bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular Transformation and Activation of the Phosphoinositide-3-Kinase–Akt Cascade by the ETV6-NTRK3 Chimeric Tyrosine Kinase Requires c-Src
Authors: Jin Wook , Yun Chohee , Hobbie Amy , Martin Matthew J. , Sorensen Poul H.B. , Kim Seong-Jin 
Published: April 2007

Abstract
The ETV6-NTRK3 (EN) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages, functions as a constitutively active protein-tyrosine kinase. ETV6-NTRK expression leads to the constitutive activation of two major effector pathways of wild-type NTRK3, namely, the Ras–mitogen-activated protein kinase (MAPK) mitogenic pathway and the phosphoinositide-3-kinase (PI3K)-Akt pathway mediating cell survival, and both are required for EN transformation. However, it remains unclear how ETV6-NTRK3 activates Ras-Erk1/2 and/or PI3K-Akt cascades. Here, we define some aspects of the molecular mechanisms regulating ETV6-NTRK–dependent Ras-Erk1/2 and PI3K-Akt activation. We show that ETV6-NTRK3 associates with c-Src, and that treatment with SU6656, a c-Src inhibitor, completely blocks ETV6-NTRK-transforming activity. Treatment of NIH3T3 cells expressing ETV6-NTRK3 with SU6656 attenuated the activation of Ras-Erk1/2 and PI3K-Akt. Suppression of c-Src by RNA interference in NIH3T3-ETV6-NTRK3 cells resulted in markedly decreased expression of cyclin D1 and suppression of activation of Ras-Erk1/2 and PI3K-Akt. However, in Src-deficient cells, the ETV6-NTRK3 failed to activate the PI3K-Atk pathway, but not the Ras-Erk1/2 pathway. Therefore, these data indicate that ETV6-NTRK3 induces the PI3K-Akt cascade through the activation of c-Src. [Cancer Res 2007;67(7):3192–200]
Induction of Cdc25B Regulates Cell Cycle Resumption after Genotoxic Stress
Authors: Bansal Pallavi , Lazo John S. 
Published: April 2007

Abstract
Cdc25 phosphatases propel cell cycle progression by activating cyclin-dependent kinases (Cdk). DNA damage is generally thought to inhibit Cdc25 functionality by inducing proteasomal degradation of Cdc25A and phosphorylation-mediated sequestration of Cdc25B and Cdc25C to the cytoplasm. More recently, a critical role for Cdc25B in the resumption of cell cycle progression through mitosis after DNA damage has been identified. In this study, the fate of Cdc25B after mechanistically distinct DNA-damaging agents (etoposide, cisplatin, bleomycin, ionizing irradiation, or UV irradiation) was examined, and surprisingly a rapid increase in cellular Cdc25B levels was observed after DNA damage. Using UV irradiation as the prototypic damaging agent, we found that the increase in Cdc25B levels was checkpoint dependent and was controlled by a p53-independent mechanism. Cdc25B levels controlled the number of cells progressing into mitosis after UV, but they did not affect G2-M checkpoint engagement immediately after DNA damage. Increased Cdc25B reduced the time required for cell cycle resumption. These data support a model in which Cdc25B accumulation is an important anticipatory event for cell cycle resumption after DNA damage. [Cancer Res 2007;67(7):3356–63]
2-Deoxy-d-Glucose Combined with Cisplatin Enhances Cytotoxicity via Metabolic Oxidative Stress in Human Head and Neck Cancer Cells
Authors: Simons Andrean L. , Ahmad Iman M. , Mattson David M. , Dornfeld Kenneth J. , Spitz Douglas R. 
Published: April 2007

