bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production
Authors: Allavena Paola , Signorelli Mauro , Chieppa Marcello , Erba Eugenio , Bianchi Giancarlo , Marchesi Federica , Olimpio Chiara Omero , Bonardi Claudia , Garbi Annalisa , Lissoni Andrea , de Braud Filippo , Jimeno José , D'Incalci Maurizio 
Published: September 2005

AbstractYondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.
Activation of Nuclear Factor-κB Contributes to Induction of Death Receptors and Apoptosis by the Synthetic Retinoid CD437 in DU145 Human Prostate Cancer Cells
Authors: Jin Fengshuo , Liu Xiangguo , Zhou Zhongmei , Yue Ping , Lotan Reuben , Khuri Fadlo R. , Chung Leland W.K. , Sun Shi-Yong 
Published: September 2005

Abstract
Activation of the transcription factor, nuclear factor-κB (NF-κB), results in up-regulation of not only antiapoptotic genes but also proapoptotic genes, including death receptor 4 (DR4) and death receptor 5 (DR5). Therefore, NF-κB activation either suppresses or promotes apoptosis depending on the type of stimulus or cell context. We showed previously that the synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), effectively induces apoptosis particularly in androgen-independent prostate carcinoma cells. This effect was associated with the ability of CD437 to induce the expression of DR4 and DR5. In the present study, we examined the hypothesis that NF-κB activation plays a role in CD437-induced death receptor expression and apoptosis. Treatment of DU145 cells with CD437 resulted in a rapid decrease (≥3 hours) of IκBα, which was accompanied by increased translocation of the NF-κB subunit p65 from the cytoplasm to the nucleus and increased NF-κB DNA-binding activity (≥4 hours). The NF-κB inhibitor, helenalin, inhibited CD437-induced IκBα reduction and p65 nuclear translocation. Accordingly, it also abrogated CD437-induced up-regulation of DR4, activation of caspase-8 and caspase-3, and increased DNA fragmentation. Overexpression of an IκBα dominant-negative mutant blocked not only CD437-induced p65 nuclear translocation but also DR4 up-regulation, caspase activation, and DNA fragmentation. CD437 was unable to decrease IκBα protein levels and up-regulate DR4 expression in CD437-resistant DU145 cells. Moreover, knockdown of Fas-associated death domain, caspase-8, and DR4, respectively, suppressed CD437-induced apoptosis. Collectively, these results indicate that CD437 activates NF-κB via decreasing IκBα protein and thereby induces DR4 expression and subsequent apoptosis in DU145 cells.
Activated Ras Enhances Insulin-Like Growth Factor I Induction of Vascular Endothelial Growth Factor in Prostate Epithelial Cells
Authors: Stearns Mark , Tran Jordan , Francis Mary Kay , Zhang Hong , Sell Christian 
Published: September 2005

Abstract
Mutations in the three closely related RAS genes, HRAS, KRAS, and NRAS are among the most common mutations found in human cancer; reaching 50% in some types of cancer, such as colorectal carcinoma, and 10% in prostate cancers. The activated Ras proteins produced by these mutations can, among other cellular changes, increase vascular endothelial growth factor (VEGF) production. Moreover, tumors bearing RAS gene mutations are more vascular than tumors without RAS mutations. We find that, in prostate epithelial cells, the introduction of an activated HRAS causes cells to produce VEGF in response to insulin-like growth factor I (IGF-I). In comparison, cells lacking an activated Ras are unable to produce VEGF in response to IGF-I. This effect of Ras may occur through stabilization of a second messenger protein, insulin receptor substrate 1, that mediates PI 3-kinase-dependent signaling. Because IGF-I is a paracrine/endocrine hormone that has been associated with increased risk for several types of cancer, these results suggest a novel interrelationship between oncogenic conversion of a cellular gene such as HRAS, and IGF-I produced locally for normal tissue homeostasis.
Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-κB Activation
Authors: Farhana Lulu , Dawson Marcia I. , Fontana Joseph A. 
Published: September 2005

