bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic Profiling of Engineered Mouse Melanomas with Manipulated Histamine Production Identifies Histamine H2 Receptor and Rho-C as Histamine-Regulated Melanoma Progression Markers
Authors: Pós Zoltán , Sáfrány Géza , Müller Kerstin , Tóth Sára , Falus András , Hegyesi Hargita 
Published: September 2005

Abstract
In the present study, the impact of acquired neoplastic l-histidine decarboxylase (HDC) expression, and its direct consequence, the release of histamine in the tumor environment, was assessed on melanoma tumor progression. B16-F10 mouse melanoma cells were manipulated via stable transfection, and nine novel transgenic variants were generated in triplicates, constitutively expressing the full-length sense mouse HDC mRNA, a mock control, and an antisense HDC RNA segment, respectively. Establishing both primary skin tumors and lung metastases in C57BL/6 mice, the nine variants with different histamine-releasing capacities were subjected to a comprehensive comparative progression profiling in vivo. Our analyses showed trends of markedly accelerated tumor growth (P &lt; 0.001), and moderately increased metastatic colony-forming potential (P = 0.010) along with rising levels of local histamine production. Using RNase protection assay for screening of the melanoma progression profile, and Western blotting for subsequent result validation, we looked for molecular progression markers affected by melanoma histamine secretion. Investigation of 21 functionally clustered markers associated with tumor proliferation, angiogenesis, invasivity, metastasis formation, local or systemic immunomodulation, and histamine signaling revealed positive correlations between histamine production, tumor histamine H2 receptor and rho-C expression (P &lt; 0.001, P = 0.002, respectively). These observations confirm the involvement of histamine in the molecular machinery of melanoma progression.
High Mobility Group A2 Potentiates Genotoxic Stress in Part through the Modulation of Basal and DNA Damage–Dependent Phosphatidylinositol 3-Kinase–Related Protein Kinase Activation
Authors: Boo Lee Ming , Lin H. Helen , Chung Vincent , Zhou Bingsen , Louie Stan G. , O'Reilly Michael A. , Yen Yun , Ann David K. 
Published: September 2005

Abstract
The high mobility group A2 (HMGA2) protein belongs to the architectural transcription factor HMGA family, playing a role in chromosomal organization and transcriptional regulation. We and others have previously reported that ectopic HMGA2 expression is associated with neoplastic transformation and anchorage-independent cell proliferation. Here, we reported a correlation between increased HMGA2 expression and enhanced chemosensitivity towards topoisomerase II inhibitor, doxorubicin, in breast cancer cells. Using cells exhibiting differential HMGA2 expression and small interfering RNA technique, we showed that HMGA2 expression modulates cellular response to the genotoxicity of DNA double-strand breaks. Notably, HMGA2 enhances doxorubicin-elicited cell cycle delay in sub-G1 and G2-M and augments cell cycle dysregulation on cotreatment of doxorubicin and caffeine. We further reported that HMGA2 induces a persistent Ser139 phosphorylation of histone 2A variant X, analogous to the activation by doxorubicin-mediated genotoxic stress. Moreover, this HMGA2-dependent enhancement of cytotoxicity is further extended to other double-strand breaks elicited by cisplatin and X-ray irradiation and is not restricted to one cell type. Together, we postulated that the enhanced cytotoxicity by double-strand breaks in HMGA2-expressing cells is mediated, at least in part, through the signaling pathway of which the physiologic function is to maintain genome integrity. These findings should contribute to a greater understanding of the role of HMGA2 in promoting tumorigenesis and conveying (chemo)sensitivity towards doxorubicin and other related double-strand breaks.
Characterization of Common CYP1B1 Variants with Different Capacity for Benzo[a]pyrene-7,8-Dihydrodiol Epoxide Formation from Benzo[a]pyrene
Authors: Aklillu Eleni , Øvrebø Steinar , Botnen Ingrid V. , Otter Charlotta , Ingelman-Sundberg Magnus 
Published: September 2005

