bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pyridone 6, A Pan-Janus–Activated Kinase Inhibitor, Induces Growth Inhibition of Multiple Myeloma Cells
Authors: Pedranzini Laura , Dechow Tobias , Berishaj Marjan , Comenzo Raymond , Zhou Ping , Azare Janeen , Bornmann William , Bromberg Jacqueline 
Published: October 2006

AbstractInterleukin-6 (IL-6) and the subsequent Janus-activated kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of multiple myeloma. Here, we compared the sensitivity and specificity of a novel pan-JAK inhibitor, tetracyclic pyridone 6 (P6), with that of AG490 in a panel of myeloma-derived cell lines. P6 induced growth arrest and subsequent apoptosis of the IL-6-dependent hybridoma and myeloma-derived cell lines (B9 and INA-6) grown either in IL-6-containing medium or in the presence of bone marrow–derived stromal cells (BMSC) using much lower concentrations of drug and with significantly faster kinetics than AG490. Myeloma-derived cell lines, which either express constitutively activated JAK/signal transducers and activators of transcription (STAT) 3 (U266) or are IL-6 growth stimulated (KMS11), are partially growth inhibited by P6. However, P6 does not inhibit the growth of myeloma-derived cell lines lacking activated JAKs/STATs nor does it inhibit mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase activity compared with AG490, which led to activation of ERK and induced robust apoptosis of all the examined cell lines. Finally, P6 inhibited the growth of primary myeloma patient samples grown in the presence of BMSCs. Thus, P6 is a more sensitive and specific inhibitor of JAK-STAT3 activity compared with AG490 and potently inhibited the growth of primary myeloma cells and myeloma-derived cell lines grown on BMSCs. (Cancer Res 2006; 66(19): 9714-21)
Identification of an Agent Selectively Targeting DPC4 (Deleted in Pancreatic Cancer Locus 4)–Deficient Pancreatic Cancer Cells
Authors: Wang Hong , Han Haiyong , Von Hoff Daniel D. 
Published: October 2006

Abstract
One of the most common types of genetic alterations in cancer is the loss-of-function mutations in tumor-suppressor genes. Such mutations are usually very specific to cancer cells and present attractive and unique opportunities for therapeutic interventions. However, for various reasons, antitumor agents that target loss-of-function mutations have not been readily identified. In this report, using the deleted in pancreatic cancer locus 4 (DPC4) gene in pancreatic cancer as an example, we show the feasibility of a novel screening strategy, which we have named Pharmacological Synthetic Lethal Screening, for the identification of agents that selectively target cancer cells with loss-of-function mutations. We created DPC4 isogenic cell lines through the restoration of wild-type DPC4 in a pancreatic cancer cell line, BxPC-3, whose DPC4 gene was homozygously deleted. The isogenic cell lines were then used in the Pharmacological Synthetic Lethal Screening to evaluate compound libraries for antiproliferative activity and selectivity against DPC4 deficiency. After screening 19,590 compounds, we identified one lead compound, UA62001, which showed 4.6-fold selectivity against DPC4 deficiency in the DPC4 isogenic cell lines. UA62001 selectivity was also seen in another set of DPC4 isogenic cell lines generated by small interfering RNA knockdown. In addition, UA62001 was evaluated in commonly used pancreatic cancer cell lines. A fairly good correlation between DPC4 deficiency and UA62001 sensitivity was observed. Cell cycle analysis indicates that UA62001 arrests cells in S and G2-M phases. The results of microarray gene expression profiling and quantitative real-time reverse transcription-PCR suggest that cyclin B/CDC2 and minichromosome maintenance complexes might be the downstream cellular targets of UA62001. (Cancer Res 2006; 66(19): 9722-30)
Targeting the Lymphotoxin-β Receptor with Agonist Antibodies as a Potential Cancer Therapy
Authors: Lukashev Matvey , LePage Doreen , Wilson Cheryl , Bailly Véronique , Garber Ellen , Lukashin Alex , Ngam-ek Apinya , Zeng Weike , Allaire Norman , Perrin Steve , Xu Xianghong , Szeliga Kendall , Wortham Kathleen , Kelly Rebecca , Bottiglio Cindy , Ding Jane , Griffith Linda , Heaney Glenna , Silverio Erika , Yang William , Jarpe Matt , Fawell Stephen , Reff Mitchell , Carmillo Amie , Miatkowski Konrad , Amatucci Joseph , Crowell Thomas , Prentice Holly , Meier Werner , Violette Shelia M. , Mackay Fabienne , Yang Dajun , Hoffman Robert , Browning Jeffrey L. 
Published: October 2006