AbstractNuclear factor-κB (NF-κB) activation has been shown to be both antiapoptotic and proapoptotic depending on the stimulus and the specific cell type involved. NF-κB activation has also been shown to be essential for apoptosis induction by a number of agents. The novel retinoid-related molecule 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) activates NF-κB with subsequent apoptosis in a number of cell types. We have found that NF-κB activation is essential for 3-Cl-AHPC–mediated apoptosis. 3-Cl-AHPC activates NF-κB through IKKα kinase activation and the subsequent degradation of IκBα. IKKα kinase activation is associated with IKKα-enhanced binding to HSP90. The HSP90 inhibitor geldanamycin enhances the degradation of IKKα and blocks 3-Cl-AHPC activation of NF-κB and 3-Cl-AHPC–mediated apoptosis. In addition, inhibition of IκBα degradation using a dominant-negative IκBα inhibits 3-Cl-AHPC–mediated apoptosis. NF-κB p65 activation is essential for 3-Cl-AHPC apoptosis induction as evidenced by the fact that inhibition of p65 activation utilizing the inhibitor helenalin or loss of p65 expression block 3-Cl-AHPC–mediated apoptosis. NF-κB has been shown to be antiapoptotic through its enhanced expression of a number of antiapoptotic proteins including X-linked inhibitor of apoptosis protein (XIAP), c-IAP1, and Bcl-XL. Whereas exposure to 3-Cl-AHPC results in NF-κB activation, it inhibits the expression of XIAP, c-IAP1, and Bcl-XL and enhances the expression of proapoptotic molecules, including the death receptors DR4 and DR5 as well as Fas and Rip1. Thus, 3-Cl-AHPC, which is under preclinical development, has pleotrophic effects on malignant cells resulting in their apoptosis.
Requirement for Focal Adhesion Kinase in the Early Phase of Mammary Adenocarcinoma Lung Metastasis Formation
Authors: van Nimwegen Maroesja J. , Verkoeijen Saertje , van Buren Liesbeth , Burg Danny , van de Water Bob 
Published: September 2005

Abstract
An increased expression of focal adhesion kinase (FAK) in a variety of cancers is associated with a poor disease prognosis. To study the role of FAK in breast tumor growth and metastasis formation, we used conditional doxycycline-regulated expression of a dominant-negative acting splice variant of FAK, FAK-related non-kinase (FRNK), in MTLn3 mammary adenocarcinoma cells in a syngeneic Fischer 344 rat tumor and metastasis model. In cell culture, doxycycline-mediated expression of FRNK inhibited MTLn3 cell spreading and migration in association with reduced formation of focal adhesions and phosphorylation of FAK on Tyr397, but FRNK did not cause apoptosis. Continuous expression of FRNK decreased the primary tumor growth in the mammary fat pad by 60%, which was not due to induction of apoptosis. Lung metastasis formation was almost completely prevented when FRNK was already expressed 1 day before tumor cell injection, whereas expression of FRNK 11 days after injection did not affect lung metastasis formation. FRNK expression during the first 5 days was sufficient to block metastasis formation, excluding the possibility of FRNK-induced dormancy of tumor cells. Together, these data fit with a model wherein FAK is required for breast tumor cell invasion/migration processes that take place in the early phase of metastasis formation. Our findings suggest that FAK is a good candidate for therapeutic intervention of metastasis formation.
Loss of Tumor Suppressor p53 Decreases PTEN Expression and Enhances Signaling Pathways Leading to Activation of Activator Protein 1 and Nuclear Factor κB Induced by UV Radiation
Authors: Wang Jian , Ouyang Weiming , Li Jingxia , Wei Lixin , Ma Qian , Zhang Zhuo , Tong Qiangsong , He Jie , Huang Chuanshu 
Published: September 2005

