bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3ε
Authors: Liou Jun-Yang , Ghelani Dipak , Yeh Sam , Wu Kenneth K. 
Published: April 2007

Abstract
To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3ε protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3ε proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 μmol/L inhibited 14-3-3ε protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3ε promoter activity. As 14-3-3ε promoter activation is mediated by peroxisome proliferator–activated receptor δ (PPARδ), we determined the correlation between 14-3-3ε inhibition and PPARδ suppression by NSAIDs. Sulindac sulfide inhibited PPARδ protein expression and PPARδ transcriptional activity. Overexpression of PPARδ by adenoviral transfer rescued 14-3-3ε proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3ε suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARδ transduction. Stable expression of 14-3-3ε in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARδ/14-3-3ε transcriptional pathway. These results suggest that 14-3-3ε is a target for the prevention and therapy of colorectal cancer. [Cancer Res 2007;67(7):3185–91]
Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells
Authors: Zhou Weibo , Han Wan Fang , Landree Leslie E. , Thupari Jagan N. , Pinn Michael L. , Bililign Tsion , Kim Eun Kyoung , Vadlamudi Aravinda , Medghalchi Susan M. , El Meskini Rajaa , Ronnett Gabriele V. , Townsend Craig A. , Kuhajda Francis P. 
Published: April 2007

Abstract
Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation. [Cancer Res 2007;67(7):2964–71]
Isoleucine, an Essential Amino Acid, Prevents Liver Metastases of Colon Cancer by Antiangiogenesis
Authors: Murata Kazumoto , Moriyama Masami 
Published: April 2007

Abstract
In spite of recent advances in the treatment of colon cancer, multiple liver metastases of colon cancer are still difficult to treat. Some chemotherapeutic regimens have been reported to be efficient, but there is a high risk of side effects associated with these. Here, we show that isoleucine, an essential amino acid, prevents liver metastases in a mouse colon cancer metastatic model. Because isoleucine is a strong inducer of β-defensin, we first hypothesized that it prevented liver metastases via the accumulation of dendritic cells or memory T cells through up-regulation of β-defensin. However, neither β-defensin nor immunologic responses were induced by isoleucine in both mouse livers and spleens. Furthermore, isoleucine prevented liver metastasis in nude mice, which lack T cells and natural killer T cells. Finally, we discovered a novel mechanism of isoleucine: down-regulation of angiogenesis via inhibition of vascular endothelial growth factor, partially through the mammalian target of the rapamycin pathway, independent of hypoxia-inducible factor 1-α. Importantly, isoleucine is safe for administration to humans because it does not affect cell viability. Isoleucine could be a novel prophylactic drug for the prevention of liver metastases of colon cancer. [Cancer Res 2007;67(7):3263–8]
IFN-γ Enhances the Antimyeloma Activity of the Fully Human Anti–Human Leukocyte Antigen-DR Monoclonal Antibody 1D09C3
Authors: Carlo-Stella Carmelo , Guidetti Anna , Di Nicola Massimo , Lavazza Cristiana , Cleris Loredana , Sia Daniela , Longoni Paolo , Milanesi Marco , Magni Michele , Nagy Zoltan , Corradini Paolo , Carbone Antonino , Formelli Franca , Gianni Alessandro M. 
Published: April 2007

AbstractTo investigate the therapeutic activity of the fully human anti–HLA-DR antibody 1D09C3 in multiple myeloma (MM), we reevaluated HLA-DR expression on CD138+ cells, analyzed the capacity of IFN-γ to up-regulate HLA-DR expression on MM cell lines, and tested the in vitro and in vivo activity of 1D09C3 alone or in combination with IFN-γ. CD138+HLA-DR+ cells were detected in 31 of 60 patients, with 15 of 60 patients having ≥20% CD138+HLA-DR+ cells (median, 50%; range, 23–100). Because primary plasma cells cannot be efficiently cultured in vitro, we used a panel of MM cell lines with a dim/negative to bright HLA-DR expression to evaluate 1D09C3-induced cell death. Annexin V/propidium iodide (PI) staining showed that 1D09C3-induced cell death correlated with constitutive HLA-DR expression. Induction of HLA-DR by IFN-γ restored the sensitivity of HLA-DR dim cell lines to 1D09C3. In vivo, the combined IFN-γ/1D09C3 treatment significantly increased the median survival of nonobese diabetic/severe combined immunodeficient mice xenografted with KMS-11 cell line, compared with controls (147 versus 48 days, P ≤ 0.0001) or mice receiving 1D09C3 alone (147 versus 92 days, P ≤ 0.03). The better therapeutic activity of IFN-γ/1D09C3 treatment over 1D09C3 alone was further shown by a 2-fold increase of mice being disease-free at 150 days after xenograft (47% versus 25%). No mice experienced any apparent treatment-related toxicity. Our data show that (a) one fourth of MM patients express HLA-DR on CD138+ cells and (b) IFN-γ–induced up-regulation of HLA-DR results in a potent enhancement of the in vivo antimyeloma activity of 1D09C3. [Cancer Res 2007;67(7):3269–75]
Tumors Initiated by Constitutive Cdk2 Activation Exhibit Transforming Growth Factor β Resistance and Acquire Paracrine Mitogenic Stimulation during Progression
Authors: Corsino Patrick , Davis Bradley , Law Mary , Chytil Anna , Forrester Elizabeth , Nørgaard Peter , Teoh Nicole , Law Brian 
Published: April 2007