AbstractThe lymphotoxin-β receptor (LTβR) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LTβR monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LTβR caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LTβR activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LTβR with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers. (Cancer Res 2006; 66(19): 9617-24)
PRL-3 Initiates Tumor Angiogenesis by Recruiting Endothelial Cells In vitro and In vivo
Authors: Guo Ke , Li Jie , Wang Haihe , Osato Motomi , Tang Jing Ping , Quah Samantha Yiling , Gan Bin Qi , Zeng Qi 
Published: October 2006

Abstract
We show here that PRL-3 protein is expressed in fetal heart, developing blood vessels, and pre-erythrocytes but not in their mature counterparts. These observations imply that PRL-3 may be involved in the early development of the circulatory system. Because PRL-3 mRNA had been reported to be consistently elevated in metastatic samples derived from colorectal cancers, we attempted to investigate if PRL-3 might be involved in tumor angiogenesis and if PRL-3-expressing cells could cross-talk to human umbilical vascular endothelial cells (HUVEC) by using an in vitro coculture system. HUVECs were grown with fibroblasts, which were later overlaid with PRL-3-expressing cells. We observed that both PRL-3-expressing Chinese hamster ovary (CHO) cells and PRL-3-expressing DLD-1 human colon cancer cells could redirect the migration of HUVECs toward them; in addition, PRL-3-expressing DLD-1 cells could enhance HUVEC vascular formation. In vivo injection of PRL-3-expressing CHO cells into nude mice to form local tumors resulted in the recruitment of host endothelial cells into the tumors and initiation of angiogenesis. We further showed that PRL-3-expressing cells reduced interleukin-4 (IL-4) expression levels and thus attenuated IL-4 inhibitory effects on the HUVEC vasculature. Our findings provide direct evidence that PRL-3 may be involved in triggering angiogenesis and establishing microvasculature and it may serve as an attractive therapeutic target with respect to both angiogenesis and cancer metastasis. (Cancer Res 2006; 66(19): 9625-35)
Absence of CD9 Enhances Adhesion-Dependent Morphologic Differentiation, Survival, and Matrix Metalloproteinase-2 Production in Small Cell Lung Cancer Cells
Authors: Saito Yoshiyuki , Tachibana Isao , Takeda Yoshito , Yamane Hiroyuki , He Ping , Suzuki Mayumi , Minami Seigo , Kijima Takashi , Yoshida Mitsuhiro , Kumagai Toru , Osaki Tadashi , Kawase Ichiro 
Published: October 2006

Abstract
While adhering to extracellular matrix proteins in vitro and in vivo, small cell lung cancer (SCLC) cells frequently show morphologic differentiation and are protected from apoptosis. Integrin β1–mediated protein phosphorylation is suggested to be an essential signaling event in these processes. CD9 is an almost ubiquitously expressed tetraspanin protein that suppresses tumor progression by regulating cell motility and signaling through complex formation with β1 integrins. We reported previously that, among tetraspanins, CD9 is selectively absent in most SCLC cells and that ectopic expression of CD9 suppresses their motility. Here, we show that the ectopic expression of CD9 suppressed neurite-like process outgrowth and promoted apoptotic death of SCLC cells that were adherent to fibronectin in serum-starved conditions. This correlated with attenuation of adhesion-dependent phosphorylation of Akt but not that of focal adhesion kinase or c-Jun NH2-terminal kinase. Treatment of CD9− parent cells with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, inhibited process outgrowth and survival, suggesting that PI3K/Akt signaling is required for the morphologic change and cell survival. Production of matrix metalloproteinase (MMP)-2 was likewise suppressed in the CD9 transfectants and in LY294002-treated parent cells. These results suggest that the absence of CD9 in SCLC cells may contribute to postadhesive morphologic differentiation, survival, and MMP-2 production via PI3K/Akt pathway. (Cancer Res 2006; 66(19): 9557-65)
Inhibition of p53 Response in Tumor Stroma Improves Efficacy of Anticancer Treatment by Increasing Antiangiogenic Effects of Chemotherapy and Radiotherapy in Mice
Authors: Burdelya Lyudmila G. , Komarova Elena A. , Hill Jason E. , Browder Timothy , Tararova Natalia D. , Mavrakis Lori , DiCorleto Paul E. , Folkman Judah , Gudkov Andrei V. 
Published: October 2006