Abstract
Transcription factor p53 and phosphatase PTEN are two tumor suppressors that play essential roles in suppression of carcinogenesis. However, the mechanisms by which p53 mediates anticancer activity and the relationship between p53 and PTEN are not well understood. In the present study, we found that pretreatment of mouse epidermal Cl41 cells with pifithrin-α, an inhibitor for p53-dependent transcriptional activation, resulted in a marked increase in UV-induced activation of activator protein 1 (AP-1) and nuclear factor κB (NF-κB). Consistent with activation of AP-1 and NF-κB, pifithrin-α was also able to enhance the UV-induced phosphorylation of c-Jun-NH2-kinases (JNK) and p38 kinase, whereas it did not show any effect on phosphorylation of extracellular signal-regulated kinases. Furthermore, the UV-induced signal activation, including phosphorylation of JNK, p38 kinase, Akt, and p70S6K, was significantly enhanced in p53-deficient cells (p53−/−), which can be reversed by p53 reconstitution. In addition, knockdown of p53 expression by its small interfering RNA also caused the elevation of AP-1 activation and Akt phosphorylation induced by UV radiation. These results show that p53 has a suppressive activity on the cell signaling pathways leading to activation of AP-1 and NF-κB in cell response to UV radiation. More importantly, deficiency of p53 expression resulted in a decrease in PTEN protein expression, suggesting that p53 plays a critical role in the regulation of PTEN expression. In addition, overexpression of wild-type PTEN resulted in inhibition of UV-induced AP-1 activity. Because PTEN is a well-known phosphatase involved in the regulation of phosphatidylinositol 3-kinase (PI-3K)/Akt signaling pathway, taken together with the evidence that PI-3K/Akt plays an important role in the activation of AP-1 and NF-κB during tumor development, we anticipate that inhibition of AP-1 and NF-κB by tumor suppressor p53 seems to be mediated via PTEN, which may be a novel mechanism involved in anticancer activity of p53 protein.
A Transforming Growth Factor-β Receptor–Interacting Protein Frequently Mutated in Human Ovarian Cancer
Authors: Ding Wei , Tang Qian , Espina Virginia , Liotta Lance A. , Mauger David T. , Mulder Kathleen M. 
Published: September 2005

Abstract
Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-β (TGF-β)–mediated growth inhibition. However, mutations in the TGF-β receptor I and receptor II (TβR-I and TβR-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-β–signaling components may play an important role in the loss of TGF-β responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-β receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (Δexon3-km23), was found in 2 of 19 tumor tissues from patients with ovarian cancer. In addition to this alteration, a stop codon mutation (TAA → CAC) was detected in two patients. This alteration results in an elongated protein, encoding 107-amino-acid residues (Δ107km23), instead of the wild-type 96-amino-acid form of km23. Furthermore, five missense mutations (T38I, S55G, T56S, I89V, and V90A) were detected in four patients, providing a total alteration rate of 42.1% (8 of 19 cases) in ovarian cancer. No km23 alterations were detected in 15 normal tissues. Such a high alteration rate in ovarian cancer suggests that km23 may play an important role in either TGF-β resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the Δexon3-km23 and S55G/I89V-km23 mutants displayed a disruption in binding to the dynein intermediate chain in vivo, suggesting a defect in cargo recruitment to the dynein motor complex. In addition, the Δexon3-km23 resulted in an inhibition of TGF-β–dependent transcriptional activation of both the p3TP-lux and activin responsive element reporters. Collectively, our results suggest that km23 alterations found in ovarian cancer patients result in altered dynein motor complex formation and/or aberrant transcriptional regulation by TGF-β.
Functional Epigenomics Identifies Genes Frequently Silenced in Prostate Cancer
Authors: Lodygin Dimitri , Epanchintsev Alexey , Menssen Antje , Diebold Joachim , Hermeking Heiko 
Published: September 2005