Abstract
Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1–Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMTV) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV–cyclin D1–Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-D1K2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor β (TGFβ), but are relatively resistant to TGFβ antiproliferative effects. Fibroblasts derived from MMTV-D1K2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70s6k and Akt on activating sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGFβ and HGF, resulting in desmoplasia. The MMTV-D1K2 mice should provide a useful model system for the development of therapeutic approaches to block the stromal desmoplastic reaction that likely plays an important role in the progression of multiple types of human tumors. [Cancer Res 2007;67(7):3135–44]
Molecular Dissection of Hyperdiploid Multiple Myeloma by Gene Expression Profiling
Authors: Chng Wee J. , Kumar Shaji , VanWier Scott , Ahmann Greg , Price-Troska Tammy , Henderson Kim , Chung Tae-Hoon , Kim Seungchan , Mulligan George , Bryant Barbara , Carpten John , Gertz Morie , Rajkumar S. Vincent , Lacy Martha , Dispenzieri Angela , Kyle Robert , Greipp Philip , Bergsagel P. Leif , Fonseca Rafael 
Published: April 2007

Abstract
Hyperdiploid multiple myeloma (H-MM) is the most common form of myeloma. In this gene expression profiling study, we show that H-MM is defined by a protein biosynthesis signature that is primarily driven by a gene dosage mechanism as a result of trisomic chromosomes. Within H-MM, four independently validated patient clusters overexpressing nonoverlapping sets of genes that form cognate pathways/networks that have potential biological importance in multiple myeloma were identified. One prominent cluster, cluster 1, is characterized by high expression of cancer testis antigen and proliferation-associated genes. Tumors from these patients were more proliferative than tumors in other clusters (median plasma cell labeling index, 3.8; P &lt; 0.05). Another cluster, cluster 3, is characterized by genes involved in tumor necrosis factor/nuclear factor-κB signaling and antiapoptosis. These patients have better response to bortezomib as compared with patients within other clusters (70% versus 29%; P = 0.02). Furthermore, for a group of patients generally thought to have better prognosis, a cluster of patients with short survival (cluster 1; median survival, 27 months) could be identified. This analysis illustrates the heterogeneity within H-MM and the importance of defining specific cytogenetic prognostic factors. Furthermore, the signatures that defined these clusters may provide a basis for tailoring treatment to individual patients. [Cancer Res 2007;67(7):2982–9]
Repression of IFN Regulatory Factor 8 by DNA Methylation Is a Molecular Determinant of Apoptotic Resistance and Metastatic Phenotype in Metastatic Tumor Cells
Authors: Yang Dafeng , Thangaraju Muthusamy , Greeneltch Kristy , Browning Darren D. , Schoenlein Patricia V. , Tamura Tomohiko , Ozato Keiko , Ganapathy Vadivel , Abrams Scott I. , Liu Kebin 
Published: April 2007

