bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peroxisome Proliferator–Activated Receptor γ as a Molecular Target of Resveratrol-Induced Modulation of Polyamine Metabolism
Authors: Ulrich Sandra , Loitsch Stefan M. , Rau Oliver , von Knethen Andreas , Brüne Bernhard , Schubert-Zsilavecz Manfred , Stein Jürgen M. 
Published: July 2006

AbstractPrevious results indicate that the polyphenol resveratrol inhibits cell growth of colon carcinoma cells via modulation of polyamine metabolic key enzymes. The aim of this work was to specify the underlying molecular mechanisms and to identify a possible role of transcription factor peroxisome proliferator–activated receptor γ (PPARγ). Cell growth was determined by bromodeoxyuridine incorporation and crystal violet staining. Protein levels were examined by Western blot analysis. Spermine/spermidine acetyltransferase (SSAT) activity was determined by a radiochemical assay. PPARγ ligand–dependent transcriptional activity was measured by a luciferase assay. A dominant-negative PPARγ mutant was transfected in Caco-2 cells to suppress PPARγ-mediated functions. Resveratrol inhibits cell growth of both Caco-2 and HCT-116 cells in a dose- and time-dependent manner (P &lt; 0.001). In contrast to Caco-2-wild type cells (P &lt; 0.05), resveratrol failed to increase SSAT activity in dominant-negative PPARγ cells. PPARγ involvement was further confirmed via ligand-dependent activation (P &lt; 0.01) as well as by induction of cytokeratin 20 (P &lt; 0.001) after resveratrol treatment. Coincubation with SB203580 abolished SSAT activation significantly in Caco-2 (P &lt; 0.05) and HCT-116 (P &lt; 0.01) cells. The involvement of p38 mitogen-activated protein kinase (MAPK) was further confirmed by a resveratrol-mediated phosphorylation of p38 protein in both cell lines. Resveratrol further increased the expression of PPARγ coactivator PGC-1α (P &lt; 0.05) as well as SIRT1 (P &lt; 0.01) in a dose-dependent manner after 24 hours of incubation. Based on our findings, p38 MAPK and transcription factor PPARγ can be considered as molecular targets of resveratrol in the regulation of cell proliferation and SSAT activity, respectively, in a cell culture model of colon cancer. (Cancer Res 2006; 66(14): 7348-54)
Detection of Low Molecular Weight Derivatives of Cyclin E1 Is a Function of Cyclin E1 Protein Levels in Breast Cancer
Authors: Spruck Charles , Sun Dahui , Fiegl Heidi , Marth Christian , Mueller-Holzner Elisabeth , Goebel Georg , Widschwendter Martin , Reed Steven I. 
Published: July 2006

Abstract
Cyclin E1 regulates the initiation of the S phase program in the mammalian cell division cycle. In normal cells, cyclin E1 protein expression is tightly controlled through a combination of transcriptional and proteolytic regulatory processes. However, in many types of human tumor, cyclin E1 expression is frequently dysregulated, including overexpression, nonperiodic expression relative to cell division, and generation of low molecular weight (LMW) derivatives. LMW derivatives of cyclin E1 have been proposed to be generated by the in vivo proteolytic cleavage of the full-length cyclin E1 protein by a yet to be identified tumor-specific protease. Recently, it was suggested that overexpression of full-length or LMW derivatives of cyclin E1 are independent variables associated with poor outcome in patients with breast cancer. However, we have extensively analyzed cyclin E1 protein expression in primary breast tumors and breast tumor-derived cell lines and found that the ability to detect LMW derivatives of cyclin E1 correlates only with the level of cyclin E1 protein. When cyclin E1 levels on Western blots are normalized, LMW derivatives of cyclin E1 were observed at roughly equal levels in all primary breast tumors, breast tumor-derived cell lines, immortalized nontransformed human mammary epithelial cells, and normal breast tissue. Therefore, the detection of LMW derivatives of cyclin E1 is likely a function of cyclin E1 protein levels, and the activity of the proteolytic machinery responsible for their generation is not a tumor-specific property. (Cancer Res 2006; 66(14): 7355-60)
Recombinant Human Insulin-like Growth Factor Binding Protein 3 Inhibits Growth of Human Epidermal Growth Factor Receptor-2–Overexpressing Breast Tumors and Potentiates Herceptin Activity In vivo
Authors: Jerome Lori , Alami Nezha , Belanger Sylvie , Page Viviane , Yu Qingnan , Paterson Jesse , Shiry Laura , Pegram Mark , Leyland-Jones Brian 
Published: July 2006

