bluuebunny/crossref_metadata_2025_split huggingface dataset:
γ-Aminobutyric Acid Inhibits Cholangiocarcinoma Growth by Cyclic AMP–Dependent Regulation of the Protein Kinase A/Extracellular Signal-Regulated Kinase 1/2 Pathway
Authors: Fava Giammarco , Marucci Luca , Glaser Shannon , Francis Heather , De Morrow Sharon , Benedetti Antonio , Alvaro Domenico , Venter Julie , Meininger Cynthia , Patel Tushar , Taffetani Silvia , Marzioni Marco , Summers Ryun , Reichenbach Ramona , Alpini Gianfranco 
Published: December 2005

Abstract
We studied the effect of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in the regulation of cholangiocarcinoma growth. We determined the in vitro effect of GABA on the proliferation of the cholangiocarcinoma cell lines (Mz-ChA-1, HuH-28, and TFK-1) and evaluated the intracellular pathways involved. The effect of GABA on migration of Mz-ChA-1 cells was also evaluated. In vivo, Mz-ChA-1 cells were s.c. injected in athymic mice, and the effects of GABA on tumor size, tumor cell proliferation, apoptosis, collagen quantity, and the expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-C (cancer growth regulators) were measured after 82 days. GABA decreased in vitro cholangiocarcinoma growth in a time-dependent and dose-dependent manner, by both cyclic AMP/protein kinase A– and d-myo-inositol-1,4,5-thriphosphate/Ca2+-dependent pathways, leading to down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation. Blocking of GABAA, GABAB, and GABAC receptors prevented GABA inhibition of cholangiocarcinoma proliferation. GABA inhibited Mz-ChA-1 cell migration and, in vivo, significantly decreased tumor volume, tumor cell proliferation, and VEGF-A/C expression whereas increasing apoptosis compared with controls. An increase in collagen was evident in GABA-treated tumors. GABA decreases biliary cancer proliferation and reduces the metastatic potential of cholangiocarcinoma. GABA may represent a therapeutic agent for patients affected by malignancies of the biliary tract. (Cancer Res 2005; 65(24): 11437-46)
Cyclooxygenase-2 Inhibition Sensitizes Human Colon Carcinoma Cells to TRAIL-Induced Apoptosis through Clustering of DR5 and Concentrating Death-Inducing Signaling Complex Components into Ceramide-Enriched Caveolae
Authors: Martin Sophie , Phillips Darren C. , Szekely-Szucs Kinga , Elghazi Lynda , Desmots Fabienne , Houghton Janet A. 
Published: December 2005

AbstractCyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane. (Cancer Res 2005; 65(24): 11447-58)
A Putative Role for Psoriasin in Breast Tumor Progression
Authors: Krop Ian , März Annette , Carlsson Hanna , Li Xiaochun , Bloushtain-Qimron Noga , Hu Min , Gelman Rebecca , Sabel Michael S. , Schnitt Stuart , Ramaswamy Sridhar , Kleer Celina G. , Enerbäck Charlotta , Polyak Kornelia 
Published: December 2005

Abstract
Psoriasin (S100A7) was identifi`ed as a gene highly expressed in psoriatic keratinocytes and highly and more frequently expressed in ductal carcinoma in situ (DCIS) than in invasive breast carcinomas (IBC), suggesting a potential role in tumor progression. Psoriasin expression is associated with poor prognostic factors in both DCIS and IBC. Several putative functions have been proposed for psoriasin in various disease types, but none of these can fully explain its involvement in breast tumor progression. Here, we show that down-regulation of endogenous psoriasin expression via stable short hairpin RNAs in a human IBC cell line (MDA-MB-468) increases cell migration and invasion without influencing cell proliferation and survival in vitro but inhibits tumor growth in vivo. These seemingly paradoxical results are potentially explained by the dramatic up-regulation and down-regulation of matrix metalloproteinase-13 and vascular endothelial growth factor (VEGF), respectively, observed in cells with decreased psoriasin levels compared with controls. Correlating with this, high psoriasin expression in human IBC is associated with increased angiogenesis and worse clinical outcome, and psoriasin mRNA levels are coordinately regulated with VEGF and other genes related to hypoxia and mitochondrial reactive oxygen species (ROS). Based on these results, we propose that psoriasin may play a role in breast tumor progression by promoting angiogenesis and enhancing the selection for cells that overcome its anti-invasive function. This hypothesis may explain why psoriasin expression is highest in high-grade and/or estrogen receptor–negative tumors, as these are associated with increased hypoxia and ROS, a setting in which the angiogenic effects of psoriasin are most important. (Cancer Res 2005; 65(24): 11326-34)
Inducible IκB Kinase/IκB Kinase ε Expression Is Induced by CK2 and Promotes Aberrant Nuclear Factor-κB Activation in Breast Cancer Cells
Authors: Eddy Sean F. , Guo Shangqin , Demicco Elizabeth G. , Romieu-Mourez Raphaëlle , Landesman-Bollag Esther , Seldin David C. , Sonenshein Gail E. 
Published: December 2005