Abstract
Cytochrome P450 1B1 (CYP1B1), an extrahepatic enzyme inducible by smoking, is overexpressed in many tumors and catalyzes the metabolic activation of procarcinogens such as polycyclic aromatic hydrocarbons. In human, CYP1B1 is genetically polymorphic and five common missense mutations causing amino acid substitution have been identified. In this study, we have investigated CYP1B1 haplotypes present in a Spanish population and carried out functional analyses of the corresponding enzymes in yeast using benzo[a]pyrene as a substrate. CYP1B1*1, CYP1B1*2, CYP1B1*3, CYP1B1*4, CYP1B1*6, and CYP1B1*7, encoding combinations of the Arg48Gly, Ala119Ser, Leu432Val, Asn453Ser, and Ala443Gly amino acid substitutions, were present at frequencies of 14.3%, 25.5%, 38.8%, 18.1%, 0.4%, and 2.6%, respectively. The variant CYP1B1 forms were heterologously expressed with human reductase in Saccharomyces cerevisiae and kinetic analyses of benzo[a]pyrene metabolism were carried out. CYP1B1.7, having the amino acid substitutions Arg48Gly, Ala119Ser, Leu432Val, and Ala443Gly, exhibited a significantly decreased capacity (P &lt; 0.001) for the formation of (±)-benzo[a]pyrene-trans-7,8-dihydrodiol from benzo[a]pyrene as indicated by lower intrinsic clearance (Vmax/Km). A somewhat decreased clearance was observed for CYP1B1.4, whereas no significant differences in kinetic properties among the remaining variant enzymes were observed as compared with CYP1B1.1. Thus, genetic polymorphism in the CYP1B1 gene, as defined by the haplotypes investigated, might cause interindividual differences in susceptibility (e.g., to lung cancer induced by smoking). The results indicate the necessity to make molecular epidemiologic investigations regarding the association of the specific CYP1B1 haplotypes and cancer risk.
Hypoxia-Inducible Protein 2 (HIG2), a Novel Diagnostic Marker for Renal Cell Carcinoma and Potential Target for Molecular Therapy
Authors: Togashi Akira , Katagiri Toyomasa , Ashida Shingo , Fujioka Tomoaki , Maruyama Osamu , Wakumoto Yoshiaki , Sakamoto Yoshiro , Fujime Makoto , Kawachi Yoshio , Shuin Taro , Nakamura Yusuke 
Published: September 2005

Abstract
To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2) was expressed exclusively in RCCs and fetal kidney. Induction of HIG2 cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression of HIG2 in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of molecular-targeting therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas.
Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal–Like Sequences for Nuclear Import Mediated by Major Vault Protein
Authors: Chung Ji-Hyun , Ginn-Pease Margaret E. , Eng Charis 
Published: September 2005

Abstract
Although phosphatase and tensin homologue deleted on chromosome 10 (PTEN) localization in the nucleus and cytoplasm is established, the mechanism is unknown. PTEN is a tumor suppressor phosphatase that causes cell cycle arrest and/or apoptosis. Nuclear-cytoplasmic compartmentalization may be a novel mechanism in regulating these events. PTEN does not contain a traditional nuclear localization sequence (NLS); however, we identified putative NLS-like sequences, which we analyzed by site-directed mutagenesis and localization studies in MCF-7 cells. Two double site mutations exhibited nuclear localization defects. Furthermore, unlike wild-type PTEN, double NLS mutant PTEN did not interact with major vault protein (MVP), a previously hypothesized nuclear-cytoplasmic transport protein. We conclude that these two NLS-like sequences are required for PTEN nuclear import that is mediated by MVP. Further, we show that this MVP-mediated nuclear import is independent of PTEN phosphorylation and of the lipid and protein phosphatase activities of PTEN.
A Novel Function for Galectin-7: Promoting Tumorigenesis by Up-regulatingMMP-9Gene Expression
Authors: Demers Mélanie , Magnaldo Thierry , St-Pierre Yves 
Published: September 2005