Abstract
Clinical studies indicate that Herceptin (trastuzumab), a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase growth factor receptor, provides a significant but transient survival advantage to a subset of patients with HER-2-overexpressing metastatic breast cancer when given as a first-line agent. Increased insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has recently been identified as a potential factor adversely influencing the response to Herceptin. We examined the effect of recombinant human IGF binding protein 3 (rhIGFBP-3), an antagonist of IGF-IR signaling, in Herceptin-resistant breast cells in vitro and in tumors in vivo. Consistent with results obtained using HER-2- or IGF-IR-transfected cells (MCF-7/HER2-18 and SKBR3/IGF-IR, respectively), we found that rhIGFBP-3 significantly reduced IGF-I-induced IGF-IR phosphorylation and displayed a synergistic interaction with Herceptin against cultured HER-2-overexpressing breast cancer cells in vitro. We show, for the first time, the antitumor activity of rhIGFBP-3 against advanced-stage MCF-7/HER2-18–transfected human breast cancer xenografts and its potentiation of Herceptin activity. We also provide evidence that IGF-IR activation counters the early suppressive effect of Herceptin on HER-2 signaling via Akt and p44/p42 mitogen-activated protein kinase (MAPK), and that inhibition of HER-2-overexpressing human breast tumor growth by rhIGFBP-3 is associated with restored down-regulation of Akt and p44/p42 MAPK phosphorylation in vitro and in vivo. These results emphasize the merit of evaluating simultaneous blockade of the HER-2 and IGF-IR pathways using combination therapy with rhIGFBP-3 plus Herceptin in human clinical trials of patients with HER-2-positive breast cancer. (Cancer Res 2006; 66(14): 7245-52)
Generation of Replication-Dependent Double-Strand Breaks by the Novel N2-G-Alkylator S23906-1
Authors: Léonce Stéphane , Kraus-Berthier Laurence , Golsteyn Roy M. , David-Cordonnier Marie-Hélène , Tardy Christelle , Lansiaux Amélie , Poindessous Virginie , Larsen Annette K. , Pierré Alain 
Published: July 2006

Abstract
S23906-1, a new DNA alkylating agent that reacts with the exocyclic 2-NH2 group of guanine residues yielding monofunctional adducts, is currently under clinical evaluation in phase I trials. To investigate the mechanism of action of S23906-1, we compared parental KB-3-1 cells and KB/S23-500 cells that are 15-fold resistant to S23906-1. Cell death induced by 1 μmol/L S23906-1 in KB-3-1 cells was associated with their irreversible arrest in the G2-M phases of the cell cycle followed by apoptosis, whereas a proportion of the resistant KB/S23-500 cells were able to exit from the G2 arrest and divide, leading to a significantly lower rate of apoptosis. The attenuated apoptotic response was associated with decreased Chk2 protein phosphorylation, indicating that the DNA damage signaling pathways are more potently activated in the sensitive cells. However, similar rates of adduct formation and repair were measured in both cell lines. Exposure to S23906-1 induced a higher formation of DNA breaks, measured by the comet assay, in sensitive cells. In agreement, a histone H2AX phosphorylation assay revealed that S23906-1 induced double-strand breaks (DSB) in a dose- and time-dependent manner and that these were more persistent in the parental cells. These DSBs were found mainly in S-phase cells and inhibited by aphidicolin, suggesting that they are DNA replication-mediated DSBs. These results suggest that secondary DNA lesions play an important role in the cytotoxicity of this compound and make histone H2AX phosphorylation an attractive marker for monitoring the efficacy of S23906-1. (Cancer Res 2006; 66(14): 7203-10)
High Levels of Dioxin-Like Potential in Cigarette Smoke Evidenced byIn vitroandIn vivoBiosensing
Authors: Kasai Ayumi , Hiramatsu Nobuhiko , Hayakawa Kunihiro , Yao Jian , Maeda Shuichiro , Kitamura Masanori 
Published: July 2006

