bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drosophila split ends Homologue SHARP Functions as a Positive Regulator of Wnt/β-Catenin/T-Cell Factor Signaling in Neoplastic Transformation
Authors: Feng Ying , Bommer Guido T. , Zhai Yali , Akyol Aytekin , Hinoi Takao , Winer Ira , Lin Hua V. , Cadigan Ken M. , Cho Kathleen R. , Fearon Eric R. 
Published: January 2007

Abstract
Wnt ligands have pleiotropic and context-specific roles in embryogenesis and adult tissues. Among other effects, certain Wnts stabilize the β-catenin protein, leading to the ability of β-catenin to activate T-cell factor (TCF)-mediated transcription. Mutations resulting in constitutive β-catenin stabilization underlie development of several human cancers. Genetic studies in Drosophila highlighted the split ends (spen) gene as a positive regulator of Wnt-dependent signaling. We have assessed the role of SHARP, a human homologue of spen, in Wnt/β-catenin/TCF function in mammalian cells. We found that SHARP gene and protein expression is elevated in human colon and ovarian endometrioid adenocarcinomas and mouse colon adenomas and carcinomas carrying gene defects leading to β-catenin dysregulation. When ectopically expressed, the silencing mediator for retinoid and thyroid receptors/histone deacetylase 1-associated repressor protein (SHARP) protein potently enhanced β-catenin/TCF transcription of a model reporter gene and cellular target genes. Inhibition of endogenous SHARP function via RNA inhibitory (RNAi) approaches antagonized β-catenin/TCF-mediated activation of target genes. The effect of SHARP on β-catenin/TCF-regulated genes was mediated via a functional interaction between SHARP and TCF. β-Catenin–dependent neoplastic transformation of RK3E cells was enhanced by ectopic expression of SHARP, and RNAi-mediated inhibition of endogenous SHARP in colon cancer cells inhibited their transformed growth. In toto, our findings implicate SHARP as an important positive regulator of Wnt signaling in cancers with β-catenin dysregulation. [Cancer Res 2007;67(2):482–91]
Human Bone Marrow Activates the Akt Pathway in Metastatic Prostate Cells through Transactivation of the α-Platelet–Derived Growth Factor Receptor
Authors: Dolloff Nathan G. , Russell Mike R. , Loizos Nick , Fatatis Alessandro 
Published: January 2007

Abstract
The factors regulating the bone tropism of disseminated prostate cancer cells are still vaguely defined. We report that prostate cancer cells that metastasize to the skeleton respond to human bone marrow with a robust stimulation of the phosphatidylinositol 3-kinase/Akt pathway, whereas prostate cells that lack bone-metastatic potential respond negligibly. The majority of this Akt activation is dependent on α-platelet–derived growth factor receptor (α-PDGFR) signaling, which was shown using the small-molecule inhibitor of PDGFR signaling AG1296. Low concentrations of PDGF-AA and PDGF-BB found in bone marrow aspirates, which were detected by ELISA, do not account for the high levels of α-PDGFR signaling. Additionally, neutralizing PDGF binding using a α-PDGFR–specific antibody (IMC-3G3) failed to produce a significant inhibition of bone marrow–induced Akt activation. However, the inhibitory effect of IMC-3G3 rivaled that of AG1296 when incubation was done under conditions that stimulated α-PDGFR internalization. We conclude that α-PDGFR is activated by multiple soluble factors contained within human bone marrow, in addition to its natural ligands, and this transactivation is dependent on receptor localization to the plasma membrane. Therefore, α-PDGFR expression may provide select prostate phenotypes with a growth advantage within the bone microenvironment. [Cancer Res 2007;67(2):555–62]
Increased β1 Integrin Is Associated with Decreased Survival in Invasive Breast Cancer
Authors: Yao Evelyn S. , Zhang Hui , Chen Yunn-Yi , Lee Brian , Chew Karen , Moore Dan , Park Catherine 
Published: January 2007

