bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCR-ABL Induces the Expression of Skp2 through the PI3K Pathway to Promote p27Kip1 Degradation and Proliferation of Chronic Myelogenous Leukemia Cells
Authors: Andreu Enrique J. , Lledó Elisa , Poch Enric , Ivorra Carmen , Albero M. Pilar , Martínez-Climent José Angel , Montiel-Duarte Cristina , Rifón José , Pérez-Calvo Javier , Arbona Cristina , Prósper Felipe , Pérez-Roger Ignacio 
Published: July 2017

Abstract
Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G1 cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27Kip1 and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27Kip1 at the level of transcription. We further show that BCR-ABL also regulates p27Kip1 protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27Kip1 by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27Kip1. We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27Kip1 mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27Kip1 contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27Kip1 and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.
Cortactin Overexpression Inhibits Ligand-Induced Down-regulation of the Epidermal Growth Factor Receptor
Authors: Timpson Paul , Lynch Danielle K. , Schramek Daniel , Walker Francesca , Daly Roger J. 
Published: July 2017

AbstractLigand-induced receptor down-regulation by endocytosis is a critical process regulating the intensity and duration of receptor tyrosine kinase signaling. Ubiquitylation of specific receptor tyrosine kinases, for example, the epidermal growth factor receptor (EGFR) by the E3 ubiquitin ligase c-Cbl, provides a sorting signal for lysosomal degradation and leads to termination of receptor signaling. Cortactin, which couples the endocytic machinery to dynamic actin networks, is encoded by EMS1, a gene commonly amplified in breast and head and neck cancers. One mechanism whereby cortactin overexpression contributes to tumor progression is by enhancing tumor cell invasion and metastasis. However, in this study, we show that overexpression of cortactin in HeLa cells markedly inhibits ligand-induced down-regulation of the EGFR. This is independent of alterations in receptor autophosphorylation and correlates with impaired c-Cbl phosphorylation and association with the EGFR, reduced EGFR ubiquitylation, and sustained EGF-induced extracellular signal-regulated kinase activation. Furthermore, analysis of a panel of head and neck squamous cell carcinoma (HNSCC) cell lines revealed that cortactin overexpression is associated with attenuated ligand-induced EGFR down-regulation. Importantly, RNAi-mediated reduction of cortactin expression in an 11q13-amplified HNSCC cell line accelerates EGFR degradation. This represents the first demonstration of modulation of growth factor receptor signaling by cortactin. Moreover, enhanced EGFR signaling due to cortactin overexpression may provide an alternative explanation for EMS1 gene amplification in human cancers.
Expression of the Brn-3b Transcription Factor Correlates with Expression of HSP-27 in Breast Cancer Biopsies and Is Required for Maximal Activation of the HSP-27 Promoter
Authors: Lee Sonia A. , Ndisang Daniel , Patel Chandrakant , Dennis Jonathan H. , Faulkes David J. , D'Arrigo Corrado , Samady Laila , Farooqui-Kabir Saleha , Heads Richard J. , Latchman David S. , Budhram-Mahadeo Vishwanie S. 
Published: July 2017