AbstractCigarette smoke contains low levels of agonists for the aryl hydrocarbon receptor (AhR; also called the dioxin receptor). However, little is understood about the whole potential of cigarette smoke for activating AhR. In this report, we evaluated the total “dioxin-like” activity of cigarette smoke using in vitro and in vivo reporter systems. Cigarette smoke extract (CSE) was prepared from seven cigarette brands (1-20 mg tar content) and subjected to in vitro bioassay based on the xenobiotic-responsive element (XRE) as the sensor and secreted alkaline phosphatase (SEAP) as the reporter. Exposure of reporter cells to CSE triggered activation of XRE in a dose-dependent manner, which was suppressed by functional inhibition of AhR. Direct, brief exposure of the cells to cigarette smoke similarly induced activation of XRE. Using 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) as the standard, the XRE-activating potential (XAP) of individual smoke was evaluated quantitatively. Positive correlation was observed between the tar content and XAP values. The XAP values estimated were extremely high with a range from 18.5 to 51.2 ng 2,3,7,8-TCDD equivalent per cigarette. To further estimate XAP of cigarette smoke in vivo, we generated transgenic reporter mice that secrete SEAP under the control of XRE. After exposure of the mice to smoke, serum levels of SEAP were significantly elevated within 12 hours, peaked at 24 hours, and declined thereafter. These results evidenced for the first time that cigarette smoke has unexpectedly high dioxin-like potential that triggers the AhR-XRE pathway in vitro and in vivo. (Cancer Res 2006; 66(14): 7143-50)
Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas
Authors: Davicioni Elai , Graf Finckenstein Friedrich , Shahbazian Violette , Buckley Jonathan D. , Triche Timothy J. , Anderson Michael J. 
Published: July 2006

Abstract
Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior. (Cancer Res 2006; 66(14): 6936-46)
Nuclear Factor-κB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer
Authors: Nakashima Hiroshi , Nakamura Masafumi , Yamaguchi Hiroshi , Yamanaka Naoki , Akiyoshi Takashi , Koga Kenichiro , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao , Katano Mitsuo 
Published: July 2006

Abstract
The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-κB (NF-κB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-κB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-κB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-κB by inflammatory stimuli, including interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-κB. NF-κB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-κB suppressed the enhanced cell proliferation. Our data suggest that NF-κB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-κB activation in part through Shh overexpression. (Cancer Res 2006; 66(14): 7041-9)
Gene Expression Profiling of Acute Myeloid Leukemia with Translocation t(8;16)(p11;p13) and MYST3-CREBBP Rearrangement Reveals a Distinctive Signature with a Specific Pattern of HOX Gene Expression
Authors: Camós Mireia , Esteve Jordi , Jares Pedro , Colomer Dolors , Rozman María , Villamor Neus , Costa Dolors , Carrió Ana , Nomdedéu Josep , Montserrat Emili , Campo Elías 
Published: July 2006