Abstract
Inactivation of p53 function, which frequently occurs in tumors, can significantly modulate tumor cell sensitivity to radiation and chemotherapeutic drugs. However, in addition to acting on malignant cells, anticancer agents act on the cells of tumor stroma, causing activation of a p53 response. The effect of this response on treatment outcome has been the subject of the present study. Tumors with p53-deficient stroma were generated using mouse tumorigenic packaging cells that produce a p53 inhibitory retrovirus, encoding a dominant-negative p53 mutant. Tumors maintaining wild-type p53 in their stroma were formed by cells of similar origin but deficient in retroviral production due to the deletion of the packaging signal in the retroviral vector. Comparison of these tumor models, differing only in p53 status of their stromas, showed that tumors with p53-deficient stroma were significantly more sensitive to experimental chemotherapy and radiotherapy. A similar effect was achieved when anticancer treatment was combined with pharmacologic suppression of p53 by the cyclic form of pifithrin α, a small-molecule inhibitor of p53. Potentiation of the anticancer effect of chemotherapy and radiotherapy by p53 suppression in the tumor stroma is likely to be due to the increased sensitivity of p53-deficient endothelium to genotoxic stress as shown both in cell culture and in experimental tumors. Thus, reversible pharmacologic suppression of p53 may be a viable approach to improving anticancer treatment via an enhanced antiangiogenic effect of chemotherapy and radiotherapy. (Cancer Res 2006; 66(19): 9356-61)
Comprehensive Assessment of Genetic Variation ofCatechol-O-Methyltransferaseand Breast Cancer Risk
Authors: Gaudet Mia M. , Chanock Stephen , Lissowska Jolanta , Berndt Sonja I. , Peplonska Beata , Brinton Louise A. , Welch Robert , Yeager Meredith , Bardin-Mikolajczak Alicja , Garcia-Closas Montserrat 
Published: October 2006

AbstractBecause catechol-O-methyltransferase (COMT) catalyzes the addition of methyl groups to stabilize catechol estrogens that may induce DNA damage, genetic variants could influence breast cancer risk. To comprehensively characterize genetic variation in this gene, we selected haplotype-tagging single nucleotide polymorphisms (htSNP) in COMT. A total of 11 htSNPs (including COMT Val158Met) were selected based on the resequencing and dense genotyping approach of the Breast and Prostate Cancer Cohort Consortium. htSNPs were genotyped in a population-based, case-control study in Poland (1,995 cases and 2,296 controls). Individual SNPs were not significantly associated with risk. Haplotypes were estimated using the expectation-maximization algorithm. Overall differences in the haplotype distribution between cases and controls were assessed using a global score test. The TGAG haplotype (frequent in 4.3% of controls), in a linkage disequilibrium (LD) block that included the 3′ untranslated region (UTR) of COMT, was associated with breast cancer risk (odds ratio, 1.29; 95% confidence interval, 1.06-1.58) compared with the most common haplotype TGAA; however, the global test for haplotype associations was not significant (P = 0.09). Haplotypes in another LD block, which included COMT Val158Met, were not associated with breast cancer risk (global P = 0.76). Haplotype-breast cancer risk associations were not significantly modified by hormonally related risk factors, family history of breast cancer, or tumor characteristics. In summary, our data does not support a substantial overall association between COMT haplotypes and breast cancer. The suggestion of increased risk associated with a haplotype in the 3′ UTR of COMT needs to be confirmed in independent study populations. (Cancer Res 2006; 66(19): 9781-5)
The 3p21.3 Tumor Suppressor NPRL2 Plays an Important Role in Cisplatin-Induced Resistance in Human Non–Small-Cell Lung Cancer Cells
Authors: Ueda Kentaro , Kawashima Hiroyuki , Ohtani Shoichiro , Deng Wu-Guo , Ravoori Murali , Bankson Jim , Gao Boning , Girard Luc , Minna John D. , Roth Jack A. , Kundra Vikas , Ji Lin 
Published: October 2006