AbstractGlucose deprivation has been hypothesized to cause cytotoxicity by inducing metabolic oxidative stress in human cancer cells. The current work tests the hypothesis that 2-deoxy-d-glucose (2DG) combined with cisplatin [cis-diamminedichloroplatinum(II)] can enhance cytotoxicity in human head and neck cancer cells (FaDu) by mechanisms involving oxidative stress. Exposure of FaDu cells to the combination of 2DG and cisplatin resulted in a significant decrease in cell survival when compared with 2DG or cisplatin alone. Treatment with 2DG and cisplatin also caused perturbations in parameters indicative of oxidative stress, including decreased intracellular total glutathione and increased percentage of glutathione disulfide. Simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC) inhibited parameters indicative of oxidative stress, as well as protected FaDu cells from the cytotoxic effects of cisplatin alone and the combination of 2DG and cisplatin. In addition, polyethylene glycol–conjugated antioxidant enzymes (PEG-superoxide dismutase and PEG-catalase) also protected FaDu cells from 2DG toxicity. An inhibitor of glutathione synthesis, l-buthionine-[S,R]-sulfoximine (BSO), sensitized FaDu cells to the cytotoxic effects of 2DG and cisplatin, and these effects were inhibited by NAC. Furthermore, the combination of 2DG, cisplatin, and BSO significantly increased the percentage of glutathione disulfide, which was also inhibited by NAC. These results support the hypothesis that exposure of human head and neck cancer cells to 2DG combined with cisplatin enhances cytotoxicity via metabolic oxidative stress. These findings provide a strong biochemical rationale for evaluating inhibitors of glucose and hydroperoxide metabolism in combination with cisplatin for the treatment of head and neck cancer. [Cancer Res 2007;67(7):3364–70]
Parthenolide Inhibits Tubulin Carboxypeptidase Activity
Authors: Fonrose Xavier , Ausseil Frédéric , Soleilhac Emmanuelle , Masson Véronique , David Bruno , Pouny Isabelle , Cintrat Jean-Christophe , Rousseau Bernard , Barette Caroline , Massiot Georges , Lafanechère Laurence 
Published: April 2007

AbstractMicrotubules are centrally involved in cell division, being the principal components of mitotic spindle. Tubulin, the constituent of microtubules, can be cyclically modified on its α-subunit by enzymatic removal of the COOH-terminal tyrosine residue by an ill-defined tubulin carboxypeptidase (TCP) and its readdition by tubulin tyrosine ligase (TTL). We and others have previously shown that suppression of TTL and resulting accumulation of detyrosinated tubulin are frequent in human cancers of poor prognosis. Explanations for the involvement of TTL and detyrosinated tubulin in tumor progression arise from the recent discovery that tubulin detyrosination leads to CAP-Gly protein mislocalization, which correlates with defects in spindle positioning during mitosis. Impaired control of spindle positioning is one factor favoring tumor invasiveness. Thus, TCP could be a target for developing novel therapeutic strategies against advanced stages of cancers. Inhibitors of TCP, by reversing abnormal detyrosinated tubulin accumulation in tumor cells, could impair tumor progression. TCP has never been isolated and this has hampered search of specific inhibitors. In this article, we describe a cell-based assay of TCP activity and its use to screen a library of natural extracts for their inhibitory potency. This led to the isolation of two sesquiterpene lactones. We subsequently found that parthenolide, a structurally related compound, can efficiently inhibit TCP. This inhibitory activity is a new specific property of parthenolide independent of its action on the nuclear factor-κB pathway. Parthenolide is also known for its anticancer properties. Thus, TCP inhibition could be one of the underlying mechanisms of these anticancer properties. [Cancer Res 2007;67(7):3371–8]
Six1 Overexpression in Ovarian Carcinoma Causes Resistance to TRAIL-Mediated Apoptosis and Is Associated with Poor Survival
Authors: Behbakht Kian , Qamar Lubna , Aldridge Carrie S. , Coletta Ricardo D. , Davidson Susan A. , Thorburn Andrew , Ford Heide L. 
Published: April 2007

Abstract
Tumorigenesis can arise from inappropriate activation of developmental genes in mature tissues. Here, we show that the developmental regulator Six1 is overexpressed in ovarian carcinoma cell lines (OCC) compared with normal ovarian surface epithelium. As observed in other cancers, Six1 overexpression in OCC leads to increased A-type cyclin expression and increased proliferation. In addition, Six1 overexpression renders OCC resistant to tumor necrosis factor–related apoptosis inducing ligand (TRAIL)–mediated apoptosis, and Six1 knockdown in the TRAIL-resistant SKOV3 ovarian carcinoma line dramatically sensitizes the cells to TRAIL. Because inactivation of the TRAIL response has been linked to metastasis, and because antibodies and recombinant ligand that activate the TRAIL pathway are currently in clinical trials against ovarian carcinoma, we screened normal ovarian and carcinoma specimens for Six1 mRNA. Six1 was overexpressed in 50% of the early-stage (stage I) and 63% of the late-stage (stages II, III, and IV) ovarian carcinomas examined, with late-stage carcinomas expressing ∼3-fold higher Six1 mRNA levels on average compared with early-stage tumors. Importantly, in patients with late-stage disease, high Six1 expression was associated with significantly shortened survival (P = 0.0015). These data suggest that Six1 may contribute to ovarian epithelial carcinogenesis by simultaneously increasing proliferation and decreasing TRAIL-mediated apoptosis and imply that Six1 may be an important determinant of TRAIL therapy response that should be considered in patient selection for TRAIL-related clinical trials. [Cancer Res 2007;67(7):3036–42]
Silibinin Inhibits Inflammatory and Angiogenic Attributes in Photocarcinogenesis in SKH-1 Hairless Mice
Authors: Gu Mallikarjuna , Singh Rana P. , Dhanalakshmi Sivanandhan , Agarwal Chapla , Agarwal Rajesh 
Published: April 2007