Abstract
In breast cancer, overexpression of the small heat shock protein, HSP-27, is associated with increased anchorage-independent growth, increased invasiveness, and resistance to chemotherapeutic drugs and is associated with poor prognosis and reduced disease-free survival. Therefore, factors that increase the expression of HSP-27 in breast cancer are likely to affect the prognosis and outcome of treatment. In this study, we show a strong correlation between elevated levels of the Brn-3b POU transcription factor and high levels of HSP-27 protein in manipulated MCF-7 breast cancer cells as well as in human breast biopsies. Conversely, HSP-27 is decreased on loss of Brn-3b. In cotransfection assays, Brn-3b can strongly transactivate the HSP-27 promoter, supporting a role for direct regulation of HSP-27 expression. Brn-3b also cooperates with the estrogen receptor (ER) to facilitate maximal stimulation of the HSP-27 promoter, with significantly enhanced activity of this promoter observed on coexpression of Brn-3b and ER compared with either alone. RNA interference and site-directed mutagenesis support the requirement for the Brn-3b binding site on the HSP-27 promoter, which facilitates maximal transactivation either alone or on interaction with the ER. Chromatin immunoprecipitation provides evidence for association of Brn-3b with the HSP-27 promoter in the intact cell. Thus, Brn-3b can, directly and indirectly (via interaction with the ER), activate HSP-27 expression, and this may represent one mechanism by which Brn-3b mediates its effects in breast cancer cells.
Proteomic-Based Prognosis of Brain Tumor Patients Using Direct-Tissue Matrix-Assisted Laser Desorption Ionization Mass Spectrometry
Authors: Schwartz Sarah A. , Weil Robert J. , Thompson Reid C. , Shyr Yu , Moore Jason H. , Toms Steven A. , Johnson Mahlon D. , Caprioli Richard M. 
Published: July 2017

Abstract
Clinical diagnosis and treatment decisions for a subset of primary human brain tumors, gliomas, are based almost exclusively on tissue histology. Approaches for glioma diagnosis can be highly subjective due to the heterogeneity and infiltrative nature of these tumors and depend on the skill of the neuropathologist. There is therefore a critical need to develop more precise, nonsubjective, and systematic methods to classify human gliomas. To this end, mass spectrometric analysis has been applied to these tumors to determine glioma-specific protein patterns. Protein profiles have been obtained from human gliomas of various grades through direct analysis of tissue samples using matrix-assisted laser desorption ionization mass spectrometry (MS). Statistical algorithms applied to the MS profiles from tissue sections identified protein patterns that correlated with tumor histology and patient survival. Using a data set of 108 glioma patients, two patient populations, a short-term and a long-term survival group, were identified based on the tissue protein profiles. In addition, a subset of 57 patients diagnosed with high-grade, grade IV, malignant gliomas were analyzed and a novel classification scheme that segregated short-term and long-term survival patients based on the proteomic profiles was developed. The protein patterns described served as an independent indicator of patient survival. These results show that this new molecular approach to monitoring gliomas can provide clinically relevant information on tumor malignancy and is suitable for high-throughput clinical screening.
A DNA Vaccine Targeting Fos-Related Antigen 1 Enhanced by IL-18 Induces Long-lived T-Cell Memory against Tumor Recurrence
Authors: Luo Yunping , Zhou He , Mizutani Masato , Mizutani Noriko , Liu Cheng , Xiang Rong , Reisfeld Ralph A. 
Published: July 2017

AbstractA novel vaccination strategy induced specific CD8+ T cell–mediated immunity that eradicated spontaneous and experimental pulmonary cancer metastases in syngeneic mice and was also effective in a therapeutic setting of established breast cancer metastases. This was achieved by targeting transcription factor Fos-related antigen 1(Fra-1), overexpressed by many tumor cells, with an ubiquitinated DNA vaccine against Fra-1, coexpressing secretory IL-18. Insight into the immunologic mechanisms involved was provided by adoptive transfer of T lymphocytes from successfully immunized BALB/c mice to syngeneic severe combined immunodeficient (SCID) mice. Specifically, long-lived T memory cells were maintained dormant in nonlymphoid tissues by IL-18 in the absence of tumor antigen. Importantly, a second tumor cell challenge of these SCID mice restored both, robust tumor-specific cytotoxicity and long-lived T-cell memory, capable of eradicating established pulmonary cancer metastases, suggesting that this vaccine could be effective against tumor recurrence.
Toluidine Blue Staining Identifies High-Risk Primary Oral Premalignant Lesions with Poor Outcome
Authors: Zhang Lewei , Williams Michele , Poh Catherine F. , Laronde Denise , Epstein Joel B. , Durham Scott , Nakamura Hisae , Berean Ken , Hovan Alan , Le Nhu D. , Hislop Greg , Priddy Robert , Hay John , Lam Wan L. , Rosin Miriam P. 
Published: July 2017

