bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitors of Ubiquitin-Activating Enzyme (E1), a New Class of Potential Cancer Therapeutics
Authors: Yang Yili , Kitagaki Jirouta , Dai Ren-Ming , Tsai Yien Che , Lorick Kevin L. , Ludwig Robert L. , Pierre Shervon A. , Jensen Jane P. , Davydov Ilia V. , Oberoi Pankaj , Li Chou-Chi H. , Kenten John H. , Beutler John A. , Vousden Karen H. , Weissman Allan M. 
Published: October 2007

AbstractThe conjugation of proteins with ubiquitin plays numerous regulatory roles through both proteasomal-dependent and nonproteasomal-dependent functions. Alterations in ubiquitylation are observed in a wide range of pathologic conditions, including numerous malignancies. For this reason, there is great interest in targeting the ubiquitin-proteasome system in cancer. Several classes of proteasome inhibitors, which block degradation of ubiquitylated proteins, are widely used in research, and one, Bortezomib, is now in clinical use. Despite the well-defined and central role of the ubiquitin-activating enzyme (E1), no cell permeable inhibitors of E1 have been identified. Such inhibitors should, in principle, block all functions of ubiquitylation. We now report 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41) as the first such inhibitor. Unexpectedly, in addition to blocking ubiquitylation, PYR-41 increased total sumoylation in cells. The molecular basis for this is unknown; however, increased sumoylation was also observed in cells harboring temperature-sensitive E1. Functionally, PYR-41 attenuates cytokine-mediated nuclear factor-κB activation. This correlates with inhibition of nonproteasomal (Lys-63) ubiquitylation of TRAF6, which is essential to IκB kinase activation. PYR-41 also prevents the downstream ubiquitylation and proteasomal degradation of IκBα. Furthermore, PYR-41 inhibits degradation of p53 and activates the transcriptional activity of this tumor suppressor. Consistent with this, it differentially kills transformed p53-expressing cells. Thus, PYR-41 and related pyrazones provide proof of principle for the capacity to differentially kill transformed cells, suggesting the potential for E1 inhibitors as therapeutics in cancer. These inhibitors can also be valuable tools for studying ubiquitylation. [Cancer Res 2007;67(19):9472–81]
Heat Shock Protein 90α Recruits FLIPS to the Death-Inducing Signaling Complex and Contributes to TRAIL Resistance in Human Glioma
Authors: Panner Amith , Murray Joseph C. , Berger Mitchel S. , Pieper Russell O. 
Published: October 2007

AbstractHeat shock protein 90 (HSP90) is a molecular chaperone that contributes to the proper folding and stability of target proteins. Because HSP90 has been suggested to interact with FLIPS, the key regulator of tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL)–induced apoptosis in glioma cells, we examined the role HSP90 played in controlling TRAIL response. HSP90α was found to associate with FLIPS in resting cells in a manner dependent on the ATP-binding NH2-terminal domain of HSP90α. Following TRAIL exposure, HSP90α and the client FLIPS protein were recruited to the death-inducing signaling complex (DISC). Short interfering RNA–mediated suppression of HSP90α did not alter the total cellular levels of FLIPS, but rather inhibited the recruitment of FLIPS and other antiapoptotic proteins such as RIP and FLIPL to the DISC, and sensitized otherwise resistant glioma cells to TRAIL-induced apoptosis. These results show that HSP90α, by localizing FLIPS to the DISC, plays a key role in the resistance of tumor cells to TRAIL, and perhaps other proapoptotic agents. The results also define a novel means of apoptotic control by a HSP90α that may in turn help explain the global antiapoptotic effects of this protein. [Cancer Res 2007;67(19):9482–9]
Reduction in IκB Kinase α Expression Promotes the Development of Skin Papillomas and Carcinomas
Authors: Park Eunmi , Zhu Feng , Liu Bigang , Xia Xiaojun , Shen Jianjun , Bustos Tracie , Fischer Susan M. , Hu Yinling 
Published: October 2007