Abstract
Sunscreens partially filter UVB and, therefore, could partially prevent skin cancer; however, efficient approaches are desired to effectively prevent photocarcinogenesis. It is hypothesized that nontoxic pharmacologically active natural compounds can increase photoprotective effects. Our completed studies suggest that silibinin, a bioactive phytochemical, strongly prevents photocarcinogenesis; however, its mechanism is not fully understood. Herein, for the first time, we used a clinically relevant UVB dose (30 mJ/cm2/day) to examine the photoprotective effect and associated mechanisms of silibinin in SKH1 hairless mice. Topical or dietary silibinin treatment caused a strong protection against photocarcinogenesis in terms of delay in tumor appearance, multiplicity, and volume. Analyses of normal skin, uninvolved skin from tumor-bearing mice, and skin tumors showed a statistically significant decrease (P &lt; 0.05–0.001) in inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) levels by silibinin. Concomitantly, phospho–signal transducers and activators of transcription 3 (Tyr705) and phospho-p65(Ser536) were also decreased by silibinin, which are potential up-stream regulators of iNOS and COX-2. Simultaneously, silibinin also decreased UVB-caused increase in cell proliferation and microvessel density. In tumors, hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor protein levels were decreased by silibinin. Further analysis showed that silibinin inhibited UVB-caused phosphorylation and nuclear translocation of STAT3 and p65, as well as nuclear factor κB (NF-κB) DNA binding activity. Together, these results suggest that silibinin causes a strong protective effect against photocarcinogenesis via down-regulation of inflammatory and angiogenic responses, involving HIF-1α, STAT3, and NF-κB transcription factors, as well as COX2 and iNOS. [Cancer Res 2007;67(7):3483–91]
Cholesterol Starvation Induces Differentiation of Human Leukemia HL-60 Cells
Authors: Sánchez-Martín Carolina C. , Dávalos Alberto , Martín-Sánchez Covadonga , de la Peña Gema , Fernández-Hernando Carlos , Lasunción Miguel A. 
Published: April 2007

Abstract
Cholesterol metabolism is particularly active in malignant, proliferative cells, whereas cholesterol starvation has been shown to inhibit cell proliferation. Inhibition of enzymes involved in cholesterol biosynthesis at steps before the formation of 7-dehydrocholesterol has been shown to selectively affect cell cycle progression from G2 phase in human promyelocytic HL-60 cells. In the present work, we explored whether cholesterol starvation by culture in cholesterol-free medium and treatment with different distal cholesterol biosynthesis inhibitors induces differentiation of HL-60 cells. Treatment with SKF 104976, an inhibitor of lanosterol 14-α demethylase, or with zaragozic acid, which inhibits squalene synthase, caused morphologic changes alongside respiratory burst activity and expression of cluster of differentiation antigen 11c (CD11c) but not cluster of differentiation antigen 14. These effects were comparable to those produced by all-trans retinoic acid, which induces HL-60 cells to differentiate following a granulocyte lineage. In contrast, they differed from those produced by vitamin D3, which promotes monocyte differentiation. The specificity of the response was confirmed by addition of cholesterol to the culture medium. Treatment with PD 98059, an inhibitor of extracellular signal–regulated kinase, abolished both the activation of NADPH oxidase and the expression of the CD11c marker. In sharp contrast, BM 15766, which inhibits sterol Δ7-reductase, failed to induce differentiation or arrest cell proliferation. These results show that changes in the sterol composition may trigger a differentiation response and highlight the potential of cholesterol pathway inhibition as a possible tool for use in cancer therapy. [Cancer Res 2007;67(7):3379–86]
Mammalian Tumor Xenografts Induce Neovascularization in Zebrafish Embryos
Authors: Nicoli Stefania , Ribatti Domenico , Cotelli Franco , Presta Marco 
Published: April 2007