AbstractMetastasis is a multistep process by which cancer cells, after acquiring several capabilities, spread to distinct sites in the body. It is the major cause of death in individuals suffering from cancer. We have recently identified galectin-7 as a new gene associated with the progression of T cell lymphoma toward a metastatic phenotype, suggesting a possible causal relationship. The present study was designed to investigate the role of galectin-7 in lymphoma. We found that the development of thymic lymphoma was accelerated when induced by lymphoma cells overexpressing galectin-7. Moreover, transfection of an expression vector containing the galectin-7 gene in low metastatic lymphoma cells increased their metastatic behavior and confers these cells with the new ability to overcome the resistance of intercellular adhesion molecule-1–deficient mice to lymphoma dissemination. Finally, we provide data suggesting that galectin-7 modulates the aggressive behavior of lymphoma cells by controlling the expression of metastatic genes, such as MMP-9. This hypothesis is based on the following evidence: (a) galectin-7 transfectants have higher levels of MMP-9 expression, (b) addition of β-lactose completely inhibits expression of MMP-9 by galectin-7 transfectants, and (c) recombinant forms of galectin-7 induces the expression of MMP-9 in both mouse and human lymphoma cells. Our results have uncovered the existence of a previously undescribed activity, the promotion of cancer cell malignancy, to galectin-7.
Bcl-2 Acts in a Proangiogenic Signaling Pathway through Nuclear Factor-κB and CXC Chemokines
Authors: Karl Elisabeta , Warner Kristy , Zeitlin Benjamin , Kaneko Tomoatsu , Wurtzel Lindsey , Jin Taocong , Chang Jia , Wang Shaomeng , Wang Cun-Yu , Strieter Robert M. , Nunez Gabriel , Polverini Peter J. , Nör Jacques E. 
Published: September 2005

Abstract
Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2–mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2–transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-α (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-κB (NF-κB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-κB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.
LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway
Authors: Poh Tze Wei , Pervaiz Shazib 
Published: September 2005

Abstract
The phosphoinositide 3-kinase (PI3K)-Akt pathway is constitutively active in many tumors, and inhibitors of this prosurvival network, such as LY294002, have been shown to sensitize tumor cells to death stimuli. Here, we report a novel, PI3K-independent mechanism of LY-mediated sensitization of LNCaP prostate carcinoma cells to drug-induced apoptosis. Preincubation of tumor cells to LY294002 or its inactive analogue LY303511 resulted in a significant increase in intracellular hydrogen peroxide (H2O2) production and enhanced sensitivity to nonapoptotic concentrations of the chemotherapeutic agent vincristine. The critical role of intracellular H2O2 in LY-induced death sensitization is corroborated by transient transfection of cells with a vector containing human catalase gene. Indeed, overexpression of catalase significantly blocked the amplifying effect of LY pretreatment on caspase-2 and caspase-3 activation and cell death triggered by vincristine. Furthermore, the inability of wortmannin, another inhibitor of PI3K, to induce an increase in H2O2 production at doses that effectively blocked Akt phosphorylation provides strong evidence to unlink inhibition of PI3K from intracellular H2O2 production. These data strongly support death-sensitizing effect of LY compounds independent of the PI3K pathway and underscore the critical role of H2O2 in creating a permissive intracellular milieu for efficient drug-induced execution of tumor cells.
Increased Proteasome Activity, Ubiquitin-Conjugating Enzymes, and eEF1A Translation Factor Detected in Breast Cancer Tissue
Authors: Chen Li , Madura Kiran 
Published: September 2005