Abstract
Aberrant microenvironments and loss of balance in cell-extracellular matrix signaling are associated with breast cancer invasion, metastasis, and resistance to therapy. We have recently shown that increased β1 integrin signaling is involved in malignant progression and that inhibitory antibody to β1 integrin leads to selective apoptosis and decreased proliferation in three-dimensional cultures and in xenograft models of breast cancer in vivo. To investigate the clinical importance of these findings, in the present study we examined the expression of β1 integrin and extracellular β1 integrin ligands fibronectin and laminin-1 in a cohort of 249 breast cancer patients who had a median follow-up of 8.4 years. Among the 149 scorable cases, the highest β1 integrin intensity score (3+ versus 0–2+) was associated with significantly decreased 10-year overall survival of 48% versus 71% (P &lt; 0.03) and decreased disease-free survival of 50% versus 80% (P &lt; 0.05). Importantly, high fibronectin expression was associated with decreased overall and disease-free survival on univariate analysis (P &lt; 0.04) and β1 integrin intensity score was significantly correlated with fibronectin expression (Kendall's tau-b = 0.19; P = 0.03). In a multivariate Cox proportional hazards model, β1 integrin intensity score remained a significant independent predictor of overall survival [hazard ratio (HR), 1.69; 95% confidence interval (95% CI), 1.19–2.38; P &lt; 0.003] and disease-free survival (HR, 1.87; 95% CI, 1.21–2.88; P &lt; 0.005). These findings show that β1 integrin expression has potential prognostic value in invasive breast cancer and that coexpression of fibronectin may help identify patients with more aggressive tumors who may benefit from targeted therapy. [Cancer Res 2007;67(2):659–64]
A Novel Mechanism of Resistance to Epidermal Growth Factor Receptor Antagonism In vivo
Authors: Rajput Ashwani , Koterba Alan P. , Kreisberg Jeffrey I. , Foster Jason M. , Willson James K.V. , Brattain Michael G. 
Published: January 2007

Abstract
Epidermal growth factor receptor (EGFR) is widely expressed in a number of solid tumors including colorectal cancers. Overexpression of this receptor is one means by which a cell can achieve positive signals for survival and proliferation; another effective means is by constitutive activation of EGFR. We have elucidated the role of constitutive EGFR signaling in malignant progression by stably transfecting colon cancer cells with a human transforming growth factor-α cDNA (a ligand for EGFR) under repressible control by tetracycline. We show that constitutive expression of transforming growth factor-α and its subsequent constitutive activation of EGFR allows for cancer cell survival in response to environmental stress in vitro and in vivo as well. The reversal of constitutive EGFR activation results in the loss of downstream mitogen-activated protein kinase and Akt activation, and a reduction in xenograft size that is associated with decreased proliferation and increased apoptosis. We used CI-1033, a small molecule antagonist of EGFR, to dissect an activation pathway that shows the ability of ERBb2 to activate Akt, but not Erk in the face of EGFR antagonism. This novel escape mechanism is a possible explanation of why anti-EGFR therapies have shown disappointing results in clinical trials. [Cancer Res 2007;67(2):665–73]
O6-Methylguanine-DNA Methyltransferase Regulation by p53 in Astrocytic Cells
Authors: Blough Michael D. , Zlatescu Magdalena C. , Cairncross J. Gregory 
Published: January 2007

Abstract
Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter (i.e., gene silencing) occurs in 40% to 50% of patients with glioblastoma and predicts benefit from temozolomide chemotherapy; when unmethylated, MGMT repairs DNA damage induced by temozolomide, contributing to chemoresistance. In this study, we tested the hypothesis that MGMT is regulated by p53 in astrocytic cells, the precursors of which may give rise to glioblastoma. p53 is of interest because, in addition to often being mutated in glioblastoma, inactivation sensitizes some astrocytoma cell lines to temozolomide. MGMT expression was examined in neonatal murine astrocytes and SF767 human astrocytic glioma cells following p53 inactivation by knockout (murine only) or RNAi methods. MGMT mRNA and protein were detected in murine wild-type p53 astrocytes. However, in knockout murine astrocytes and wild-type cells in which p53 was inhibited by RNAi, MGMT expression was reduced by &gt;90%. This effect of p53 on MGMT expression was unrelated to MGMT promoter methylation—in both wild-type and p53-null astrocytes, the MGMT promoter was unmethylated. In wild-type astrocytes, the p53 protein localized to a regulatory region of the MGMT promoter. In SF767 human astrocytic glioma cells, transient knockdown of p53 led to the down-regulation of MGMT gene expression. In murine astrocytes and SF767 cells, p53 regulates MGMT expression without affecting promoter methylation; in astrocytes, this effect may be due to direct binding of p53 to the MGMT promoter. These results imply that the best use of temozolomide requires a thorough understanding of MGMT regulation. [Cancer Res 2007;67(2):580–4]
Systemic Efficacy with Oncolytic Virus Therapeutics: Clinical Proof-of-Concept and Future Directions
Authors: Liu Ta-Chiang , Kirn David 
Published: January 2007