Abstract
Aberrant activation of nuclear factor-κB (NF-κB) transcription factors has been implicated in the pathogenesis of breast cancer. We previously showed elevated activity of IκB kinase α (IKKα), IKKβ, and protein kinase CK2 in primary human breast cancer specimens and cultured cells. A novel inducible IKK protein termed IKK-i/IKKε has been characterized as a potential NF-κB activator. Here, we provide evidence that implicates IKK-i/IKKε in the pathogenesis of breast cancer. We show IKK-i/IKKε expression in primary human breast cancer specimens and carcinogen-induced mouse mammary tumors. Multiple breast cancer cell lines showed higher levels of IKK-i/IKKε and kinase activity compared with untransformed MCF-10F breast epithelial cells. Interestingly, IKK-i/IKKε expression correlated with CK2α expression in mammary glands and breast tumors derived from MMTV-CK2α transgenic mice. Ectopic CK2 expression in untransformed cells led to increased IKK-i/IKKε mRNA and protein levels. Inhibition of CK2α via the pharmacologic inhibitor apigenin or upon transfection of a CK2 kinase-inactive subunit reduced IKK-i/IKKε levels. Expression of a kinase-inactive IKK-i/IKKε mutant in breast cancer cells reduced NF-κB activity as judged by transfection assays of reporters driven either by NF-κB elements or the promoters of two NF-κB target genes, cyclin D1 and relB. Importantly, the kinase-inactive IKK-i/IKKε mutant reduced the endogenous levels of these genes as well as the ability of breast cancer cells to grow in soft agar or form invasive colonies in Matrigel. Thus, CK2 induces functional IKK-i/IKKε, which is an important mediator of the activation of NF-κB that plays a critical role in the pathogenesis of breast cancer. (Cancer Res 2005; 65(24): 11375-83)
Prognostic and Functional Significance of Thromboxane Synthase Gene Overexpression in Invasive Bladder Cancer
Authors: Moussa Omar , Yordy John S. , Abol-Enein Hassan , Sinha Debajyoti , Bissada Nabil K. , Halushka Perry V. , Ghoneim Mohamed A. , Watson Dennis K. 
Published: December 2005

Abstract
Thromboxane synthase (TXAS) is one of the enzymes downstream from cyclooxygenase-2 and catalyzes the synthesis of thromboxane A2 (TXA2). TXAS was among the genes we identified based on its overexpression in invasive bladder tumors. TXAS is overexpressed in common forms of bladder tumors: 69 of 97 (71.1%) transitional cell carcinoma (TCC), 38 of 53 (71.6%) squamous cell carcinoma, and 5 of 11 (45.5%) adenocarcinoma relative to nontumor tissue. Overall, 112 of 161 (69.5%) invasive tumors exhibited elevated expression. Significantly, patients with tumors having &gt;4-fold levels of TXAS expression showed significant statistical evidence of lower overall survival expressed by the estimated hazard ratio of 2.74 with P = 0.009 in Cox's regression analysis. TXAS mRNA expression was found to be an independent prognostic marker for patients with bladder cancer. Treatment of bladder cancer cell lines (T24 and TCC-SUP) with TXAS inhibitors and TXA2 (TP) receptor antagonists reduced cell growth, migration, and invasion, whereas TP agonists stimulated cell migration and invasion. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor invasion and metastases and suggests that modulation of the TXAS pathway may offer a novel therapeutic approach. (Cancer Res 2005; 65(24): 11581-7)
Development of Ewing's Sarcoma from Primary Bone Marrow–Derived Mesenchymal Progenitor Cells
Authors: Riggi Nicolò , Cironi Luisa , Provero Paolo , Suvà Mario-Luca , Kaloulis Konstantinos , Garcia-Echeverria Carlos , Hoffmann Francesco , Trumpp Andreas , Stamenkovic Ivan 
Published: December 2005