Abstract
We reported recently a marked reduction in IκB kinase α (IKKα) expression in a large proportion of human poorly differentiated squamous cell carcinomas (SCC) and the occurrence of Ikkα mutations in human SCCs. In addition, overexpression of IKKα in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKKα expression promotes skin tumor development is currently unknown. Here, we assessed the susceptibility of Ikkα hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikkα+/− mice developed 2 times more papillomas and 11 times more carcinomas than did Ikkα+/+ mice. The tumors were larger in Ikkα+/− than in Ikkα+/+ mice, but tumor latency was shorter in Ikkα+/− than in Ikkα+/+ mice. Some of the Ikkα+/− papillomas and most Ikkα+/− carcinomas lost the remaining Ikkα wild-type allele. Somatic Ikkα mutations were detected in carcinomas and papillomas. The chemical carcinogen-induced H-Ras mutations were detected in all the tumors. The phorbol ester tumor promoter induced higher mitogenic and angiogenic activities in Ikkα+/− than in Ikkα+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKKα expression provided a selective growth advantage, which cooperated with H-Ras mutations to promote papilloma formation. Furthermore, excessive extracellular signal-regulated kinase and IKK kinase activities were observed in carcinomas compared with those in papillomas. Thus, the combined mitogenic, angiogenic, and IKK activities might contribute to malignant conversion. Our findings provide evidence that a reduction in IKKα expression promotes the development of papillomas and carcinomas and that the integrity of the Ikkα gene is required for suppressing skin carcinogenesis. [Cancer Res 2007;67(19):9158–68]
The Multikinase Inhibitor Sorafenib Potentiates TRAIL Lethality in Human Leukemia Cells in Association with Mcl-1 and cFLIPL Down-regulation
Authors: Rosato Roberto R. , Almenara Jorge A. , Coe Stefanie , Grant Steven 
Published: October 2007

Abstract
Interactions between the multikinase inhibitor sorafenib and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were examined in malignant hematopoietic cells. Pretreatment (24 h) of U937 leukemia cells with 7.5 μmol/L sorafenib dramatically increased apoptosis induced by sublethal concentrations of TRAIL/Apo2L (75 ng/mL). Similar interactions were observed in Raji, Jurkat, Karpas, K562, U266 cells, primary acute myelogenous leukemia blasts, but not in normal CD34+ bone marrow cells. Sorafenib/TRAIL–induced cell death was accompanied by mitochondrial injury and release of cytochrome c, Smac, and AIF into the cytosol and caspase-9, caspase-3, caspase-7, and caspase-8 activation. Sorafenib pretreatment down-regulated Bcl-xL and abrogated Mcl-1 expression, whereas addition of TRAIL sharply increased Bid activation, conformational change of Bak (ccBak) and Bax (ccBax), and Bax translocation. Ectopic Mcl-1 expression significantly attenuated sorafenib/TRAIL–mediated lethality and dramatically reduced ccBak while minimally affecting levels of ccBax. Similarly, inhibition of the receptor-mediated apoptotic cascade with a caspase-8 dominant-negative mutant significantly blocked sorafenib/TRAIL–induced lethality but not Mcl-1 down-regulation or Bak/Bax conformational change, indicating that TRAIL-mediated receptor pathway activation is required for maximal lethality. Sorafenib/TRAIL did not increase expression of DR4/DR5, or recruitment of procaspase-8 or FADD to the death-inducing signaling complex (DISC), but strikingly increased DISC-associated procaspase-8 activation. Sorafenib also down-regulated cFLIPL, most likely through a translational mechanism, in association with diminished eIF4E phosphorylation, whereas ectopic expression of cFLIPL significantly reduced sorafenib/TRAIL lethality. Together, these results suggest that in human leukemia cells, sorafenib potentiates TRAIL-induced lethality by down-regulating Mcl-1 and cFLIPL, events that cooperate to engage the intrinsic and extrinsic apoptotic cascades, culminating in pronounced mitochondrial injury and apoptosis. [Cancer Res 2007;67(19):9490–500]
Serial Assessment of Human Tumor Burdens in Mice by the Analysis of Circulating DNA
Authors: Rago Carlo , Huso David L. , Diehl Frank , Karim Baktiar , Liu Guosheng , Papadopoulos Nickolas , Samuels Yardena , Velculescu Victor E. , Vogelstein Bert , Kinzler Kenneth W. , Diaz Luis A. 
Published: October 2007