Abstract
Oncolytic viruses that can destroy cancer cells have been engineered in a variety of ways with the aim of improving their selectivity and efficacy. Here, we review data from clinical investigations of these virotherapeutic agents, specifically those that have shown systemic efficacy: vaccinia, measles, mumps, viruses, Newcastle disease virus, and reovirus. Further directions for optimizing i.v. delivery and efficacy are discussed. [Cancer Res 2007;67(2):429–32]
Single Chemical Modifications of the C-1027 Enediyne Core, a Radiomimetic Antitumor Drug, Affect Both Drug Potency and the Role of Ataxia-Telangiectasia Mutated in Cellular Responses to DNA Double-Strand Breaks
Authors: Kennedy Daniel R. , Gawron Loretta S. , Ju Jianhua , Liu Wen , Shen Ben , Beerman Terry A. 
Published: January 2007

Abstract
The radiomimetic enediyne C-1027 induces almost exclusively DNA double-strand breaks (DSB) and is extremely cytotoxic. Unique among radiomimetics, ataxia-telangiectasia mutated (ATM) is dispensable for cellular responses to C-1027-induced DNA damage. This study explores the biological activity of three recently bioengineered C-1027 analogues: 7″-desmethyl-C-1027 (desmethyl), 20′-deschloro-C-1027 (deschloro), and 22′-deshydroxy-C-1027 (deshydroxy). Each compound maintains the characteristic ability of radiomimetics to cleave DNA in cell-free systems, varying in activity from 2-fold (deschloro) to 55-fold (desmethyl) less than C-1027. The induction of cellular DNA breaks based on pulsed field gel electrophoresis, comet analysis, and γH2AX activation was in the same rank order as cell-free DNA break induction, although the amount of breaks induced by desmethyl is greatly reduced compared with the other analogues. Despite the disparity in inducing DNA DSBs, all of the analogues produced G2-M cell cycle arrest and activated DNA DSB damage response proteins, such as p53-Ser15 and Chk2-Thr68, at concentrations in concordance with their ability to inhibit cell growth. Interestingly, of the three analogues, only the desmethyl-induced DNA damage response was similar to C-1027, as it did not cause hypersensitive cell growth inhibition in the absence of ATM nor require the kinase to phosphorylate p53 or Chk2. These findings show that simple modifications of the chromophore of C-1027 can result in varied induction of, and cellular response to, DNA DSBs. [Cancer Res 2007;67(2):773–81]
Nur77 Agonists Induce Proapoptotic Genes and Responses in Colon Cancer Cells through Nuclear Receptor–Dependent and Nuclear Receptor–Independent Pathways
Authors: Cho Sung Dae , Yoon Kyungsil , Chintharlapalli Sudhakar , Abdelrahim Maen , Lei Ping , Hamilton Stanley , Khan Shaheen , Ramaiah Shashi K. , Safe Stephen 
Published: January 2007

