bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ceramide Promotes Apoptosis in Lung Cancer-Derived A549 Cells by a Mechanism Involving c-Jun NH2-Terminal Kinase
Authors: Kurinna Svitlana M. , Tsao Chun Chui , Nica Alina Felicia , Jiffar Tilahun , Ruvolo Peter P. 
Published: September 2005

Abstract
Ceramide regulates diverse signaling pathways involving cell senescence, the cell cycle, and apoptosis. Ceramide is known to potently activate a number of stress-regulated enzymes, including the c-Jun NH2-terminal kinase (JNK). Although ceramide promotes apoptosis in human lung cancer-derived A549 cells, a role for JNK in this process is unknown. Here, we report that ceramide promotes apoptosis in A549 cells by a mechanism involving JNK. The JNK inhibitor SP600125 proved effective at protecting cells from the lethal effects of ceramide. To understand which JNK-mediated pathway may be involved, a number of JNK target proteins were examined, including the transcription factor, c-Jun, and the apoptotic regulatory proteins Bcl-XL and Bim. A549 cells exhibited basal levels of phosphorylated c-Jun in nuclear fractions, revealing that active c-Jun is present in these cells. Ceramide was found to inhibit c-Jun phosphorylation, suggesting that JNK-mediated phosphorylation of c-Jun is not likely involved in ceramide-induced apoptosis. Ceramide did not promote Bcl-XL phosphorylation. On the other hand, ceramide promoted phosphorylation of Bim and induced translocation of active JNK from the nucleus to the cytoplasm and mitochondrial fraction. Ceramide-mediated changes in localization of JNK were consistent with the observed changes in phosphorylation status of c-Jun and Bim. Furthermore, ceramide promoted Bim translocation to the mitochondria. Mitochondrial localization of Bim has been shown recently to promote apoptosis. These results suggest that JNK may participate in ceramide-induced apoptosis in A549 cells by a mechanism involving Bim.
Differentiation of Human Prostate Cancer PC-3 Cells Induced by Inhibitors of Inosine 5′-Monophosphate Dehydrogenase
Authors: Floryk Daniel , Tollaksen Sandra L. , Giometti Carol S. , Huberman Eliezer 
Published: September 2005

Abstract
To establish a system to study differentiation therapy drugs, we used the androgen-independent human prostate PC-3 tumor cell line as a target and mycophenolic acid (MPA), tiazofurin, or ribavirin, which are inhibitors of IMP dehydrogenase, as inducers. These inhibitors evoked replication arrest, caused an increase in cell size, and triggered vacuolization of the cytoplasm. By Northern and Western blotting and immunostaining, we demonstrated MPA-induced expression of 12 proteins reported to reside in prostasomes, organelles released by secretory luminal prostate cells. Additional MPA-induced proteins were identified by two-dimensional gel electrophoresis. Among these was keratin 17, a prostate cell differentiation marker. By Northern blotting, we also demonstrated the constitutive expression of keratins 8 and 18 and induced expression of keratin 19, three other prostate cell differentiation markers. In addition, we established that cells were committed to differentiate after the 2nd day of MPA treatment using guanosine, which can abrogate the effects of MPA. Based on the expression patterns of prostasomal proteins and keratins and the presence of tentative secretory vacuoles, we hypothesize that IMP dehydrogenase inhibitors induce androgen-independent PC-3 cells to mature into cells with a phenotype that resembles normal prostate luminal cells, but at their intermediate state of differentiation.
Tumor-Associated Endothelial Cells with Cytogenetic Abnormalities
Authors: Hida Kyoko , Hida Yasuhiro , Amin Dhara N. , Flint Alan F. , Panigrahy Dipak , Morton Cynthia C. , Klagsbrun Michael 
Published: September 2005