Abstract
Ewing's sarcoma is a member of Ewing's family tumors (EFTs) and the second most common solid bone and soft tissue malignancy of children and young adults. It is associated in 85% of cases with the t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5′ segment of the EWS gene with the 3′ segment of the ETS family gene FLI-1. The EWS-FLI-1 fusion protein behaves as an aberrant transcriptional activator and is believed to contribute to EFT development. However, EWS-FLI-1 induces growth arrest and apoptosis in normal fibroblasts, and primary cells that are permissive for its putative oncogenic properties have not been discovered, hampering basic understanding of EFT biology. Here, we show that EWS-FLI-1 alone can transform primary bone marrow–derived mesenchymal progenitor cells and generate tumors that display hallmarks of Ewing's sarcoma, including a small round cell phenotype, expression of EFT-associated markers, insulin like growth factor-I dependence, and induction or repression of numerous EWS-FLI-1 target genes. These observations provide the first identification of candidate primary cells from which EFTs originate and suggest that EWS-FLI-1 expression may constitute the initiating event in EFT pathogenesis. (Cancer Res 2005; 65(24): 11459-68)
Gene Expression Profiles Associated with Treatment Response in Oligodendrogliomas
Authors: French Pim J. , Swagemakers Sigrid M.A. , Nagel Jord H.A. , Kouwenhoven Mathilde C.M. , Brouwer Eric , van der Spek Peter , Luider Theo M. , Kros Johan M. , van den Bent Martin J. , Sillevis Smitt Peter A. 
Published: December 2005

Abstract
Oligodendrogliomas are a specific subtype of brain tumor of which the majority responds favorably to chemotherapy. In this study, we made use of expression profiling to identify chemosensitive oligodendroglial tumors. Correlation of expression profiles to loss of heterozygosity on 1p and 19q, common chromosomal aberrations associated with response to treatment, identified 376, 64, and 60 differentially expressed probe sets associated with loss of 1p, 19q or 1p, and 19q, respectively. Correlation of expression profiles to the tumors' response to treatment identified 16 differentially expressed probe sets. Because transcripts associated with chemotherapeutic response were identified independent of common chromosomal aberrations, expression profiling may be used as an alternative approach to the tumors' 1p status to identify chemosensitive oligodendroglial tumors. Finally, we correlated expression profiles to survival of the patient after diagnosis and identified 103 differentially expressed probe sets. The observation that many genes are differentially expressed between long and short survivors indicates that the genetic background of the tumor is an important factor in determining the prognosis of the patient. Furthermore, these transcripts can help identify patient subgroups that are associated with favorable prognosis. Our study is the first to correlate gene expression with chromosomal aberrations and clinical performance (response to treatment and survival) in oligodendrogliomas. The differentially expressed transcripts can help identify patient subgroups with good prognosis and those that will benefit from chemotherapeutic treatments. (Cancer Res 2005; 65(24): 11335-44)
Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs
Authors: Bindra Ranjit S. , Gibson Shannon L. , Meng Alice , Westermark Ulrica , Jasin Maria , Pierce Andrew J. , Bristow Robert G. , Classon Marie K. , Glazer Peter M. 
Published: December 2005