Abstract
NPRL2 is one of the novel candidate tumor suppressor genes identified in the human chromosome 3p21.3 region. The NPRL2 has shown potent tumor suppression activity in vitro and in vivo and has been suggested to be involved in DNA mismatch repair, cell cycle checkpoint signaling, and regulation of the apoptotic pathway. In this study, we analyzed the endogenous expression of the NPRL2 protein and the cellular response to cisplatin in 40 non–small-cell lung cancer cell lines and found that expression of NPRL2 was significantly and reciprocally correlated to cisplatin sensitivity, with a Spearman correlation coefficient of −0.677 (P &lt; 0.00001). Exogenously introduced expression of NPRL2 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate:cholesterol nanoparticle–mediated gene transfer significantly resensitized the response to cisplatin, yielding a 40% greater inhibition of tumor cell viability and resulting in a 2- to 3-fold increase in induction of apoptosis by activation of multiple caspases in NPRL2-transfected cells compared with untransfected cells at an equal dose of cisplatin. Furthermore, a systemic treatment with a combination of NPRL2 nanoparticles and cisplatin in a human H322 lung cancer orthotopic mouse model significantly enhanced the therapeutic efficacy of cisplatin and overcame cisplatin-induced resistance (P &lt; 0.005). These findings implicate the potential of NPRL2 as a biomarker for predicting cisplatin response in lung cancer patients and as a molecular therapeutic agent for enhancing response and resensitizing nonresponders to cisplatin treatment. (Cancer Res 2006; 66(19): 9682-90)
Distinct Effects of Annexin A7 and p53 on Arachidonate Lipoxygenation in Prostate Cancer Cells Involve 5-Lipoxygenase Transcription
Authors: Torosyan Yelizaveta , Dobi Albert , Naga Shanmugam , Mezhevaya Katerina , Glasman Mirta , Norris Christine , Jiang Guisen , Mueller Gregory , Pollard Harvey , Srivastava Meera 
Published: October 2006

Abstract
Tumor suppressor function for Annexin A7 (ANXA7; 10q21) is based on cancer-prone phenotype in Anxa7(+/−) mouse and ANXA7 prognostic role in human cancers. Because ANXA7-caused liposome aggregation can be promoted by arachidonic acid (AA), we hypothesized that the phospholipid-binding tumor suppressor ANXA7 is associated with AA cascade. In a comparative study of ANXA7 versus canonical tumor suppressor p53 effects on AA lipoxygenation pathway in the p53-mutant and androgen-insensitive DU145 prostate cancer cells, both tumor suppressors altered gene expression of major 5-lipoxygenase (LOX) and 15-LOXs, including response to T helper 2 (Th2)-cytokine [interleukin-4 (IL-4)] and endogenous steroids (mimicked by dexamethasone). Wild-type and mutant ANXA7 distinctly affected expression of the dexamethasone-induced 15-LOX-2 (a prostate-specific endogenous tumor suppressor) as well as the IL-4-induced 15-LOX-1. On the other hand, wild-type p53 restored 5-LOX expression in DU145 to levels comparable to benign prostate epithelial cells. Using mass spectrometry of DNA affinity–enriched nuclear proteins, we detected different proteins that were bound to adjacent p53 and estrogen response elements in the 5-LOX promoter in DU145 cells introduced with ANXA7 versus p53. Sex hormone regulator 17-β hydroxysteroid dehydrogenase 4 was identified under p53 introduction, which induced the 5-LOX expression. Meantime, nuclear proteins bound to the same 5-LOX promoter site under introduction of ANXA7 (that was associated with the repressed 5-LOX) were identified as zinc finger proteins ZNF433 and Aiolos, pyrin domain–containing NALP10, and the p53-regulating DNA repair enzyme APEX1. Thus, ANXA7 and p53 can distinctly regulate LOX transcription that is potentially relevant to the AA-mediated cell growth control in tumor suppression. (Cancer Res 2006; 66(19): 9609-16)
The COOH-Terminal Globular Domain of Fibrinogen γ Chain Suppresses Angiogenesis and Tumor Growth
Authors: Akakura Nobuaki , Hoogland Case , Takada Yoko K. , Saegusa Jun , Ye Xiaojing , Liu Fu-Tong , Cheung Anthony Tze-Wai , Takada Yoshikazu 
Published: October 2006