Abstract
Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, although these endothelial cells are structurally and functionally abnormal. However, we hypothesized that given the phenotypic differences between tumor and normal blood vessels, there may be genotypic alterations as well. Mouse endothelial cells were isolated from two different human tumor xenografts, melanoma and liposarcoma, and from two normal endothelial cell counterparts, skin and adipose. Tumor-associated endothelial cells expressed typical endothelial cell markers, such as CD31. They had relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells were cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid and had abnormal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. Multicolor FISH indicated that the structural chromosomal aberrations in tumor endothelial cells were heterogeneous, indicating that the cytogenetic alterations were not clonal. There was no evidence of human tumor-derived chromosomal material in the mouse tumor endothelial cells. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid, had normal centrosomes, and remained cytogenetically stable in culture even up to 20 passages. FISH analysis of tumor sections also showed endothelial cell aneuploidy. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment.
A Major Role for Mitotic cdc2 Kinase Inactivation in the Establishment of the Mitotic DNA Damage Checkpoint
Authors: Bayart Emilie , Grigorieva Olga , Leibovitch Serge , Onclercq-Delic Rosine , Amor-Guéret Mounira 
Published: September 2005

Abstract
Cdc2 kinase is inactivated when DNA damage occurs during the spindle assembly checkpoint. Here, we show that the level of mitotic Bloom syndrome protein phosphorylation reflects the level of cdc2 activity. A complete inactivation of cdc2 by either introduction of DNA double-strand breaks or roscovitine treatment prevents exit from mitosis. Thus, mitotic cdc2 inactivation plays a major role in the establishment of the mitotic DNA damage checkpoint. In response to mitotic cdc2 inactivation, the M/G1 transition is delayed after releasing the drug block in nonmalignant cells, whereas tumor cells exit mitosis without dividing and rereplicate their DNA, which results in mitotic catastrophe. This opens the way for new chemotherapeutic strategies.
Dendritic Cells Strongly Boost the Antitumor Activity of Adoptively Transferred T Cells
In vivo
Authors: Lou Yanyan , Wang Gang , Lizée Gregory , Kim Grace J. , Finkelstein Steven E. , Feng Chiguang , Restifo Nicholas P. , Hwu Patrick 
Published: September 2005

Abstract
Dendritic cells (DCs) have been well characterized for their ability to initiate cell-mediated immune responses by stimulating naive T cells. However, the use of DCs to stimulate antigen-activated T cells in vivo has not been investigated. In this study, we determined whether DC vaccination could improve the efficacy of activated, adoptively transferred T cells to induce an enhanced antitumor immune response. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without concurrent peptide-pulsed DC vaccination. In this model, antigen-specific DC vaccination induced cytokine production, enhanced proliferation, and increased tumor infiltration of adoptively transferred T cells. Furthermore, the combination of DC vaccination and adoptive T-cell transfer led to a more robust antitumor response than the use of each treatment individually. Collectively, these findings illuminate a new potential application for DCs in the in vivo stimulation of adoptively transferred T cells and may be a useful approach for the immunotherapy of cancer.
PTEN Up-Regulates the Tumor Metastasis Suppressor Gene
Drg-1
in Prostate and Breast Cancer
Authors: Bandyopadhyay Sucharita , Pai Sudha K. , Hirota Shigeru , Hosobe Sadahiro , Tsukada Taisei , Miura Kunio , Takano Yukio , Saito Ken , Commes Therese , Piquemal David , Watabe Misako , Gross Steven , Wang Ying , Huggenvik Jodi , Watabe Kounosuke 
Published: September 2005

Abstract
PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.
Regulation of α-Fetoprotein by Nuclear Factor-κB Protects Hepatocytes from Tumor Necrosis Factor-α Cytotoxicity during Fetal Liver Development and Hepatic Oncogenesis
Authors: Cavin Lakita G. , Venkatraman Manickam , Factor Valentina M. , Kaur Swayamjot , Schroeder Insa , Mercurio Frank , Beg Amer A. , Thorgeirsson Snorri S. , Arsura Marcello 
Published: September 2005