Abstract
There is a pressing need for the development of visual aids that will facilitate the detection of oral premalignant lesions (OPLs) with a high-risk of progression. Preliminary data suggest that toluidine blue stain may be preferentially retained by OPLs with high-risk molecular clones. In this study, we monitored OPLs from 100 patients without any history of oral cancer for an average of 44 months in order to evaluate the association of toluidine blue status with clinicopathologic risk factors, molecular patterns (microsatellite analysis on seven chromosome arms: 3p, 9p, 4q, 8p, 11q, 13q, and 17p) and outcome. Toluidine blue–positive staining correlated with clinicopathologic risk factors and high-risk molecular risk patterns. Significantly, a &gt;6-fold elevation in cancer risk was observed for toluidine blue–positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (P = 0.0008). This association of toluidine blue status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. Our results suggest the potential use of toluidine blue in identifying high-risk OPLs.
Selenium Disrupts Estrogen Signaling by Altering Estrogen Receptor Expression and Ligand Binding in Human Breast Cancer Cells
Authors: Lee Soo Ok , Nadiminty Nagalakshmi , Wu Xiu Xian , Lou Wei , Dong Yan , Ip Clement , Onate Sergio A. , Gao Allen C. 
Published: July 2017

Abstract
Cancer prevention studies suggest that selenium is effective in reducing the incidence of cancers including prostate, colon, and lung cancers. Previous reports showed that selenium inhibits premalignant human breast MCF-10AT1 and MCF10AT3B cell growth in vitro and reduces mammary tumor incidence after exposure to carcinogens in tumor models. Because estrogen is critical to the development and differentiation of estrogen target tissues, including the breast, the present study was designed to examine the effect of selenium on estrogen receptor (ER) expression and activation using methylseleninic acid (MSA), an active form of selenium in vitro. Selenium decreased the levels of expression of ERα mRNA and protein and reduced the binding of labeled estradiol to estrogen receptor in MCF-7 cells. Selenium inhibited the trans-activating activity of estrogen receptor in MCF-7 cells expressing functional estrogen receptor using a luciferase reporter construct linked to estrogen responsive element. Selenium decreased the binding of estrogen receptor to the estrogen responsive element site using an electrophoretic mobility gel shift assay. Selenium suppressed estrogen induction of the endogenous target gene c-myc. In contrast to the effect on ERα in MCF-7 cells, selenium increased ERβ mRNA expression in MDA-MB231 human breast cancer cells. Thus, differential regulation of ERα and ERβ in breast cancer cells may represent a novel mechanism of selenium action and provide a rationale for selenium breast cancer prevention trial.
Defective p38 Mitogen-Activated Protein Kinase Signaling Impairs Chemotaxic but not Proliferative Responses to Stromal-Derived Factor-1α in Acute Lymphoblastic Leukemia
Authors: Bendall Linda J. , Baraz Rana , Juarez Julius , Shen Wei , Bradstock Kenneth F. 
Published: July 2017

AbstractThe chemokine stromal-derived factor-1α (SDF-1α) regulates leukemic cell motility and proliferation; however, the importance of these functions in the growth and dissemination of leukemia is unclear. We examined SDF-1α–mediated responses of cells from 27 cases of acute lymphoblastic leukemia (ALL). Although cells from the majority of cases showed chemotactic and proliferative responses to SDF-1α, a subset of cases did not undergo chemotaxis in response to SDF-1α, while still demonstrating dependence on SDF-1α for proliferation in stroma-supported cultures. This chemotactic defect was associated with an absence of phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by SDF-1α, and of SDF-1α–induced augmentation of β1 integrin–mediated adhesion. Signaling through phosphoinositide 3-kinase and MEK was not affected. No correlation was observed between CXCR4 expression and chemotactic function, in vitro migration into bone marrow stromal layers, and engraftment of leukemic cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This study suggests that signaling through p38 MAPK is required for ALL cell chemotaxis but not for proliferation, and that the loss of a chemotactic response to SDF-1α does not impede engraftment in NOD/SCID mice.
Fetal Stromal–Dependent Paracrine and Intracrine Vascular Endothelial Growth Factor-A/Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Proliferation and Motility of Human Primary Myeloma Cells
Authors: Vincent Loïc , Jin David K. , Karajannis Matthias A. , Shido Koji , Hooper Andrea T. , Rashbaum William K. , Pytowski Bronislaw , Wu Yan , Hicklin Daniel J. , Zhu Zhenping , Bohlen Peter , Niesvizky Ruben , Rafii Shahin 
Published: July 2017