Abstract
In many cases, silencing of gene expression by CpG methylation is causally involved in carcinogenesis. Furthermore, cancer-specific CpG methylation may serve as a tumor marker. In order to identify candidate genes for inactivation by CpG methylation in prostate cancer, the prostate cancer cell lines LNCaP, PC3, and Du-145 were treated with 5-aza-2′ deoxycytidine and trichostatin A, which leads to reversion of epigenetic silencing. By microarray analysis of 18,400 individual transcripts, several hundred genes were found to be induced when compared with cells treated with trichostatin A. Fifty re-expressed genes were selected for further analysis based on their known function, which implied a possible involvement in tumor suppression. Twelve of these genes showed a significant degree of CpG methylation in their promoters. Six genes were silenced by CpG methylation in the majority of five analyzed prostate cancer cell lines, although they displayed robust mRNA expression in normal prostate epithelial cells obtained from four different donors. In primary prostate cancer samples derived from 41 patients, the frequencies of CpG methylation detected in the promoter regions of these genes were: GPX3, 93%; SFRP1, 83%; COX2, 78%; DKK3, 68%; GSTM1, 58%; and KIP2/p57, 56%. Ectopic expression of SFRP1 or DKK3 resulted in decreased proliferation. The expression of DKK3 was accompanied by attenuation of the mitogen-activated protein kinase pathway. The high frequency of CpG methylation detected in the promoters of the identified genes suggests a potential causal involvement in prostate cancer and may prove useful for diagnostic purposes.
Choline Kinase Is a Novel Oncogene that Potentiates RhoA-Induced Carcinogenesis
Authors: Ramírez de Molina Ana , Gallego-Ortega David , Sarmentero Jacinto , Bañez-Coronel Mónica , Martín-Cantalejo Yolanda , Lacal Juan Carlos 
Published: September 2005

Abstract
Choline kinase is overexpressed in human breast, lung, colorectal, and prostate tumors, a finding that suggests the involvement of this enzyme in carcinogenesis. Here we show that overexpression of choline kinase induce oncogenic transformation of human embryo kidney fibroblasts and canine epithelial Madin-Darby canine kidney cells. Choline kinase lays downstream of RhoA signaling and is activated through ROCK kinase, one of the best-characterized RhoA effectors. In keeping with this, coexpression of RhoA and choline kinase potentiates both anchorage independent growth and tumorigenesis. Finally, choline kinase–mediated transformation is sensitive to MN58b, a well-characterized specific choline kinase inhibitor. These results provide the definitive evidence that choline kinase has oncogenic properties and that choline kinase inhibition constitutes a novel valid antitumor strategy.
Impairment of Stromelysin-1 Transcriptional Activity by Promoter Mutations in High Microsatellite Instability Colorectal Tumors
Authors: Morán Alberto , Iniesta Pilar , de Juan Carmen , García-Aranda Cristina , Díaz-López Antonio , Benito Manuel 
Published: September 2005

Abstract
Colorectal tumorigenesis is characterized by the sequential inactivation of a series of tumor suppressor genes (microsatellite-stable tumors) and genetic or epigenetic alterations in mismatch repair genes in nonpoliposic hereditary tumours and 13% to 15% of sporadic colorectal cancer [high microsatellite instability (MSI-H) tumors]. We hypothesized a molecular mechanism for MSI-H colorectal tumors related to matrix metalloproteinase 3 (MMP-3) promoter mutations, down-regulation of MMP-3 expression, and impairment of MMP-9 activation. We have now analyzed the 2.2-kb full MMP-3 promoter to assess the mutation distribution. The mutations found are restricted to the polymorphic region that includes the zinc-binding protein (ZBP-89) binding element. To show that these alterations were the cause of the low expression of this gene, we have generated three constructs with different MMP-3 promoters (wild type and two mutants) and we have expressed them in SW480 human colorectal cells. The basal transcriptional activity of wild-type MMP-3 promoter was much higher than the mutants activity. In addition, 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced transcriptional activity of wild-type MMP-3 promoter was 10-fold higher than the mutants activity. Dexamethasone inhibited the basal transcriptional activity of wild-type MMP-3 promoter and of the two mutants found in the MSI-H subgroup of colorectal tumors. Significantly, dexamethasone almost completely blunted the TPA-induced effect on wild-type MMP-3 promoter transcriptional activity and on the mutants, even below their basal activity. Our data show that mutations found in the polymorphic region of the MMP-3 promoter from MSI-H colorectal tumors impair its basal and induced transcriptional activity, which may contribute to their better clinical outcome.
Enforced Expression of Superoxide Dismutase 2/Manganese Superoxide Dismutase Disrupts Autocrine Interleukin-6 Stimulation in Human Multiple Myeloma Cells and Enhances Dexamethasone-Induced Apoptosis
Authors: Hodge David R. , Xiao Weihua , Peng Benjamin , Cherry James C. , Munroe David J. , Farrar William L. 
Published: September 2005