Abstract
Nuclear factor-κB (NF-κB) plays a critical role during fetal liver development and hepatic oncogenesis. Here, we have assessed whether NF-κB activity is required for murine hepatocellular carcinoma cell survival. We show that adenoviral-mediated inhibition of inhibitor of NF-κB kinase-β (IKK-2) activity in hepatocellular carcinomas derived from transforming growth factor (TGF)-α/c-myc bitransgenic mice leads to inhibition of NF-κB and promotes tumor necrosis factor (TNF)-α–mediated cell death of malignant hepatocytes but not the surrounding peritumorous tissue. Induction of apoptosis is accompanied by inhibition of Bcl-XL and XIAP, two pro-survival NF-κB target genes. In addition, we have identified the α-fetoprotein (AFP) as a novel downstream target of NF-κB. We show that repression of IKK-2 activity in hepatocellular carcinomas promotes down-regulation of AFP gene expression. Likewise, genetic disruption of the RelA subunit results in reduced AFP gene expression during embryonic liver development, at a time in which fetal hepatocytes are sensitized to TNF-α–mediated cell killing. In this regard, we show that AFP inhibits TNF-α–induced cell death of murine hepatocellular carcinomas through association with TNF-α and inhibition of TNFRI signaling. Thus, NF-κB-mediated regulation of AFP gene expression during liver tumor formation and embryonic development of the liver constitutes a potential novel mechanism used by malignant and fetal hepatocytes to evade immune surveillance.
CYP3A4
,
CYP3A5
, and
CYP3A43
Genotypes and Haplotypes in the Etiology and Severity of Prostate Cancer
Authors: Zeigler-Johnson Charnita , Friebel Tara , Walker Amy H. , Wang Yiting , Spangler Elaine , Panossian Saarene , Patacsil Margerie , Aplenc Richard , Wein Alan J. , Malkowicz S. Bruce , Rebbeck Timothy R. 
Published: September 2005

Abstract
The CYP3A genes reside on chromosome 7q21 in a multigene cluster. The enzyme products of CYP3A4 and CYP3A43 are involved in testosterone metabolism. CYP3A4 and CYP3A5 have been associated previously with prostate cancer occurrence and severity. To comprehensively examine the effects of these genes on prostate cancer occurrence and severity, we studied 622 incident prostate cancer cases and 396 controls. Substantial and race-specific linkage disequilibrium was observed between CYP3A4 and CYP3A5 in both races but not between other pairs of loci. We found no association of CYP3A5 genotypes with prostate cancer or disease severity. CYP3A43*3 was associated with family history-positive prostate cancer (age- and race-adjusted odds ratio = 5.86, 95% confidence interval, 1.10–31.16). CYP3A4*1B was associated inversely with the probability of having prostate cancer in Caucasians (age-adjusted odds ratio = 0.54, 95% confidence interval, 0.32–0.94). We also observed significant interactions among these loci associated with prostate cancer occurrence and severity. There were statistically significant differences in haplotype frequencies involving these three genes in high-stage cases (P &lt; 0.05) compared with controls. The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity.
Maspin Expression Is Transactivated by p63 and Is Critical for the Modulation of Lung Cancer Progression
Authors: Kim Sejin , Han Joungho , Kim Jhingook , Park Chaehwa 
Published: September 2005

Abstract
Maspin inhibits metastasis of some cancer cells, and clinical studies have identified correlations between maspin loss and poor prognosis in several cancer types. Maspin was found to be significantly overexpressed in lung cancer samples as compared with matched normal lung tissues. However, the regulatory mechanism of maspin expression remains unclear. We show here that differential expression of maspin in carcinoma-derived lung cancer cells is regulated at the transcriptional level. We found that p63 is a critical factor for the transcription of maspin, which is lost in highly invasive cancer cells such as NCI-H157, NCI-322, and NCI-358. No correlation was found between maspin expression and the previously associated transcription factors, p53, Ets1, and Pdef. Instead, maspin expression was strictly dependent on the presence of p63 in lung cancer tissues (P &lt; 0.001) and in the tested cell lines. Transient expression of p63 transactivated the maspin promoter with remarkable fold changes in cells expressing the TAp63, suggesting that TAp63 might be a novel stimulator of the maspin promoter in lung cancer. We have also demonstrated the binding of p63 protein to a previously identified p53-binding site on the maspin promoter by gel shift and chromatin immunoprecipitation assays. In tumor tissues, maspin expression was associated with lymph node involvement (P = 0.035) and tumor stage (P = 0.063) in all tested cases, except squamous carcinoma. In terms of function, ectopic expression of maspin inhibited cell invasion in squamous carcinoma as well as adenocarcinoma. Taken together, these results define maspin as a new molecular target of p63 that eventually inhibits the invasion of lung cancer.
C-Type Lectin-Like Molecule-1
Authors: Bakker Alexander B. H. , van den Oudenrijn Sonja , Bakker Arjen Q. , Feller Nicole , van Meijer Marja , Bia Judith A. , Jongeneelen Mandy A. C. , Visser Therese J. , Bijl Nora , Geuijen Cecilia A. W. , Marissen Wilfred E. , Radosevic Katarina , Throsby Mark , Schuurhuis Gerrit Jan , Ossenkoppele Gert J. , de Kruif John , Goudsmit Jaap , Kruisbeek Ada M. 
Published: September 2005