AbstractApoptotic resistance is often associated with metastatic phenotype in tumor cells and is considered a hallmark of tumor progression. In this study, IFN regulatory factor 8 (IRF8) expression was found to be inversely correlated with an apoptotic-resistant and metastatic phenotype in human colon carcinoma cell lines in vitro. This inverse correlation was further extended to spontaneously arising primary mammary carcinoma and lung metastases in a mouse tumor model in vivo. Exogenous expression of IRF8 in the metastatic tumor cell line restored, at least partially, the sensitivity of the tumor cells to Fas-mediated apoptosis, and disruption of IRF8 function conferred the poorly metastatic tumors with enhanced apoptotic resistance and metastatic capability. DNA demethylation restored IRF8 expression and sensitized the metastatic tumor cells to Fas-mediated apoptosis. Analysis of genomic DNA isolated from both primary and metastatic tumor cells with methylation-sensitive PCR revealed hypermethylation of the IRF8 promoter in metastatic tumor cells but not in primary tumor cells. Taken together, our data suggest that IRF8 is both an essential regulator in Fas-mediated apoptosis pathway and a metastasis suppressor in solid tumors and that metastatic tumor cells use DNA hypermethylation to repress IRF8 expression to evade apoptotic cell death and to acquire a metastatic phenotype. [Cancer Res 2007;67(7):3301–9]
Autoantibody Profiles Reveal Ubiquilin 1 as a Humoral Immune Response Target in Lung Adenocarcinoma
Authors: Chen Guoan , Wang Xiaoju , Yu Jianjun , Varambally Sooryanarayana , Yu Jindan , Thomas Dafydd G. , Lin Mu-Yen , Vishnu Prakash , Wang Zhuwen , Wang Rui , Fielhauer Jeff , Ghosh Debashis , Giordano Thomas J. , Giacherio Donald , Chang Andrew C. , Orringer Mark B. , El-Hefnawy Talal , Bigbee William L. , Beer David G. , Chinnaiyan Arul M. 
Published: April 2007

Abstract
There is considerable evidence that the presence of cancer can elicit a humoral immune response to specific proteins in the host, and these resulting autoantibodies may have potential as noninvasive biomarkers. To characterize the autoantibody repertoire present in the sera of patients with lung adenocarcinoma, we developed a high-density peptide microarray derived from biopanning a lung cancer phage display library. Using a 2,304-element microarray, we interrogated a total of 250 sera from Michigan lung cancer patients and noncancer controls to develop an “autoantibody profile” of lung adenocarcinoma. A set of 22 discriminating peptides derived from a training set of 125 serum samples from lung adenocarcinoma patients and control subjects was found to predict cancer status with 85% sensitivity and 86% specificity in an independent test set of 125 sera. Sequencing of the immunoreactive phage-peptide clones identified candidate humoral immune response targets in lung adenocarcinoma, including ubiquilin 1, a protein that regulates the degradation of several ubiquitin-dependent proteasome substrates. An independent validation set of 122 serum samples from Pittsburgh was examined using two overlapping clones of ubiquilin 1 that showed 0.79 and 0.74 of the area under the receiver operating characteristics curve, respectively. Significantly increased levels of both ubiquilin 1 mRNA and protein, as well as reduced levels of the phosphorylated form of this protein, were detected in lung tumors. Immunofluorescence using anti–ubiquilin 1 antibodies confirmed intracellular expression within tumors cells. These studies indicate that autoantibody profiles, as well as individual candidates, may be useful for the noninvasive detection of lung adenocarcinoma. [Cancer Res 2007;67(7):3461–7]
p18Ink4c Collaborates with Men1 to Constrain Lung Stem Cell Expansion and Suppress Non–Small-Cell Lung Cancers
Authors: Pei Xin-Hai , Bai Feng , Smith Matthew D. , Xiong Yue 
Published: April 2007

Abstract
Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18Ink4c and p27Kip1 develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice and showed that p18, but not p27, functionally collaborates with Men1 in suppressing lung tumorigenesis. Lung tumors developed in both Men1+/− and p18−/−;Men1+/− mice at a high penetrance and contain both neuroendocrine and nonneuroendocrine cells. The remaining wild-type Men1 allele was lost in most lung tumors from Men1+/− mice but was retained in most tumors from p18−/−;Men1+/− mice, showing a functional collaboration between p18 and Men1 in lung tumor suppression. Phosphorylation of Rb protein at both CDK2 and CDK4/CDK6 sites were significantly increased in normal bronchial epithelia and tumor cells derived from p18−/−;Men1+/− mice compared to those from single p18−/− or Men1+/− mice. Lung tumors developed in p18−/−;Men1+/− mice were multifocal, more heterogeneous, and highly invasive compared to those developed in either p18−/− or Men1+/− mice. Bronchioalveolar stem cells are expanded in normal and tumorigenic lungs of p18−/− mice and are further expanded in p18−/−;Men1+/− lung tumors. These results reveal a previously unrecognized function of p18 in lung tumor suppression through collaboration with Men1 to control lung stem cell proliferation. [Cancer Res 2007;67(7):3162–70]
Materializing the Potential of Small Interfering RNA via a Tumor-Targeting Nanodelivery System
Authors: Pirollo Kathleen F. , Rait Antonina , Zhou Qi , Hwang Sung Hee , Dagata John A. , Zon Gerald , Hogrefe Richard I. , Palchik Guillermo , Chang Esther H. 
Published: April 2007