Abstract
Nerve growth factor–induced Bα (NGFI-Bα, Nur77) is an orphan nuclear receptor with no known endogenous ligands; however, recent studies on a series of methylene-substituted diindolylmethanes (C-DIM) have identified 1,1-bis(3′-indolyl)-1-(phenyl)methane (DIM-C-Ph) and 1,1-bis(3′-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) as Nur77 agonists. Nur77 is expressed in several colon cancer cell lines (RKO, SW480, HCT-116, HT-29, and HCT-15), and we also observed by immunostaining that Nur77 was overexpressed in colon tumors compared with normal colon tissue. DIM-C-Ph and DIM-C-pPhOCH3 decreased survival and induced apoptosis in RKO colon cancer cells, and this was accompanied by induction of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) protein. The induction of apoptosis and TRAIL by DIM-C-pPhOCH3 was significantly inhibited by a small inhibitory RNA for Nur77 (iNur77); however, it was evident from RNA interference studies that DIM-C-pPhOCH3 also induced Nur77-independent apoptosis. Analysis of DIM-C-pPhOCH3–induced gene expression using microarrays identified several proapoptotic genes, and analysis by reverse transcription-PCR in the presence or absence of iNur77 showed that induction of programmed cell death gene 1 was Nur77 dependent, whereas induction of cystathionase and activating transcription factor 3 was Nur77 independent. DIM-C-pPhOCH3 (25 mg/kg/d) also inhibited tumor growth in athymic nude mice bearing RKO cell xenografts. These results show that Nur77-active C-DIM compounds represent a new class of anti–colon cancer drugs that act through receptor-dependent and receptor-independent pathways. [Cancer Res 2007;67(2):674–83]
Inhibition of Indoleamine 2,3-Dioxygenase in Dendritic Cells by Stereoisomers of 1-Methyl-Tryptophan Correlates with Antitumor Responses
Authors: Hou De-Yan , Muller Alexander J. , Sharma Madhav D. , DuHadaway James , Banerjee Tinku , Johnson Maribeth , Mellor Andrew L. , Prendergast George C. , Munn David H. 
Published: January 2007

AbstractIndoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that contributes to tolerance in a number of biological settings. In cancer, IDO activity may help promote acquired tolerance to tumor antigens. The IDO inhibitor 1-methyl-tryptophan is being developed for clinical trials. However, 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties, and it has been unclear which isomer might be preferable for initial development. In this study, we provide evidence that the d and l stereoisomers exhibit important cell type–specific variations in activity. The l isomer was the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell–based assays. However, the d isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte–derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the d isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The d isomer of 1-methyl-tryptophan specifically targeted the IDO gene because the antitumor effect of d-1-methyl-tryptophan was completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Taken together, our findings support the suitability of d-1-methyl-tryptophan for human trials aiming to assess the utility of IDO inhibition to block host-mediated immunosuppression and enhance antitumor immunity in the setting of combined chemo-immunotherapy regimens. [Cancer Res 2007;67(2):792–801]
The Inflammatory Cytokine Tumor Necrosis Factor-α Generates an Autocrine Tumor-Promoting Network in Epithelial Ovarian Cancer Cells
Authors: Kulbe Hagen , Thompson Richard , Wilson Julia L. , Robinson Stephen , Hagemann Thorsten , Fatah Rewas , Gould David , Ayhan Ayse , Balkwill Frances 
Published: January 2007

Abstract
Constitutive expression of the inflammatory cytokine tumor necrosis factor-α (TNF-α) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF-α generates and sustains a network of other mediators that promote peritoneal cancer growth and spread. When compared with two ovarian cancer cell lines that did not make TNF-α, constitutive production of TNF-α was associated with greater release of the chemokines CCL2 and CXCL12, the cytokines interleukin-6 (IL-6) and macrophage migration-inhibitory factor (MIF), and the angiogenic factor vascular endothelial growth factor (VEGF). TNF-α production was associated also with increased peritoneal dissemination when the ovarian cancer cells were xenografted. We next used RNA interference to generate stable knockdown of TNF-α in ovarian cancer cells. Production of CCL2, CXCL12, VEGF, IL-6, and MIF was decreased significantly in these cells compared with wild-type or mock-transfected cells, but in vitro growth rates were unaltered. Tumor growth and dissemination in vivo were significantly reduced when stable knockdown of TNF-α was achieved. Tumors derived from TNF-α knockdown cells were noninvasive and well circumscribed and showed high levels of apoptosis, even in the smallest deposits. This was reflected in reduced vascularization of TNF-α knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF-α by ovarian cancer cells stimulates a constitutive network of other cytokines, angiogenic factors, and chemokines that may act in an autocrine/paracrine manner to promote colonization of the peritoneum and neovascularization of developing tumor deposits. [Cancer Res 2007;67(2):585–92]
Activation of Integrin-Linked Kinase Is a Critical Prosurvival Pathway Induced in Leukemic Cells by Bone Marrow–Derived Stromal Cells
Authors: Tabe Yoko , Jin Linhua , Tsutsumi-Ishii Yuko , Xu Yuanyuan , McQueen Teresa , Priebe Waldemar , Mills Gordon B. , Ohsaka Akimichi , Nagaoka Isao , Andreeff Michael , Konopleva Marina 
Published: January 2007