Abstract
Acute myeloid leukemia (AML) has a poor prognosis due to treatment-resistant relapses. A humanized anti-CD33 antibody (Mylotarg) showed a limited response rate in relapsed AML. To discover novel AML antibody targets, we selected a panel of single chain Fv fragments using phage display technology combined with flow cytometry on AML tumor samples. One selected single chain Fv fragment broadly reacted with AML samples and with myeloid cell lineages within peripheral blood. Expression cloning identified the antigen recognized as C-type lectin-like molecule-1 (CLL-1), a previously undescribed transmembrane glycoprotein. CLL-1 expression was analyzed with a human anti-CLL-1 antibody that was generated from the single chain Fv fragment. CLL-1 is restricted to the hematopoietic lineage, in particular to myeloid cells present in peripheral blood and bone marrow. CLL-1 is absent on uncommitted CD34+/CD38− or CD34+/CD33− stem cells and present on subsets of CD34+/CD38+ or CD34+/CD33+ progenitor cells. CLL-1 is not expressed in any other tissue. In contrast, analysis of primary AMLs demonstrated CLL-1 expression in 92% (68 of 74) of the samples. As an AML marker, CLL-1 was able to complement CD33, because 67% (8 of 12) of the CD33− AMLs expressed CLL-1. CLL-1 showed variable expression (10–60%) in CD34+ cells in chronic myelogenous leukemia and myelodysplastic syndrome but was absent in 12 of 13 cases of acute lymphoblastic leukemia. The AML reactivity combined with the restricted expression on normal cells identifies CLL-1 as a novel potential target for AML treatment.
A Gene Expression Signature Associated with Metastatic Outcome in Human Leiomyosarcomas
Authors: Lee Yin-Fai , John Megan , Falconer Alison , Edwards Sandra , Clark Jeremy , Flohr Penny , Roe Toby , Wang Rubin , Shipley Janet , Grimer Robert J. , Mangham D. Chas , Thomas J. Meirion , Fisher Cyril , Judson Ian , Cooper Colin S. 
Published: September 2005

Abstract
Metastasis is a major factor associated with poor prognosis in cancer, but little is known of its molecular mechanisms. Although the clinical behavior of soft tissue sarcomas is highly variable, few reliable determinants of outcome have been identified. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Here, we have chosen leiomyosarcoma as a model for examining the relationship between gene expression profile and the development of metastasis in soft tissue sarcomas. Using cDNA microarray, we have identified a gene expression signature associated with metastasis in sarcoma that allowed prediction of the future development of metastases of primary tumors (Kaplan-Meier analysis P = 0.001). Our finding may aid the tailoring of therapy for individual sarcoma patients, where the aggressiveness of treatment is affected by the predicted outcome of disease.
Cyclooxygenase 2-Dependent Expression of Survivin Is Critical for Apoptosis Resistance in Non-Small Cell Lung Cancer
Authors: Krysan Kostyantyn , Dalwadi Harnisha , Sharma Sherven , Põld Mehis , Dubinett Steven 
Published: September 2005