Abstract
Decreased BRCA1 expression in the absence of genetic mutation is observed frequently in sporadic cancers of the breast and other sites, although little is known regarding the mechanisms by which the expression of this gene can be repressed. Here, we show that activating and repressive E2Fs simultaneously bind the BRCA1 promoter at two adjacent E2F sites in vivo, and that hypoxia induces a dynamic redistribution of promoter occupancy by these factors resulting in the transcriptional repression of BRCA1 expression. Functionally, we show that hypoxia is associated with impaired homologous recombination, whereas the nonhomologous end-joining (NHEJ) repair pathway is unaffected under these conditions. Repression of BRCA1 expression by hypoxia represents an intriguing mechanism of functional BRCA1 inactivation in the absence of genetic mutation. We propose that hypoxia-induced decreases in BRCA1 expression and consequent suppression of homologous recombination may lead to genetic instability by shifting the balance between the high-fidelity homologous recombination pathway and the error-prone NHEJ pathway of DNA repair. Furthermore, these findings provide a novel link between E2Fs and the transcriptional response to hypoxia and provide insight into the mechanisms by which the tumor microenvironment can contribute to genetic instability in cancer. (Cancer Res 2005; 65(24): 11597-604)
BRCA1 Regulates RAD51 Function in Response to DNA Damage and Suppresses Spontaneous Sister Chromatid Replication Slippage: Implications for Sister Chromatid Cohesion, Genome Stability, and Carcinogenesis
Authors: Cousineau Isabelle , Abaji Christine , Belmaaza Abdellah 
Published: December 2005

Abstract
The breast/ovarian cancer susceptibility proteins BRCA1 and BRCA2 maintain genome stability, at least in part, through a functional role in DNA damage repair. They both colocalize with RAD51 at sites of DNA damage/replication and activate RAD51-mediated homologous recombination repair of DNA double-strand breaks (DSB). Whereas BRCA2 interacts directly with and regulates RAD51, the role of BRCA1 in this process is unclear. However, BRCA1 may regulate RAD51 in response to DNA damage or through its ability to interact with and regulate MRE11/RAD50/NBS1 (MRN) during the processing of DSBs into single-strand DNA (ssDNA) ends, prerequisite substrates for RAD51, or both. To test these hypotheses, we measured the effect of BRCA1 on the competition between RAD51-mediated homologous recombination (gene conversion and crossover) versus RAD51-independent homologous recombination [single-strand annealing (SSA)] for ssDNA at a site-specific chromosomal DSB within a DNA repeat, a substrate for both homologous recombination pathways. Expression of wild-type BRCA1 in BRCA1-deficient human recombination reporter cell lines promoted both gene conversion and SSA but greatly enhanced gene conversion. In addition, BRCA1 also suppressed both spontaneous gene conversion and deletion events, which can arise from either crossover or sister chromatid replication slippage (SCRS), a RAD51-independent process. BRCA1 does not seem to block crossover. From these results, we conclude that (a) BRCA1 regulates RAD51 function in response to the type of DNA damage and (b) BRCA1 suppresses SCRS, suggesting a role for this protein in sister chromatid cohesion/alignment. Loss of such control in response to estrogen-induced DNA damage after BRCA1 inactivation may be a key initial event that triggers genome instability and carcinogenesis. (Cancer Res 2005; 65(24): 11384-91)
Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis
Authors: Nawrocki Steffan T. , Carew Jennifer S. , Pino Maria S. , Highshaw Ralph A. , Dunner Kenneth , Huang Peng , Abbruzzese James L. , McConkey David J. 
Published: December 2005

Abstract
Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. We have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective mechanism, we hypothesized that bortezomib would sensitize pancreatic cancer cells to ER stress-mediated apoptosis. Here, we show that bortezomib promotes apoptosis triggered by classic ER stress inducers (tunicamycin and thapsigargin) via a c-Jun NH2-terminal kinase (JNK)–dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca2+ levels, and cell death. Importantly, combined therapy with bortezomib plus cisplatin induced JNK activation and apoptosis in orthotopic pancreatic tumors resulting in a reduction in tumor burden. Taken together, our data establish that bortezomib sensitizes pancreatic cancer cells to ER stress-induced apoptosis and show that bortezomib strongly enhances the anticancer activity of cisplatin. (Cancer Res 2005; 65(24): 11658-66)
TRAIL Receptor-Selective Mutants Signal to Apoptosis via TRAIL-R1 in Primary Lymphoid Malignancies
Authors: MacFarlane Marion , Kohlhaas Susan L. , Sutcliffe Michael J. , Dyer Martin J.S. , Cohen Gerald M. 
Published: December 2005