Abstract
Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) is an infrequent leukemia subtype with characteristic clinicobiological features. This translocation leads to fusion of MYST3 (MOZ) and CREBBP (CBP) genes, probably resulting in a disturbed transcriptional program of a myelomonocytic precursor. Nonetheless, its gene expression profile is unknown. We have analyzed the gene expression profile of 23 AML patients, including three with molecularly confirmed MYST3-CREBBP fusion gene, using oligonucleotide U133A arrays (Affymetrix). MYST3-CREBBP cases clustered together and clearly differentiated from samples with PML-RARα, RUNX1-RUNX1T1, and CBFβ-MYH11 rearrangements. The relative expression of 46 genes, selected according to their differential expression in the high-density array study, was analyzed by low-density arrays in an additional series of 40 patients, which included 7 MYST3-CREBBP AML cases. Thus, genes such as prolactin (PRL) and proto-oncogene RET were confirmed to be specifically overexpressed in MYST3-CREBBP samples whereas genes such as CCND2, STAT5A, and STAT5B were differentially underexpressed in this AML category. Interestingly, MYST3-CREBBP AML exhibited a characteristic pattern of HOX expression, with up-regulation of HOXA9, HOXA10, and cofactor MEIS1 and marked down-regulation of other homeobox genes. This profile, with overexpression of FLT3, HOXA9, MEIS1, AKR7A2, CHD3, and APBA2, partially resembles that of AML with MLL rearrangement. In summary, this study shows the distinctive gene expression profile of MYST3-CREBBP AML, with overexpression of RET and PRL and a specific pattern of HOX gene expression. (Cancer Res 2006; 66(14): 6947-54)
Cancers as Wounds that Do Not Heal: Differences and Similarities between Renal Regeneration/Repair and Renal Cell Carcinoma
Authors: Riss Joseph , Khanna Chand , Koo Seongjoon , Chandramouli Gadisetti V.R. , Yang Howard H. , Hu Ying , Kleiner David E. , Rosenwald Andreas , Schaefer Carl F. , Ben-Sasson Shmuel A. , Yang Liming , Powell John , Kane David W. , Star Robert A. , Aprelikova Olga , Bauer Kristin , Vasselli James R. , Maranchie Jodi K. , Kohn Kurt W. , Buetow Ken H. , Linehan W. Marston , Weinstein John N. , Lee Maxwell P. , Klausner Richard D. , Barrett J. Carl 
Published: July 2006

Abstract
Cancers have been described as wounds that do not heal, suggesting that the two share common features. By comparing microarray data from a model of renal regeneration and repair (RRR) with reported gene expression in renal cell carcinoma (RCC), we asked whether those two processes do, in fact, share molecular features and regulatory mechanisms. The majority (77%) of the genes expressed in RRR and RCC were concordantly regulated, whereas only 23% were discordant (i.e., changed in opposite directions). The orchestrated processes of regeneration, involving cell proliferation and immune response, were reflected in the concordant genes. The discordant gene signature revealed processes (e.g., morphogenesis and glycolysis) and pathways (e.g., hypoxia-inducible factor and insulin-like growth factor-I) that reflect the intrinsic pathologic nature of RCC. This is the first study that compares gene expression patterns in RCC and RRR. It does so, in particular, with relation to the hypothesis that RCC resembles the wound healing processes seen in RRR. However, careful attention to the genes that are regulated in the discordant direction provides new insights into the critical differences between renal carcinogenesis and wound healing. The observations reported here provide a conceptual framework for further efforts to understand the biology and to develop more effective diagnostic biomarkers and therapeutic strategies for renal tumors and renal ischemia. (Cancer Res 2006; 66(14): 7216-24)
Cancer Immunotherapy by Interleukin-21: Potential Treatment Strategies Evaluated in a Mathematical Model
Authors: Cappuccio Antonio , Elishmereni Moran , Agur Zvia 
Published: July 2006