Abstract
Fibrinogen is a major plasma protein (350 kDa) that induces proliferative signals by serving as a scaffold to support the binding of growth factors and to promote the cellular responses of adhesion, proliferation, and migration during wound healing, angiogenesis, and tumor growth. Fibrin(ogen) degradation products generated during fibrinolysis are implicated in tissue injury. The fibrinogen γ chain has a COOH-terminal globular domain (γC, residues 151-411 of the γ chain, 30 kDa) to which several integrin cell adhesion receptors (e.g., platelet αIIbβ3, endothelial αvβ3, and leukocyte αMβ2) bind. Integrins play a critical role in signal transduction from fibrin(ogen). We found that γC and its truncation mutant (designated γC399tr), with a deletion of the COOH-terminal 12 residues, induced apoptosis of endothelial cells and blocked tube formation of endothelial cells. DLD-1 human colon cancer cells that secrete γC or γC399tr grew at similar levels in vitro but grew much slower in vivo than mock-transfected cells. The recombinant purified γC399tr fragment markedly suppressed tumor growth, development of intratumoral vasculature, and tumor metastasis in vivo in the highly metastatic Met-1 breast cancer model. The determinant responsible for binding to endothelial cells is cryptic in native fibrinogen but is exposed in γC and γC399tr. These results suggest that fibrinogen has a novel cryptic determinant, which can exert apoptosis-inducing activity on endothelial cells when exposed, and polypeptides containing this determinant have therapeutic potential. (Cancer Res 2006; 66(19): 9691-7)
An EBF3-Mediated Transcriptional Program That Induces Cell Cycle Arrest and Apoptosis
Authors: Zhao Lisa Y. , Niu Yuxin , Santiago Aleixo , Liu Jilin , Albert Sara H. , Robertson Keith D. , Liao Daiqing 
Published: October 2006

Abstract
In a genome-wide screen for putative tumor suppressor genes, the EBF3 locus on the human chromosome 10q26.3 was found to be deleted or methylated in 73% of the examined cases of brain tumors. EBF3 is expressed in normal brain but is silenced in brain tumors. Therefore, it is suggested that EBF3 is a tumor suppressor. However, it remains unknown whether inactivation of EBF3 locus also occurs in other types of tumors and what functions of EBF3 underlie EBF3-mediated tumor suppression. We show here that expression of EBF3 resulted in cell cycle arrest and apoptosis. The expression of cyclin-dependent kinase inhibitors was profoundly affected with early activation and then repression of p21cip1/waf1 and persistent activation of both p27kip1 and p57kip2, whereas genes involved in cell survival and proliferation were suppressed. EBF3 bound directly to p21cip1/waf1 promoter and regulated transcription from both p21cip1/waf1 and p27kip1 promoters in reporter assays. Apoptosis occurred 48 hours after EBF3 expression with caspase-3 activation. Silencing of the EBF3 locus was observed in brain, colorectal, breast, liver, and bone tumor cell lines and its reactivation was achieved on treatment with 5-aza-2′-deoxycytidine and trichostatin A in a significant portion of these tumor cells. Therefore, EBF3 regulates a transcriptional program underlying a putative tumor suppression pathway. (Cancer Res 2006; 66(19): 9445-52)
Estrogen-Induced Activation of Mammalian Target of Rapamycin Is Mediated via Tuberin and the Small GTPase Ras Homologue Enriched in Brain
Authors: Yu Jane , Henske Elizabeth Petri 
Published: October 2006

Abstract
Inhibitors of the mammalian target of rapamycin (mTOR) are currently in clinical trials for the treatment of breast cancer. The mechanisms through which mTOR are activated in breast cancer and the relationship of mTOR activation to steroid hormones, such as estrogen, that are known to influence breast cancer pathogenesis, are not yet understood. Using MCF-7 cells as a model, we found that 17-β estradiol (E2) rapidly increased the phosphorylation of downstream targets of mTOR: p70 ribosomal protein S6 kinase, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 1. The phosphoinositide-3-kinase inhibitor, wortmannin, and the mTOR inhibitor, rapamycin, blocked E2-induced activation of p70 ribosomal protein S6 kinase. We hypothesized that tuberin and the small GTPase Ras homologue enriched in brain (Rheb), regulators of the mTOR pathway, mediate E2-induced activation of mTOR. Consistent with this hypothesis, E2 rapidly (within 5 minutes) stimulated tuberin phosphorylation at T1462, a site at which Akt phosphorylates and inactivates tuberin. E2 also rapidly decreased the inactive, GDP-bound form of Rheb. Finally, we found that small interfering RNA down-regulation of endogenous Rheb blocked the E2-stimulated proliferation of MCF-7 cells, demonstrating that Rheb is a key determinant of E2-dependent cell growth. Taken together, these data reveal that the TSC/Rheb/mTOR pathway plays a critical role in the regulation of E2-induced proliferation, and highlight Rheb as a novel molecular target for breast cancer therapy. (Cancer Res 2006; 66(19): 9461-6)