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its agonistic antibodies, which are currently in early clinical trials for treating various malignancies, induce apoptosis through triggering of either TRAIL-R1 or TRAIL-R2. Based on studies using agonistic monoclonal antibodies, we recently proposed that primary chronic lymphocytic leukemic cells seem to signal apoptosis primarily through TRAIL-R1. We have now synthesized mutant forms of TRAIL specific for TRAIL-R1 or TRAIL-R2. The selectivity of these mutants to induce apoptosis in cell lines is due to selective binding to their cognate receptors resulting in apoptosis via formation of a death-inducing signaling complex. Using these mutants, we now unequivocally show that primary cells from patients with chronic lymphocytic leukemia and mantle cell lymphoma signal to apoptosis almost exclusively through TRAIL-R1. Thus, no significant therapeutic benefit can be anticipated from treating such patients with agents currently in clinical trials that signal predominantly through TRAIL-R2, such as HGS-ETR2 or Apo2L/TRAIL. Our study highlights the necessity to determine whether primary cells from a particular tumor signal via TRAIL-R1 or TRAIL-R2. Such information will provide a rational approach to optimize TRAIL therapy. (Cancer Res 2005; 65(24): 11265-70)
Loss of Imprinting ofIGF2: A Common Epigenetic Modifier of Intestinal Tumor Risk
Authors: Kaneda Atsushi , Feinberg Andrew P. 
Published: December 2005

AbstractEpigenetic alterations in cancer occur at least as commonly as genetic mutations, but epigenetic alterations could occur secondarily to the tumor process itself. To establish a causal role of epigenetic changes, investigators have turned to genetically engineered mouse models. Here, we review a recent study showing that a mouse model of loss of imprinting (LOI) of the insulin-like growth factor II gene (Igf2), which shows aberrant activation of the normally silent maternal allele, modifies the risk of intestinal neoplasia caused by mutations of the adenomatous polyposis coli (Apc) gene. This increased risk corresponds to the apparent increased risk of colorectal cancer in patients with LOI of IGF2. The model suggests that preexisting epigenetic alterations in normal cells increase tumor risk by expanding the target cell population and/or modulating the effect of subsequent genetic alterations on these cells, providing a novel idea for cancer risk management. (Cancer Res 2005; 65(24): 11236-40)
Loss of Phosphatase and Tensin Homologue Increases Transforming Growth Factor β–Mediated Invasion with Enhanced SMAD3 Transcriptional Activity
Authors: Hjelmeland Anita B. , Hjelmeland Mark D. , Shi Qing , Hart Janet L. , Bigner Darell D. , Wang Xiao-Fan , Kontos Christopher D. , Rich Jeremy N. 
Published: December 2005

Abstract
In normal epithelial tissues, the multifunctional cytokine transforming growth factor-β (TGF-β) acts as a tumor suppressor through growth inhibition and induction of differentiation whereas in advanced cancers, TGF-β promotes tumor progression through induction of tumor invasion, neoangiogenesis, and immunosuppression. The molecular mechanisms through which TGF-β shifts from a tumor suppressor to a tumor enhancer are poorly understood. We now show a role for the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in repressing the protumorigenic effects of TGF-β. The TGF-β effector SMAD3 inducibly interacts with PTEN on TGF-β treatment under endogenous conditions. RNA interference (RNAi) suppression of PTEN expression enhances SMAD3 transcriptional activity and TGF-β–mediated induction of SMAD3 target genes whereas reconstitution of PTEN in a null cancer cell line represses the expression of TGF-β–regulated target genes. Targeting PTEN expression through RNAi in a PTEN wild-type cell line increases TGF-β–mediated invasion but does not affect TGF-β–mediated growth inhibition. Reconstitution of PTEN expression in a PTEN-null cell line blocks TGF-β–induced invasion but does not modulate TGF-β–mediated growth regulation. These effects are distinct from Akt and Forkhead family members that also interact with SMAD3 to regulate apoptosis or proliferation, respectively. Pharmacologic inhibitors targeting TGF-β receptors and phosphatidylinositol 3-kinase signaling downstream from PTEN cooperate to block TGF-β–mediated invasion. Thus, the loss of PTEN expression in human cancers may contribute to a role for TGF-β as a tumor enhancer with specific effects on cellular motility and invasion. (Cancer Res 2005; 65(24): 11276-81)