AbstractThe newly characterized interleukin (IL)-21 plays a central role in the transition from innate immunity to adaptive immunity and shows substantial tumor regression in mice. IL-21 is now developed as a cancer immunotherapeutic drug, but conditions for efficacious therapy, and the conflicting immunostimulatory and immunoinhibitory influence of the cytokine, are yet to be defined. We studied the effects of IL-21 on tumor eradication in a mathematical model focusing on natural killer (NK) cell–mediated and CD8+ T-cell-mediated lysis of tumor cells. Model parameters were estimated using results in tumor-bearing mice treated with IL-21 via cytokine gene therapy (CGT), hydrodynamics-based gene delivery (HGD), or standard interval dosing (SID). Our model accurately retrieved experimental growth dynamics in the nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8+ T-cell balance on tumor immunogenicity. Moreover, in melanoma, simulations of CGT-like dosing regimens, dynamically determined according to tumor mass changes, resulted in efficient disease elimination. In contrast, in fibrosarcoma, such a strategy was not superior to that of fixed dosing regimens, HGD or SID. Our model supports clinical use of IL-21 as a potent stimulator of cellular immunity against cancer, and suggests selecting the immunotherapy strategy according to tumor immunogenicity. Nonimmunogenic tumors, but not highly immunogenic tumors, should be controlled by IL-21 dosing, which depends on tumor mass at the time of administration. This method imitates, yet amplifies, the natural anticancer immune response rather than accelerates only one of the response arms in an unbalanced manner. (Cancer Res 2006; 66(14): 7293-300)
ChIP-chip Comes of Age for Genome-wide Functional Analysis
Authors: Wu Jiejun , Smith Laura T. , Plass Christoph , Huang Tim H-M. 
Published: July 2006

Abstract
In the post-genome era, attention has focused on the functions of genome sequences and how they are regulated. The emerging epigenomic changes and the interactions between cis-acting elements and protein factors may play a central role in gene regulation. To understand the crosstalk between DNA and protein on a genome-wide scale, one emerging technique, called ChIP-chip, takes the strategy of combining chromatin immunoprecipitation with microarray. This new high-throughput strategy helps screen the targets of critical transcription factors and profile the genome-wide distribution of histone modifications, which will enable the feasibility of conducting a large-scale study, such as the Human Epigenome Project. (Cancer Res 2006; 66(14): 6899-902)
Primary Cilium Formation Requires von Hippel-Lindau Gene Function in Renal-Derived Cells
Authors: Lutz Mallory S. , Burk Robert D. 
Published: July 2006

Abstract
Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, occurs in the majority of renal clear cell carcinomas (RCC). VHL's function, regulating the degradation of hypoxia-inducible factor α (HIFα) subunits, explains the angiogenic nature of these tumors, but not tumor initiation. Because the development of renal cysts precedes tumor formation, and because the dysfunction of primary cilium is a common pathogenic mechanism in polycystic kidney diseases, we determined whether kidney-derived VHL− cells required VHL for the generation of cilium. Ectopic expression of VHL in RCC(VHL−) cells induced increased polarization and primary cilium formation. Cilium formation correlated directly with the expression of both wild-type VHL isoforms and a VHL mutant not associated with RCC development, whereas expression of RCC-associated VHL mutants did not support ciliogenesis. Requirement of VHL for ciliogenesis was independent of HIFα abundance. These data indicate separable independent functions for VHL (HIFα degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis. (Cancer Res 2006; 66(14): 6903-07)
p73 or p53 Directly Regulates Human p53 Transcription to Maintain Cell Cycle Checkpoints
Authors: Wang Shulin , El-Deiry Wafik S. 
Published: July 2006

Abstract
Whereas the p53 tumor suppressor protein plays a central role in cellular checkpoints that respond to damage or stress to prevent tumorigenesis, the transcriptional control of the p53 gene has remained unclear. We show that chemotherapeutic agents induce p53 transcription and that p73 or p53 transactivates endogenous p53 expression through direct binding to the p53 promoter. Silencing of p53 or p73 by RNA interference significantly suppresses p53 transcription under physiologic conditions or in response to cellular stress. Mutational analysis of the human p53 promoter localized a p53 DNA-binding site, which confers p53- or p73-dependent p53 promoter activation. Importantly, impaired p53-mediated autoregulation of p53 transcription by inducible-interfering RNA results in aberrant cell cycle regulation and suppression of p53-mediated apoptosis. Thus, a positive feedback loop regulates human p53 expression and involves p73 and p53. Disruption of p53 transcription contributes to defective checkpoint control. (Cancer Res 2006; 66(14): 6982-9)