Abstract
The zebrafish (Danio rerio)/tumor xenograft model represents a powerful new model system in cancer. Here, we describe a novel exploitation of the zebrafish model to investigate tumor angiogenesis, a pivotal step in cancer progression and target for antitumor therapies. Human and murine tumor cell lines that express the angiogenic fibroblast growth factor (FGF) 2 and/or vascular endothelial growth factor (VEGF) induce the rapid formation of a new microvasculature when grafted close to the developing subintestinal vessels of zebrafish embryos at 48 h postfertilization. Instead, no angiogenic response was exerted by related cell clones defective in the production of these angiogenic growth factors. The newly formed blood vessels sprout from the subintestinal plexus of the zebrafish embryo, penetrate the tumor graft, and express the transcripts for the zebrafish orthologues of the early endothelial markers Fli-1, VEGF receptor-2 (VEGFR2/KDR), and VE-cadherin. Accordingly, green fluorescent protein–positive neovessels infiltrate the graft when tumor cells are injected in transgenic VEGFR2:G-RCFP zebrafish embryos that express green fluorescent protein under the control of the VEGFR2/KDR promoter. Systemic exposure of zebrafish embryos immediately after tumor cell injection to prototypic antiangiogenic inhibitors, including the FGF receptor tyrosine kinase inhibitor SU5402 and the VEGFR2/KDR tyrosine kinase inhibitor SU5416, suppresses tumor-induced angiogenesis without affecting normal blood vessel development. Accordingly, VE-cadherin gene inactivation by antisense morpholino oligonucleotide injection inhibits tumor neovascularization without affecting the development of intersegmental and subintestinal vessels. These data show that the zebrafish/tumor xenograft model represents a novel tool for investigating the neovascularization process exploitable for drug discovery and gene targeting in tumor angiogenesis. [Cancer Res 2007;67(7):2927–31]
Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (S-Farnesylthiosalicylic Acid)
Authors: Blum Roy , Elkon Ran , Yaari Shira , Zundelevich Adi , Jacob-Hirsch Jasmine , Rechavi Gideon , Shamir Ron , Kloog Yoel 
Published: April 2007

AbstractDeregulation of Ras pathways results in complex abnormalities of multiple signaling cascades that contribute to human malignancies. Ras is therefore considered an appropriate target for cancer therapy. In light of the complexity of the deregulated Ras pathway, it is important to decipher at the molecular level the response of cancer cells to Ras inhibitors that would reregulate it. In the present study, we used gene expression profiling as a robust method for the global dissection of gene expression alterations that resulted from treatment with the Ras inhibitor S-farnesylthiosalicylic acid (FTS; salirasib). Use of a ranking-based procedure, combined with functional analysis and promoter sequence analysis, enabled us to decipher the common and most prominent patterns of the transcriptional response of five different human cancer cell lines to FTS. Remarkably, the analysis identified a distinctive core transcriptional response to FTS that was common to all cancer cell lines tested. This signature fits well to a recently described deregulated Ras pathway signature that predicted sensitivity to FTS. Taken together, these studies provide strong support for the conclusion that FTS specifically reregulates defective Ras pathways in human tumor cells. Ras pathway reregulation by FTS was manifested by repression of E2F-regulated and NF-Y–regulated genes and of the transcription factor FOS (all of which control cell proliferation), repression of survivin expression (which blocks apoptosis), and induction of activating transcription factor–regulated and Bach2-regulated genes (which participate in translation and stress responses). Our results suggest that cancer patients with deregulated Ras pathway tumors might benefit from FTS treatment. [Cancer Res 2007;67(7):3320–8]
Hyperthermia Activates a Subset of Ataxia-Telangiectasia Mutated Effectors Independent of DNA Strand Breaks and Heat Shock Protein 70 Status
Authors: Hunt Clayton R. , Pandita Raj K. , Laszlo Andrei , Higashikubo Ryuji , Agarwal Manjula , Kitamura Tetsuya , Gupta Arun , Rief Nicole , Horikoshi Nobuo , Baskaran Rajeskaran , Lee Ji-Hoon , Löbrich Markus , Paull Tanya T. , Roti Roti Joseph L. , Pandita Tej K. 
Published: April 2007