Abstract
Internal human xenografts provide valuable animal models to study the microenvironments and metastatic processes occurring in human cancers. However, the use of such models is hampered by the logistical difficulties of reproducibly and simply assessing tumor burden. We developed a high-sensitivity assay for quantifying human DNA in small volumes of mouse plasma, enabling in-life monitoring of systemic tumor burden. Growth kinetics analyses of various xenograft models showed the utility of circulating human DNA as a biomarker. We found that human DNA concentration reproducibly increased with disease progression and decreased after successful therapeutic intervention. A marked, transient spike in circulating human tumor DNA occurred immediately after cytotoxic therapy or surgery. This simple assay may find broad utility in target validation studies and preclinical drug development programs. [Cancer Res 2007;67(19):9364–70]
In vivo Imaging of the Systemic Recruitment of Fibroblasts to the Angiogenic Rim of Ovarian Carcinoma Tumors
Authors: Granot Dorit , Addadi Yoseph , Kalchenko Vyacheslav , Harmelin Alon , Kunz-Schughart Leoni A. , Neeman Michal 
Published: October 2007

Abstract
Tumor-associated stroma, in general, and tumor fibroblasts and myofibroblasts, in particular, play a role in tumor progression. We previously reported that myofibroblast infiltration into implanted ovarian carcinoma spheroids marked the exit of tumors from dormancy and that these cells contributed to vascular stabilization in ovarian tumors by expression of angiopoietin-1 and angiopoietin-2. Ex vivo labeling of fibroblasts with either magnetic resonance or optical probes rendered them detectable for in vivo imaging. Thus, magnetic resonance imaging (MRI) follow-up was feasible by biotin-bovine serum albumin-gadolinium diethylenetriaminepentaacetic acid or iron oxide particles, whereas labeling with near-IR and fluorescent vital stains enabled in vivo visualization by near-IR imaging and two-photon microscopy. Using this approach, we show here that prelabeled fibroblasts given i.p. to CD-1 nude mice can be followed in vivo by MRI and optical imaging over several days, revealing their extensive recruitment into the stroma of remote s.c. MLS human epithelial ovarian carcinoma tumors. Two-photon microscopy revealed the alignment of these invading fibroblasts in the outer rim of the tumor, colocalizing with the angiogenic neovasculature. Such angiogenic vessels remained confined to the stroma tracks within the tumor and did not penetrate the tumor nodules. These results provide dynamic evidence for the role of tumor fibroblasts in maintenance of functional tumor vasculature and offer means for image-guided targeting of these abundant stroma cells to the tumor as a possible mechanism for cellular cancer therapy. [Cancer Res 2007;67(19):9180–9]
Targeting Cyclooxygenase-2 and the Epidermal Growth Factor Receptor for the Prevention and Treatment of Intestinal Cancer
Authors: Buchanan F. Gregory , Holla Vijay , Katkuri Sharada , Matta Pranathi , DuBois Raymond N. 
Published: October 2007

Abstract
Clinical and animal studies indicate a role for cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) in the development and progression of intestinal polyps and cancers. Although this combination of enzyme inhibition has shown synergy in intestinal polyp and tumor models, the exact mechanism for these effects remains undefined. Therefore, we sought to define the molecular mechanisms through which this process occurs. We observed a significant reduction in the number and size of small intestinal polyps in APCmin+/− mice treated with either celecoxib (a selective COX-2 inhibitor) or erlotinib (Tarceva, an EGFR inhibitor). However, in combination, there was an overall prevention in the formation of polyps by over 96%. Furthermore, we observed a 70% reduction of colorectal xenograft tumors in mice treated with the combination and microarray analysis revealed genes involved in cell cycle progression were negatively regulated. Although we did not observe significant changes in mRNAs of genes with known apoptotic function, there was a significant increase of apoptosis in tumors from animals treated with the combination. The inhibition of EGFR also induced the down-regulation of COX-2 and further inhibited prostaglandin E2 formation. We observed similar effects on the prevention of intestinal adenomas and reduction of xenograft tumor volume when nonselective COX inhibitors were used in combination with erlotinib. Together, these findings suggest that the inhibition of both COX-2 and EGFR may provide a better therapeutic strategy than either single agent through a combination of decreased cellular proliferation and prostaglandin signaling as well as increased apoptosis. [Cancer Res 2007;67(19):9380–8]
Aberrant Expression of Cortactin in Head and Neck Squamous Cell Carcinoma Cells Is Associated with Enhanced Cell Proliferation and Resistance to the Epidermal Growth Factor Receptor Inhibitor Gefitinib
Authors: Timpson Paul , Wilson Ashleigh S. , Lehrbach Gillian M. , Sutherland Robert L. , Musgrove Elizabeth A. , Daly Roger J. 
Published: October 2007