Abstract
Elevated tumor cyclooxygenase 2 (COX-2) expression is associated with increased angiogenesis, tumor invasion, and promotion of tumor cell resistance to apoptosis. In our previous studies using non-small cell lung cancer (NSCLC) cell lines constitutively expressing COX-2 cDNA in sense and antisense orientations, we demonstrated that constitutive overexpression of COX-2 leads to stabilization of the inhibitor of apoptosis protein survivin resulting in the elevated apoptosis resistance of COX-2–overexpressing cells. Genetic or pharmacologic suppression of COX-2 activity increased proteasomal degradation of survivin and cellular response to apoptosis induction. Our data show that expression of survivin in non-small cell lung cancer cells can be significantly down-regulated by RNA interference. Whereas COX-2–overexpressing NSCLC cells have significantly higher apoptosis resistance than the parental cells, inhibition of survivin expression by small interfering RNA decreases apoptosis resistance to the level of the parental non-small cell lung cancer. We conclude that COX-2-dependent expression of survivin is critical for apoptosis resistance in non-small cell lung cancer.
Convection-Enhanced Delivery of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand with Systemic Administration of Temozolomide Prolongs Survival in an Intracranial Glioblastoma Xenograft Model
Authors: Saito Ryuta , Bringas John R. , Panner Amith , Tamas Matyas , Pieper Russell O. , Berger Mitchel S. , Bankiewicz Krystof S. 
Published: September 2005

Abstract
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent activator of cell death, preferentially killing neoplastic cells over normal cells, the efficacy of TRAIL for the treatment of glioma might be limited due to cellular resistance and, importantly, poor distribution after systemic administration. TRAIL and temozolomide (TMZ) were recently shown to have a synergistic antitumor effect against U87MG glioma cells in vitro. Convection-enhanced delivery (CED) can effectively distribute TRAIL protein throughout a brain tumor mass. In this study, we evaluated CED of TRAIL, alone and in conjunction with systemic TMZ administration, for antitumor efficacy. CED of TRAIL demonstrated safe and effective distribution in both normal brain and a U87MG intracranial xenograft model. Individually, both CED of TRAIL and systemic TMZ administration prolonged survival in tumor-bearing rats. However, the combination of these two treatments was significantly more effective than either treatment alone. CED of TRAIL in conjunction with systemic TMZ treatment is a promising strategy for the treatment of malignant gliomas.
Characterization of a Carcinogenesis Rat Model of Ovarian Preneoplasia and Neoplasia
Authors: Stewart Sherri L. , Querec Troy D. , Ochman Alexander R. , Gruver Briana N. , Bao Rudi , Babb James S. , Wong Thang S. , Koutroukides Theodoros , Pinnola Aaron D. , Klein-Szanto Andres , Hamilton Thomas C. , Patriotis Christos 
Published: September 2005

Abstract
Animal models of ovarian cancer are crucial for understanding the pathogenesis of the disease and for testing new treatment strategies. A model of ovarian carcinogenesis in the rat was modified and improved to yield ovarian preneoplastic and neoplastic lesions that pathogenetically resemble human ovarian cancer. A significantly lower dose (2 to 5 μg per ovary) of 7,12-dimethylbenz(a)anthracene (DMBA) was applied to the one ovary to maximally preserve its structural integrity. DMBA-induced mutagenesis was additionally combined with repetitive gonadotropin hormone stimulation to induce multiple cycles of active proliferation of the ovarian surface epithelium. Animals were treated in three arms of different doses of DMBA alone or followed by hormone administration. Comparison of the DMBA-treated ovaries with the contralateral control organs revealed the presence of epithelial cell origin lesions at morphologically distinct stages of preneoplasia and neoplasia. Their histopathology and path of dissemination to other organs are very similar to human ovarian cancer. Hormone cotreatment led to an increased lesion severity, indicating that gonadotropins may promote ovarian cancer progression. Point mutations in the Tp53 and Ki-Ras genes were detected that are also characteristic of human ovarian carcinomas. Additionally, an overexpression of estrogen and progesterone receptors was observed in preneoplastic and early neoplastic lesions, suggesting a role of these receptors in ovarian cancer development. These data indicate that this DMBA animal model gives rise to ovarian lesions that closely resemble human ovarian cancer and it is adequate for additional studies on the mechanisms of the disease and its clinical management.