with wild-type tumors, whereas the expression of thrombospondin-1 (TSP-1) is significantly elevated in LDC-treated tumors. We used mice with an absence of type XVIII collagen (endostatin) or type IV collagen α3 chain (tumstatin) or TSP-1 to assess the contribution of these endogenous inhibitors of angiogenesis on LDC-mediated tumor suppression. Lack of TSP-1 in the host in addition to tumor cells leads to diminished capacity of LDC to suppress tumor growth, whereas the absence of endostatin and tumstatin did not alter the effect of LDC. LDC treatment predominantly induces selective expression of TSP-1 in tumor cells and peri-vascular cells and facilitates apoptosis of proliferating endothelial cells, with minimal direct effect on tumor cells and peri-vascular cells. These studies indicate that TSP-1 contributes to tumor growth suppression induced by LDC and suggest that tumors that express high basal level of TSP-1 may be more susceptible to tumor suppression by such a regimen. This study also makes a strong case for TSP-1 expression levels as a potential predictive marker for the successful use of LDC in cancer patients.
Genome-Wide Array-Based Comparative Genomic Hybridization Reveals Multiple Amplification Targets and Novel Homozygous Deletions in Pancreatic Carcinoma Cell Lines
Authors: Heidenblad Markus , Schoenmakers Eric F. P. M. , Jonson Tord , Gorunova Ludmila , Veltman Joris A. , van Kessel Ad Geurts , Höglund Mattias 
Published: September 2005

Abstract
Pancreatic carcinomas display highly complex chromosomal abnormalities, including many structural and numerical aberrations. There is ample evidence indicating that some of these abnormalities, such as recurrent amplifications and homozygous deletions, contribute to tumorigenesis by altering expression levels of critical oncogenes and tumor suppressor genes. To increase the understanding of gene copy number changes in pancreatic carcinomas and to identify key amplification/deletion targets, we applied genome-wide array-based comparative genomic hybridization to 31 pancreatic carcinoma cell lines. Two different microarrays were used, one containing 3,565 fluorescence in situ hybridization-verified bacterial artificial chromosome clones and one containing 25,468 cDNA clones representing 17,494 UniGene clusters. Overall, the analyses revealed a high genomic complexity, with several copy number changes detected in each case. Specifically, 60 amplicons at 32 different locations were identified, most frequently located within 8q (8 cases), 12p (7 cases), 7q (5 cases), 18q (5 cases), 19q (5 cases), 6p (4 cases), and 8p (4 cases). Amplifications of 8q and 12p were mainly clustered at 8q23–24 and 12p11–12, respectively, whereas amplifications on other chromosome arms were more dispersed. Furthermore, our analyses identified several novel homozygously deleted segments located to 9p24, 9p21, 9q32, 10p12, 10q22, 12q24, and 18q23. The individual complexity and aberration patterns varied substantially among cases, i.e., some cell lines were characterized mainly by high-level amplifications, whereas others showed primarily whole-arm imbalances and homozygous deletions. The described amplification and deletion targets are likely to contain genes important in pancreatic tumorigenesis.