AbstractThe CTTN gene (formerly designated EMS1), encodes cortactin, a key regulator of dynamic actin networks. Both CTTN and CCND1, the latter encoding the cell cycle regulator cyclin D1, reside at chromosomal locus 11q13, a region commonly amplified in breast cancers and head and neck squamous cell carcinoma (HNSCC). Previously, we identified a novel role for cortactin in cancer cells, whereby cortactin overexpression attenuated ligand-induced down-regulation of the epidermal growth factor (EGF) receptor (EGFR), leading to sustained signaling. However, how this affected growth factor–induced cellular responses was unclear. Here, by modulation of cortactin expression in a panel of HNSCC cell lines, we show that cortactin overexpression enhances serum- and EGF-stimulated proliferation under both anchorage-dependent and anchorage-independent conditions and also increases resistance to anoikis (detachment-induced apoptosis). These effects are associated with increased activation of extracellular signal-regulated kinase and/or AKT. Furthermore, we report that cortactin stabilizes the c-MET receptor tyrosine kinase and enhances hepatocyte growth factor–induced mitogenesis and cell scattering. Therefore, cortactin may modulate signaling by a broader range of receptors than originally proposed and thereby affect a variety of responses. Finally, we have determined that cortactin overexpression, either alone or in combination with cyclin D1 up-regulation, promotes resistance to the EGFR kinase inhibitor gefitinib. These findings indicate that cortactin may play multiple roles in progression of HNSCC and should be evaluated as a marker of prognosis, disease progression, and therapeutic responsiveness, particularly to EGFR-directed agents. [Cancer Res 2007;67(19):9304–14]
Opposing Function of the Proprotein Convertases Furin and PACE4 on Breast Cancer Cells' Malignant Phenotypes: Role of Tissue Inhibitors of Metalloproteinase-1
Authors: Lapierre Marion , Siegfried Geraldine , Scamuffa Nathalie , Bontemps Yannick , Calvo Fabien , Seidah Nabil G. , Khatib Abdel-Majid 
Published: October 2007

Abstract
Proteolytic cleavage of various cancer-related substrates by the proprotein convertases (PC) was reported to be important in the processes of neoplasia. These enzymes are inhibited by their naturally occurring inhibitors, the prosegments (ppPC), and by the engineered general PC inhibitor, the serpin variant α1-PDX. In the present study, we sought to compare the effect of these PC inhibitors on malignant phenotypes of breast cancer cells. Overexpression in a stable manner of α1-PDX and the prosegment ppPACE4 in MDA-MB-231 breast cancer cells resulted in increased matrix metalloproteinase (MMP)-9 (but not MMP-2) activity and a reduced secretion of tissue inhibitor of metalloproteinase 1 (TIMP-1). This was associated with significant enhancement in cell motility, migration, and invasion of collagen in vitro. In contrast, ppFurin expression in these cells decreased MMP-9 activity and diminished these biological functions, but had no significant effect on TIMP-1 secretion. Taken together, these data showed the specific and opposing roles of Furin and PACE4 in the regulation of MMP-9/TIMP-1–mediated cell motility and invasion. [Cancer Res 2007;67(19):9030–4]
Local Administration of Interleukin-11 Ameliorates Intestinal Radiation Injury in Rats
Authors: Boerma Marjan , Wang Junru , Burnett Alexander F. , Santin Alessandro D. , Roman Juan J. , Hauer-Jensen Martin 
Published: October 2007

AbstractIntestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 ± 0.6 in the vehicle group versus 4.0 ± 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 ± 0.1 versus 0.5 ± 0.03; P &lt; 0.0001), and intestinal wall thickening (842 ± 66 μm versus 643 ± 54 μm; P = 0.02), reduced postradiation transforming growth factor-β overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic. [Cancer Res 2007;67(19):9501–6]
Snail-Induced Down-Regulation of ΔNp63α Acquires Invasive Phenotype of Human Squamous Cell Carcinoma
Authors: Higashikawa Koichiro , Yoneda Shingo , Tobiume Kei , Taki Masayuki , Shigeishi Hideo , Kamata Nobuyuki 
Published: October 2007

Abstract
p63 is a member of the p53 family and regulates crucial events in the formation of epithelial structures, but the role of p63 in tumor is unclear. We found that Snail-induced epithelial-to-mesenchymal transition (EMT) is accompanied by down-regulation of p63 in human squamous cell carcinomas (SCC). ΔNp63α is the predominantly expressed p63 isoform in SCC cells. ΔNp63 promoter activity required a CAAT/enhancer binding protein (C/EBP) binding element and was reduced remarkably by Snail. Down-regulation of ΔNp63α and reduction of C/EBPα were observed in EMT phenotype cells, which exhibited invasive activity in vitro. p63 knockdown in cells enhanced invasive activity in the presence of E-cadherin. Conversely, forced expression of ΔNp63α blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail down-regulates ΔNp63α, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by down-regulation of ΔNp63α does not require down-regulation of E-cadherin. [Cancer Res 2007;67(19):9207–13]
Evidence for Calpain-Mediated Androgen Receptor Cleavage as a Mechanism for Androgen Independence
Authors: Libertini Stephen J. , Tepper Clifford G. , Rodriguez Veronica , Asmuth David M. , Kung Hsing-Jien , Mudryj Maria 
Published: October 2007

Abstract
Prostate carcinoma is the most commonly diagnosed cancer in men and the second leading cause of death due to cancer in Western civilization. Androgen ablation therapy is effective in treating androgen-dependent tumors, but eventually, androgen-independent tumors recur and are refractory to conventional chemotherapeutics. Hence, the emergence of androgen independence is the most challenging problem in managing prostate tumors. We report a novel mechanism of androgen independence: calpain cleaves the androgen receptor (AR) into an androgen-independent isoform. In vitro and in vivo analyses show that calpain removes the COOH-terminal ligand binding domain generating a constitutively active molecule. Analysis of human prostate tumors indicates that several tumors express higher levels of this truncated AR than noncancerous prostate tissue. In transient transfection studies, the truncated AR is three to five times more potent than the full-length receptor in transactivating transcription. The androgen-independent Rv1 cells express high levels of the truncated AR, and treatment of these cells with a calpain inhibitor reduces truncated AR expression. In the absence of androgen, inhibition of calpain activity induces apoptosis. The HIV protease inhibitor amprenavir inhibits calpain activity and is also effective in inducing apoptosis in the Rv1 cell line. The cell culture studies were reproduced in a mouse xenograft model, where, in the absence of androgens, amprenavir significantly reduces tumor growth. Together, these studies indicate that calpain-dependent proteolysis of the AR may be a mechanism of androgen independence. The calpain inhibition studies suggest that inhibiting this activity may be a potential treatment for some androgen-independent prostate tumors. [Cancer Res 2007;67(19):9001–5]
Whole-Genome Profiling in Liposarcomas Reveals Genetic Alterations Common to Specific Telomere Maintenance Mechanisms
Authors: Johnson Jay E. , Gettings Edward J. , Schwalm Jaclyn , Pei Jianming , Testa Joseph R. , Litwin Samuel , von Mehren Margaret , Broccoli Dominique 
Published: October 2007

Abstract
Telomere attrition ultimately leads to the activation of protective cellular responses, such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we use a liposarcoma model system to assay telomere maintenance mechanism (TMM)–specific genetic alterations. A multiassay approach was used to assess the TMMs active in tumors. Genomic DNA from these samples was then analyzed by high-resolution DNA mapping array to identify genetic alterations. Our data reveal a higher level of genome instability in alternative lengthening of telomere (ALT)–positive tumors compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance used. We also identified genetic changes specific to the ALT mechanism (e.g., deletion of chromosome 1q32.2-q44) as well as changes that are underrepresented among ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. [Cancer Res 2007;67(19):9221–8]