Abstract
All cells have intricately coupled sensing and signaling mechanisms that regulate the cellular outcome following exposure to genotoxic agents such as ionizing radiation (IR). In the IR-induced signaling pathway, specific protein events, such as ataxia-telangiectasia mutated protein (ATM) activation and histone H2AX phosphorylation (γ-H2AX), are mechanistically well characterized. How these mechanisms can be altered, especially by clinically relevant agents, is not clear. Here we show that hyperthermia, an effective radiosensitizer, can induce several steps associated with IR signaling in cells. Hyperthermia induces γ-H2AX foci formation similar to foci formed in response to IR exposure, and heat-induced γ-H2AX foci formation is dependent on ATM but independent of heat shock protein 70 expression. Hyperthermia also enhanced ATM kinase activity and increased cellular ATM autophosphorylation. The hyperthermia-induced increase in ATM phosphorylation was independent of Mre11 function. Similar to IR, hyperthermia also induced MDC1 foci formation; however, it did not induce all of the characteristic signals associated with irradiation because formation of 53BP1 and SMC1 foci was not observed in heated cells but occurred in irradiated cells. Additionally, induction of chromosomal DNA strand breaks was observed in IR-exposed but not in heated cells. These results indicate that hyperthermia activates signaling pathways that overlap with those activated by IR-induced DNA damage. Moreover, prior activation of ATM or other components of the IR-induced signaling pathway by heat may interfere with the normal IR-induced signaling required for chromosomal DNA double-strand break repair, thus resulting in increased cellular radiosensitivity. [Cancer Res 2007;67(7):3010–7]
Detection of DNA Copy Number Changes and Oncogenic Signaling Abnormalities from Gene Expression Data RevealsMYCActivation in High-Grade Papillary Renal Cell Carcinoma
Authors: Furge Kyle A. , Chen Jindong , Koeman Julie , Swiatek Pamela , Dykema Karl , Lucin Kseniji , Kahnoski Richard , Yang Ximing J. , Teh Bin Tean 
Published: April 2007

AbstractPapillary renal cell carcinoma (RCC) represents 10% to 15% of adult renal neoplasms; however, the molecular genetic events that are associated with the development and progression of sporadic papillary RCC remain largely unclear. Papillary RCCs can be divided into two subtypes based on histologic, cytogenetic, and gene expression differences. Type 1 tumors (∼60–70%) are generally low grade with favorable outcome, whereas type 2 tumors (∼30–40%) are associated with increased cytogenetic complexity, high tumor grade, and poor prognosis. In this study, computational analysis of gene expression data derived from papillary RCC revealed that a transcriptional signature indicative of MYC pathway activation is present in high-grade type 2 papillary RCC. The MYC signature is associated with amplification of chromosome 8q and overexpression of MYC that maps to chromosome 8q24. The importance of MYC activation was confirmed by both pharmacologic and short interfering RNA–mediated inhibition of active Myc signaling in a cell line model of type 2 papillary RCC. These results provide both computational and genetic evidence that activation of Myc is associated with the aggressiveness of papillary type 2 RCC. Therefore, it will be useful to consider inhibition of components of the MYC signaling pathway as avenues for therapeutic intervention in high-grade papillary RCC. [Cancer Res 2007;67(7):3171–6]
Targeting Multiple Arms of the Apoptotic Regulatory Machinery
Authors: Dai Yun , Grant Steven 
Published: April 2007

Abstract
ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which confers resistance to this novel agent. Here, we summarize recent findings indicating that Mcl-1 represents a critical determinant of ABT-737 sensitivity and resistance, and that Mcl-1 down-regulation by various pharmacologic agents or genetic approaches dramatically increases ABT-737 lethality in diverse malignant cell types. These findings also show that the multidomain proapoptotic proteins Bax and Bak play important functional roles in ABT-737–mediated apoptosis, and that Bak activation is essential in potentiation of ABT-737 lethality by agents that down-regulate Mcl-1. Collectively, these findings suggest a novel therapeutic strategy targeting multiple arms of the apoptotic machinery. [Cancer Res 2007;67(7):2908–11]
Natural killer cell–derived human granzyme H induces an alternative, caspase-independent cell-death program
Authors: Fellows Edward , Gil-Parrado Shirley , Jenne Dieter E. , Kurschus Florian C. 
Published: April 2007

AbstractGranzyme H (GzmH) belongs to a family of 5 human serine proteases that are expressed by cytotoxic immune effector cells. Although GzmH is most closely related to the caspase-activating granzyme B (GzmB), neither a natural substrate nor a role in immune defense reactions has been demonstrated for this orphan granzyme. In rodents, multiple related genes exist, but none of these can be regarded as functional homologs. Here we show that host cells are efficiently killed by GzmH after perforin and streptolysin O–mediated delivery into the cytosol. Dying cells show typical hallmarks of programmed cell death, such as mitochondrial depolarization, reactive oxygen species (ROS) generation, DNA degradation, and chromatin condensation. Contrary to GzmB, cell death by GzmH does not involve the activation of executioner caspases, the cleavage of Bid or inhibitor of caspase-activated DNase (ICAD), or the release of cytochrome c. The high expression levels of GzmH in naive natural killer (NK) cells and its potent killing ability strongly support the role of the protease in triggering an alternative cell-death pathway in innate immunity.