Abstract
Induction of neoangiogenesis plays an important role in the pathogenesis of multiple myeloma. However, the mechanism by which expression of vascular endothelial growth factor (VEGF)-A and its receptors modulate the interaction of multiple myeloma cells with stromal cells is not known. Here, we describe a novel in vitro coculture system using fetal bone stromal cells as a feeder layer, which facilitates the survival and growth of human primary multiple myeloma cells. We show that stromal-dependent paracrine VEGF-A signaling promotes proliferation of human primary multiple myeloma cells. Primary multiple myeloma cells only expressed functional VEGF receptor (VEGFR)-1, but not VEGFR-2 or VEGFR-3. VEGFR-1 expression was detected in the cytoplasm and the nuclei of proliferating multiple myeloma cells. Inhibition of VEGFR-1 abrogated multiple myeloma cell proliferation and motility, suggesting that the functional interaction of VEGF-A with its cognate receptor is essential for the growth of primary multiple myeloma cells. Collectively, our results suggest that stromal-dependent paracrine and intracrine VEGF-A/VEGFR-1 signaling contributes to human primary multiple myeloma cell growth and therefore, VEGFR-1 blockade is a potential therapeutic strategy for the treatment of multiple myeloma.
Protein Kinase C Inhibition and X-Linked Inhibitor of Apoptosis Protein Degradation Contribute to the Sensitization Effect of Luteolin on Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Cancer Cells
Authors: Shi Ran-Xin , Ong Choon-Nam , Shen Han-Ming 
Published: July 2017

Abstract
Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is an important member of the TNF superfamily with great potential in cancer therapy. Luteolin is a dietary flavonoid commonly found in some medicinal plants. Here we found that pretreatment with a noncytotoxic concentration of luteolin significantly sensitized TRAIL-induced apoptosis in both TRAIL-sensitive (HeLa) and TRAIL-resistant cancer cells (CNE1, HT29, and HepG2). Such sensitization is achieved through enhanced caspase-8 activation and caspase-3 maturation. Further, the protein level of X-linked inhibitor of apoptosis protein (XIAP) was markedly reduced in cells treated with luteolin and TRAIL, and ectopic expression of XIAP protected against cell death induced by luteolin and TRAIL, showing that luteolin sensitizes TRAIL-induced apoptosis through down-regulation of XIAP. In search of the molecular mechanism responsible for XIAP down-regulation, we found that luteolin and TRAIL promoted XIAP ubiquitination and proteasomal degradation. Next, we showed that protein kinase C (PKC) activation prevented cell death induced by luteolin and TRAIL via suppression of XIAP down-regulation. Moreover, luteolin inhibited PKC activity, and bisindolylmaleimide I, a general PKC inhibitor, simulated luteolin in sensitizing TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of luteolin and support its potential application in cancer therapy in combination with TRAIL. In addition, our data reveal a new function of PKC in cell death: PKC activation stabilizes XIAP and thus suppresses TRAIL-induced apoptosis.
Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone
Authors: Gordon Andrew H. , O'Keefe Regis J. , Schwarz Edward M. , Rosier Randy N. , Puzas J. Edward 
Published: July 2017