Abstract
Integrin-linked kinase (ILK) directly interacts with β integrins and phosphorylates Akt in a phosphatidylinositol 3-kinase (PI3K)–dependent manner. In this study, we examined the functional role of ILK activation in leukemic and bone marrow stromal cells on their direct contact. Coculture of leukemic NB4 cells with bone marrow–derived stromal mesenchymal stem cells (MSC) resulted in robust activation of multiple signaling pathways, including ILK/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducers and activators of transcription 3 (STAT3), and Notch1/Hes. Blockade of PI3K or ILK signaling with pharmacologic inhibitors LY294002 or QLT0267 specifically inhibited stroma-induced phosphorylation of Akt and glycogen synthase kinase 3β, suppressed STAT3 and ERK1/2 activation, and decreased Notch1 and Hes1 expression in leukemic cells. This resulted in induction of apoptosis in both leukemic cell lines and in primary acute myelogenous leukemia samples that was not abrogated by MSC coculture. In turn, leukemic cells growing in direct contact with bone marrow stromal elements induce activation of Akt, ERK1/2, and STAT3 signaling in MSC, accompanied by significant increase in Hes1 and Bcl-2 proteins, which were all suppressed by QLT0267 and LY294002. In summary, our results indicate reciprocal activation of ILK/Akt in both leukemic and bone marrow stromal cells. We propose that ILK/Akt is a proximal signaling pathway critical for survival of leukemic cells within the bone marrow microenvironment. Hence, disruption of these interactions by ILK inhibitors represents a potential novel therapeutic strategy to eradicate leukemia in the bone marrow microenvironment by simultaneous targeting of both leukemic cells and activated bone marrow stromal cells. [Cancer Res 2007;67(2):684–94]
2-Methoxyestradiol Inhibits the Anaphase-Promoting Complex and Protein Translation in Human Breast Cancer Cells
Authors: Bhati Rajendra , Gökmen-Polar Yesim , Sledge George W. , Fan Cheng , Nakshatri Harikrishna , Ketelsen David , Borchers Christoph H. , Dial Michael J. , Patterson Cam , Klauber-DeMore Nancy 
Published: January 2007

Abstract
2-Methoxyestradiol (2ME2), an estradiol metabolite with antiproliferative and antiangiogenic activities, is in phase I/II clinical trials for breast cancer. 2ME2 inhibits microtubule polymerization and causes cells to arrest in G2-M. The purpose of this study was to further elucidate the molecular mechanism of 2ME2. MDA-MB-435 breast cancer cells were treated with 2ME2 (2 μmol/L) or vehicle alone. RNA was extracted and genomic profiling was done using 22k Agilent microarrays. Expression Analysis Systematic Explorer was used to determine enrichment of Gene Ontology categories. Protein isolates were subjected to Western blot analysis. Protein synthesis was measured with a [35S]methionine pulse assay. An MDA-MB-435 cell line with two β-tubulin mutations (2ME2R) was used to determine whether novel mechanisms were tubulin-dependent. Gene Ontology categories enriched include genes that regulate the mitotic spindle assembly checkpoint, apoptosis, and the cytosolic ribosome. The target of the mitotic spindle assembly checkpoint is the anaphase-promoting complex (APC). APC inhibition was confirmed by measuring protein levels of its targets securin and cyclin B1, which were increased in 2ME2-treated cells. Because gene expression in the cytosolic ribosome category was decreased, we evaluated whether 2ME2 decreases protein translation. This was confirmed with a pulse assay, which showed decreased isotope incorporation in 2ME2-treated cells, which was maintained in the tubulin-resistant 2ME2R cells. APC inhibition was not maintained in 2ME2R cells. 2ME2 induces tubulin-dependent cell cycle arrest through regulation of genes involved in the mitotic spindle assembly checkpoint, which results in inhibition of the APC and tubulin-independent inhibition of protein translation. [Cancer Res 2007;67(2):702–8]