Abstract
The ubiquitin (Ub)/proteasome pathway facilitates the degradation of damaged proteins and regulators of growth and stress response. The activation of this pathway in various cancers and malignancies has been described, and several genetic determinants of breast cancer, including BRCA1 and BRCA2, are linked to protein degradation. To investigate the involvement of the Ub/proteasome system in breast cancer, we examined a collection of 25 patient-matched breast cancer and normal adjacent tissues and detected activation of numerous components of the Ub/proteasome pathway. The activity of the proteasome, and levels of proteasome subunits and various targeting factors, were increased in &gt;90% of primary breast cancer tissue specimens. In contrast, no activation was observed in benign solid tumors, indicating that the response is specific to abnormal growth in neoplastic cells. Additionally, the accumulation of high levels of certain Ub-conjugating enzymes (UbcH1, UbcH2, and UbcH5), was specific to breast cancer, as no change in abundance was detected in primary colon cancer tissue extracts. Surprisingly, the Ub/proteasome system was not activated in a well-characterized cell culture–based breast cancer model system. Collectively, these findings suggest that the analysis of primary breast cancer tissue samples will be indispensable for the biochemical characterization of neoplastic growth and for the development of therapeutics.
4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone from Cigarette Smoke Stimulates Colon Cancer Growth via β-Adrenoceptors
Authors: Wu William K.K. , Wong Helen P.S. , Luo Shi W. , Chan Kevin , Huang Fung Y. , Hui Marco K.C. , Lam Emily K.Y. , Shin Vivian Y. , Ye Yi N. , Yang Ying H. , Cho Chi H. 
Published: September 2005

AbstractCigarette smoking is a risk factor for colorectal cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, the proliferative response of a cultured colon cancer cell line HT-29 to NNK was determined. It was found that NNK dose-dependently stimulated HT-29 cell proliferation. In this regard, the stimulatory action of NNK was abolished by atenolol and ICI 118,551, a β1- and β2-selective antagonist, respectively. In addition, cell growth was stimulated by the nonselective adrenergic agonist, noradrenaline, and more effectively by the β-selective agonist, isoproterenol. The second message cyclic AMP level for β-adrenoceptor activation was elevated by isoproterenol and NNK treatment. These agents also up-regulated cyclooxygenase-2 expression, cytosolic phospholipase A2 expression, and prostaglandin E2 release. β2-adrenoceptor blockade with ICI 118,551, in contrast, significantly decreased cyclooxygenase-2 expression, cytosolic phospholipase A2 expression and prostaglandin E2 release induced by NNK and isoproterenol. To conclude, it is proposed that NNK stimulates HT-29 cell proliferation through β-adrenoceptors, preferentially β2 receptors. Activation of the β-adrenoceptors, and the consequent cyclic AMP elevation coupled with the downstream arachidonic acid pathway, is perhaps an important mechanistic cascade in the promotion of colon cancer growth. These findings partly elucidate the carcinogenic actions of cigarette smoke and shed new light on the novel modulatory role of β-adrenoceptors in the development of colon cancer.
Diverse Biological Effect and Smad Signaling of Bone Morphogenetic Protein 7 in Prostate Tumor Cells
Authors: Yang Shangxin , Zhong Chen , Frenkel Baruch , Reddi A. Hari , Roy-Burman Pradip 
Published: September 2005

Abstract
We found that bone morphogenetic protein (BMP) 7, a member of the BMP family, was strikingly up-regulated during the development of primary prostatic adenocarcinoma in the conditional Pten deletion mouse model. To determine the relevance of this finding to human prostate cancer, we examined the expression of BMPs and BMP receptors (BMPR) as well as the responsiveness to recombinant human BMP7 in a series of human prostate tumor cell lines. All prostatic cell lines tested expressed variable levels of BMP2, BMP4, and BMP7 and at least two of each type I and II BMPRs. In all cases, BMP7 induced Smad phosphorylation in a dose-dependent manner, with Smad5 activation clearly demonstrable. However, the biological responses to BMP7 were cell type specific. BPH-1, a cell line representing benign prostatic epithelial hyperplasia, was growth arrested at G1. In the bone metastasis-derived PC-3 prostate cancer cells, BMP7 induced epithelial-mesenchymal transdifferentiation with classic changes in morphology, motility, invasiveness, and molecular markers. Finally, BMP7 inhibited serum starvation–induced apoptosis in the LNCaP prostate cancer cell line and more remarkably in its bone metastatic variant C4-2B line. Each of the cell lines influenced by BMP7 was also responsive to BMP2 in a corresponding manner. The antiapoptotic activity of BMP7 in the LNCaP and C4-2B cell lines was not associated with a significant alteration in the levels of the proapoptotic protein Bax or the antiapoptotic proteins Bcl-2, Bcl-xl, and X-linked inhibitor of apoptosis. However, in C4-2B cells but not in LNCaP cells, a starvation-induced decrease in the level of survivin was counteracted by BMP7. Taken together, these findings suggest that BMPs are able to modulate the biological behavior of prostate tumor cells in diverse and cell type–specific manner and point to certain mechanisms by which these secreted signaling molecules may contribute to prostate cancer growth and metastasis.
Increased Tumorigenicity and Sensitivity to Ionizing Radiation upon Loss of Chromosomal Protein HMGN1
Authors: Birger Yehudit , Catez Frédéric , Furusawa Takashi , Lim Jae-Hwan , Prymakowska-Bosak Marta , West Katherine L. , Postnikov Yuri V. , Haines Diana C. , Bustin Michael 
Published: September 2005