AbstractA central mediator of a wide host of target genes, the nuclear factor-κB (NF-κB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-κB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the bone-seeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IκB that prevents phosphorylation of IκBα and associated nuclear translocation of NF-κB. Blockade of NF-κB signaling in MDA-MB-231 cells by the mutant IκB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-κB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-κB at the bone-tumor interface. NF-κB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-κB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden.
Activation of Mammalian Target of Rapamycin in Transformed B Lymphocytes Is Nutrient Dependent but Independent of Akt, Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase, Insulin Growth Factor-I, and Serum
Authors: Wlodarski Pawel , Kasprzycka Monika , Liu Xiaobin , Marzec Michal , Robertson Erle S. , Slupianek Artur , Wasik Mariusz A. 
Published: July 2017

Abstract
The study examines the preponderance and mechanism of mammalian target of rapamycin (mTOR) activation in three distinct types of transformed B lymphocytes that differ in expression of the EBV genome. All three types [EBV-immortalized cells that express a broad spectrum of the virus-encoded genes (type III latency; EBV+/III), EBV-positive cells that express only a subset of the EBV-encoded genes (EBV+/I), and EBV-negative, germinal center–derived cells (EBV−)] universally displayed activation of the mTOR signaling pathway. However, only the EBV+/III transformed B cells displayed also activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway that is considered to be the key activator of mTOR and of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway that coactivates one of the immediate targets of mTOR, p70 S6K1. Activation of the PI3K/Akt and MEK/ERK, but not of the mTOR pathway, was inhibited by serum withdrawal and restored by insulin growth factor-I. In contrast, activation of mTOR, but not PI3K/Akt and MEK/ERK, was sensitive to nutrient depletion. Both direct Akt (Akt inhibitors I-III) and a PI3K inhibitor (wortmannin at 1 nmol/L) suppressed Akt phosphorylation without significantly affecting mTOR activation. Furthermore, rapamycin, a potent and specific mTOR inhibitor, suppressed profoundly proliferation of cells from all three types of transformed B cells. U0126, a MEK inhibitor, had a moderate antiproliferative effect only on the EBV+/III cells. These results indicate that mTOR kinase activation is mediated in the transformed B cells by the mechanism(s) independent of the PI3K/Akt signaling pathway. They also suggest that inhibition of mTOR signaling might be effective in therapy of the large spectrum of B-cell lymphomas.
Interference with the Microenvironmental Support Impairs the De novo Formation of Bone Metastases In vivo
Authors: van der Pluijm Gabri , Que Ivo , Sijmons Bianca , Buijs Jeroen T. , Löwik Clemens W.G.M. , Wetterwald Antoinette , Thalmann George N. , Papapoulos Socrates E. , Cecchini Marco G. 
Published: July 2017

Abstract
Interference with the microenvironmental growth support is an attractive therapeutic strategy for repressing metastatic tumor growth. Bone is a highly dynamic tissue that is continuously remodeled by bone resorption and subsequent bone formation. Growth factors supporting bone metastatic growth are released especially during bone resorption. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates, are available for bone. In the present study, we tested the hypothesis that inhibition of bone turnover can affect development and growth progression of experimental bone metastasis. Whole-body bioluminescent reporter imaging was used for the detection, monitoring, and quantification in vivo of the growth progression of bone metastases induced by intracardiac or intraosseous injection of luciferase-transfected breast cancer cells (MDA-231-B/luc+) to nude mice. Suppression of bone turnover by bisphosphonates, before bone colonization by cancer cells, inhibited by a great extent the number of developing bone metastasis. Tumor growth in the few, but still developing, bone metastases was affected only transiently. Reduction of bone turnover had no effect on growth progression of bone metastases, which were already established when bisphosphonate treatment was initiated, despite a substantial reduction in osteolysis. Therefore, cancer cells metastatic to bone, after an initial growth phase that depends on the interaction with the local stroma, become independent of microenvironmental growth factor support and progress autonomously. Inhibition of bone turnover may represent a useful adjuvant therapy especially for cancer patients at risk to develop bone metastasis.