AbstractThe field of small interfering RNA (siRNA) as potent sequence-selective inhibitors of transcription is rapidly developing. However, until now, low transfection efficiency, poor tissue penetration, and nonspecific immune stimulation by in vivo administered siRNAs have delayed their therapeutic application. Their potential as anticancer therapeutics hinges on the availability of a vehicle that can be systemically administered, safely and repeatedly, and will deliver the siRNA specifically and efficiently to the tumor, both primary tumors and metastases. We have developed a nanosized immunoliposome-based delivery complex (scL) that, when systemically administered, will preferentially target and deliver molecules useful in gene medicine, including plasmid DNA and antisense oligonucleotides, to tumor cells wherever they occur in the body. This tumor-targeting nanoparticle delivery vehicle can also deliver siRNA to both primary and metastatic disease. We have also enhanced the efficiency of this complex by the inclusion of a pH-sensitive histidine-lysine peptide in the complex (scL-HoKC) and by delivery of a modified hybrid (DNA-RNA) anti-HER-2 siRNA molecule. Scanning probe microscopy confirms that this modified complex maintains its nanoscale size. More importantly, we show that this nanoimmunoliposome anti-HER-2 siRNA complex can sensitize human tumor cells to chemotherapeutics, silence the target gene and affect its downstream pathway components in vivo, and significantly inhibit tumor growth in a pancreatic cancer model. Thus, this complex has the potential to help translate the potent effects of siRNA into a clinically viable anticancer therapeutic. [Cancer Res 2007;67(7):2938–43]
Nuclear Factor-κB Accounts for the Repressor Effects of High Stromal Cell–Derived Factor-1α Levels on Tac1 Expression in Nontumorigenic Breast Cells
Authors: Corcoran Kelly E. , Rameshwar Pranela 
Published: April 2007

Abstract
Stromal cell–derived factor-1α (SDF-1α) is a CXC chemokine that interacts with CXCR4 receptor. Tac1 encodes peptides belonging to the tachykinins, including substance P. SDF-1α production is decreased in Tac1 knockdown breast cancer cells and is also reduced in these cancer cells following contact with bone marrow stroma when Tac1 expression is increased. Here, we report on the effects of relatively high and low SDF-1α levels on Tac1 expression in nontumorigenic breast cells MCF12A. Reporter gene assays, Northern analyses, and ELISA for substance P showed increased Tac1 expression at 20 and 50 ng/mL SDF-1α and reduced expression at 100 ng/mL. Omission of the untranslated region showed a dose-dependent effect of SDF-1α on reporter gene activity, suggesting that receptor desensitization cannot account for the suppressive effects at 100 ng/mL SDF-1α. Tac1 expression at high SDF-1α involves an intracellular signaling pathway that incorporates the activation of phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-AKT-nuclear factor-κB (NF-κB). The major repressive effect occurs via NF-κB located within exon 1. In summary, NF-κB is involved in the repression of Tac1 at higher levels of SDF-1α in MCF12A. These results are relevant to dysfunction of Tac1 in breast cancer cells and also provide insights on the behavior of breast cancer cells as they traverse across gradient changes of SDF-1α. (Mol Cancer Res 2007;5(4):373–81)
Investigating fluid penetration of rolling contact fatigue cracks in rails using a newly developed full-scale test facility
Authors: Fletcher D I , Hyde P , Kapoor A 
Published: April 2007

Fluid penetration of surface breaking rolling contact fatigue cracks in rails is believed to be a key factor in their growth to dangerous lengths. Fluid entry has been proved for surface breaking cracks in laboratory twin disc contact simulations, but the authors are not aware of direct evidence for fluid penetration of cracks in full-scale rail-wheel contacts. There is, however, a widely held view that the behaviour observed in the laboratory will translate to full-scale cases. To investigate fluid penetration of cracks in full-scale rail-wheel contacts, cracked rails with a range of rolling contact fatigue severity were removed from mainline railway track and re-installed at a newly developed test facility. Investigation was undertaken using two different water-based marker fluids, and the rails subjected to over 1000 wheel passes with a locomotive. The rails were subsequently removed and selected crack faces broken open for observation by placing the rail in four-point bending. Ultra-violet and visible light were used to assess the degree to which the marker fluids had entered the surface breaking cracks. Good evidence of fluid penetration was found for one of the marker fluids, but the second fluid was not observed inside the cracks. The possible reasons behind this difference in behaviour are discussed.