Abstract
We report that loss of HMGN1, a nucleosome-binding protein that alters the compaction of the chromatin fiber, increases the cellular sensitivity to ionizing radiation and the tumor burden of mice. The mortality and tumor burden of ionizing radiation–treated Hmgn1−/− mice is higher than that of their Hmgn1+/+ littermates. Hmgn1−/− fibroblasts have an altered G2-M checkpoint activation and are hypersensitive to ionizing radiation. The ionizing radiation hypersensitivity and the aberrant G2-M checkpoint activation of Hmgn1−/− fibroblasts can be reverted by transfections with plasmids expressing wild-type HMGN1, but not with plasmids expressing mutant HMGN proteins that do not bind to chromatin. Transformed Hmgn1−/− fibroblasts grow in soft agar and produce tumors in nude mice with a significantly higher efficiency than Hmgn1+/+ fibroblasts, suggesting that loss of HMGN1 protein disrupts cellular events controlling proliferation and growth. Hmgn1−/− mice have a higher incidence of multiple malignant tumors and metastases than their Hmgn1+/+ littermates. We suggest that HMGN1 optimizes the cellular response to ionizing radiation and to other tumorigenic events; therefore, loss of this protein increases the tumor burden in mice.
Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells
Authors: Shiraishi Takumi , Yoshida Tatsushi , Nakata Susumu , Horinaka Mano , Wakada Miki , Mizutani Yoichi , Miki Tsuneharu , Sakai Toshiyuki 
Published: September 2005

Abstract
Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor–related apoptosis–inducing ligand (TRAIL/Apo2L). In this study, we showed that tunicamycin, a naturally occurring antibiotic, is a potent enhancer of TRAIL-induced apoptosis through up-regulation of DR5 expression. Tunicamycin significantly sensitized PC-3, androgen-independent human prostate cancer cells, to TRAIL-induced apoptosis. The tunicamycin-mediated enhancement of TRAIL-induced apoptosis was markedly blocked by a recombinant human DR5/Fc chimeric protein. Tunicamycin and TRAIL cooperatively activated caspase-8, -10, -9, and -3 and Bid cleavage and this activation was also blocked in the presence of the DR5/Fc chimera. Tunicamycin up-regulated DR5 expression at the mRNA and protein levels in a dose-dependent manner. Furthermore, the tunicamycin-mediated sensitization to TRAIL was efficiently reduced by DR5 small interfering RNA, suggesting that the sensitization was mediated through induction of DR5 expression. Tunicamycin increased DR5 promoter activity and this enhanced activity was diminished by mutation of a CHOP-binding site. In addition, suppression of CHOP expression by small interfering RNA reduced the tunicamycin-mediated induction of DR5. Of note, tunicamycin-mediated induction of CHOP and DR5 protein expression was not observed in normal human peripheral blood mononuclear cells. Moreover, tunicamycin did not sensitize the cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may be a promising candidate for prostate cancer therapy.