Abstract
Autocrine pathways of proliferative and antiapoptotic growth factors represent a serious impediment to the treatment of many types of tumors. In particular, interleukin-6 (IL-6), a pleiotropic cytokine known to play a critical role in the survival and growth of multiple myeloma cells, participates in an autocrine stimulation loop that serves to inhibit the induction of apoptosis during chemotherapy. Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme encoded by the SOD2 gene that attenuates oxidative free radicals in the mitochondria by catalyzing the formation of hydrogen peroxide from superoxide radicals. Transcription factor activity and binding is influenced by the oxidative state of cells, and dysregulation of MnSOD levels can result in abnormal patterns of gene expression. In the human multiple myeloma cell line IM-9, an autocrine IL-6 loop exists, which enables the cell to resist the effects of dexamethasone, a common treatment for multiple myeloma. Here, we show that SOD2 expression is epigenetically silenced in IM-9 cells, and replacement of MnSOD reduces cell proliferation and partially restores susceptibility to dexamethasone. The restoration of MnSOD also serves to decrease the expression levels of IL-6 by reducing the ability of activator protein-1, an important mediator of IL-6 expression in multiple myeloma cells, to bind to its enhancer site. These results show the importance of free radical–mediated dysregulation of autocrine growth factor loops in tumor cells and their effect on cell growth and response to chemotherapy.
Detection of Prostate Cancer with a Blood-Based Assay for Early Prostate Cancer Antigen
Authors: Paul Barbara , Dhir Rajiv , Landsittel Douglas , Hitchens Moira R. , Getzenberg Robert H. 
Published: September 2005

Abstract
Prostate-specific antigen lacks specificity for prostate cancer, so the identification and characterization of a unique blood-based marker for the disease would provide for a more accurate diagnosis, reducing both unnecessary biopsies and patient uncertainty. We previously identified a novel biomarker for prostate cancer, early prostate cancer antigen (EPCA). EPCA antibodies positively stained the negative biopsies of men who, as much as 5 years later, were diagnosed with prostate cancer. The goal of this study was to determine whether EPCA antibodies could be used in a clinically applicable plasma-based immunoassay to specifically detect prostate cancer. Using an EPCA-based ELISA, the protein was measured in the plasma of 46 individuals, including prostate cancer patients, healthy individuals, other cancer patients, spinal cord injury victims, and patients with prostatitis. With a predetermined cutoff value of 1.7 absorbance at 450 nm, only the prostate cancer population, as a whole, expressed plasma-EPCA levels above the cutoff. Statistical analysis showed a significant difference in EPCA levels between the prostate cancer population and each of the other groups, specifically the healthy donors (P &lt; 0.0001), bladder cancer patients (P = 0.03), and spinal cord injury patients (P = 0.001). Sensitivity of the EPCA assay for prostate cancer patients was 92% whereas the overall specificity was 94%. Specificity for the healthy donors was 100%. Although larger trials are required, this initial study shows the potential of EPCA to serve as a highly specific blood-based marker for prostate cancer. EPCA, when coupled with prostate-specific antigen, may help reduce the number of both unnecessary biopsies and undetected prostate tumors.