bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1066: Combination synergy of JAK inhibitor, BVB808, and FGFR inhibitor, BGJ398, in an FGFR3-driven multiple myeloma model
Authors: Pinzon-Ortiz Maria , Tan Lujian , Yao Yao , Schlegel Robert , Radimerski Thomas , Cao Z. Alexander 
Published: August 2012

Abstract
Multiple myeloma is a genetically heterogenous malignancy. Several clinical studies have indicated that the t(4:14)(p16:q32) translocation is associated with poor clinical prognosis. Two key target genes in this translocation are FGFR3 and MMSET. Additionally, activating mutations of FGFR3 have been identified, further implicating the involvement of this target in multiple myeloma. Recent advances have shed more light on the interaction between tumor cells and their microenvironment. The bone marrow stroma, endothelial cells, osteoclasts and others could promote the proliferation, survival and resistance to therapies of the malignant plasma cells. IL-6 is one of the major cytokines implicated in the tumor microenvironment. IL-6 signaling, mediated through receptor-coupled JAK-STAT pathway, has been reported to play an important role in cancer cell survival. Here we examine the combination effects of JAK inhibitor BVB808 and FGFR inhibitor BGJ398 against multiple myeloma in the preclinical setting. Combination of BVB808 and BGJ398 was tested in vitro in a panel of multiple myeloma models across broad drug concentrations. Significant synergy is noted in OPM II, a cell line harboring both t(4:14) translocation and FGFR3 K650E mutation. This combination benefit is further confirmed in the xenograft model bearing OPM II. We propose 2 hypotheses for this combination effect: 1) FGFR3 and IL-6/JAK-STAT may represent 2 parallel survival pathways in MM. When one pathway is inhibited, tumor cells would rely on the other axis as the alternative survival pathway. Synergy is noted only when both pathways are inhibited. 2) JAK-STAT may cooperate with FGFR3 to promote its activity. Synergy is achieved when potent and sustained inhibition of FGFR3 signaling is achieved with the combination of BVB808 and BGJ398. While it is an intriguing finding, the combination benefit is not observed across other MM models harboring FGFR3 lesions. Elucidation of the underlying molecular mechanism would enable more targeted therapies against two important targets in multiple myeloma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1066. doi:1538-7445.AM2012-1066
Abstract 1069: Mutant p53 disrupts the role of ShcA in balancing the Smad-dependent and -independent signaling activity of TGF-β
Authors: Lin Shu , Yu Lan , Yang Junhua , Liu Zhao , Karia Bijal , Bishop Alexander J. R. , Jackson James , Lozano Guillermina , Copland John A. , Mu Xiaoxin , Sun Beicheng , Sun Lu-Zhe 
Published: August 2012

Abstract
Biomarkers are lacking for identifying the switch of transforming growth factor-beta (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Further, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling, but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Since TGF-β is known to activate MAPK/ERK pathway through direct phosphorylation of adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of TGF-β's role during carcinogenesis. We found that mp53 expression led to decrease of phosphorylated p52ShcA/ERK levels and increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines, and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we show that TGF-β's role in regulating anchorage-dependent and -independent growth, and migration, can be shifted between growth suppression and migration promotion. Thus, our results, for the first time, suggest that mp53 disrupts ShcA's role in balancing Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1069. doi:1538-7445.AM2012-1069
Abstract 1075: Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines
Authors: Langenfeld John E. 
Published: August 2012

Abstract
Bone morphogenetic proteins (BMPs) are growth-promoting morphogens during embryonic development. BMP-2 is aberrantly expressed in 98% of non-small cell lung carcinomas (NSCLC) independent of cell type. The role the BMP signaling cascade in cancer and its effects on cell growth and survival is poorly understood. We show that in unstimulated lung cancer cell lines, that BMP signaling is basally active. Lung cancer cell lines express the BMP type I receptors alk2, alk3, and alk6. Inhibition of a single BMP type I receptor was not sufficient to decrease signaling. Inhibition of all BMP type I receptors with siRNA effectively decreased BMP signaling. BMP type I receptor antagonists, Dorsomorphin, DMH1, DMH2, and LDN decreased BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of all BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth of lung cancer cell lines. The selective antagonist, DMH2 caused the greatest reduction in the activity of the BMP type I receptors and also caused the greatest reduction in cell growth. These studies show that basally active BMP signaling in lung cancer cells regulates the expression of Id family members and promotes cell growth and survival. BMP type I receptors antagonists represents a potential means to pharmacologically treat carcinomas with an activated BMP signaling cascade.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1075. doi:1538-7445.AM2012-1075
Abstract 1190: SIRT1 links tumor suppressive NOTCH signaling to p53
Authors: Ban Jozef , Fourtouna Argyro , Machado Isidro , Aryee Dave NT , Jug Gunhild , Llombart-Bosch Antonio , Kauer Max , Kovar Heinrich 
Published: August 2012

Abstract
Besides its important role in organismal development, NOTCH receptor signaling exerts tissue specific proliferative or antiproliferative functions. While the oncogenic role of NOTCH has been extensively investigated due to its constitutive activation in T-cell leukemias and several epithelial cancers, little is known about NOTCH mediated tumor suppression. We have previously reported that in Ewing's sarcoma, a pediatric bone tumor driven by the chimeric ETS oncogene EWS-FLI1, auto-stimulatory NOTCH signaling is suppressed and that reactivation results in p53 and consequently growth inhibitory p21 induction via activation of the NOTCH effector HEY1. We now demonstrate that HEY1-mediated p53 stimulation is accompanied by C-terminal p53 acetylation as a consequence of downregulation of nuclear deacetylase sirtuin 1 (SIRT1). We found that both EWS-FLI1 and HEY1 bind to the SIRT1 promoter with opposite transcriptional consequences. Thus, knockdown of EWS-FLI1 and ectopic HEY1 expression resulted in similar SIRT1 modulation and p53 acetylation which could be reversed by ectopically expressed SIRT1. Consistent with these results, treatment of Ewing's sarcoma cell lines with the sirtuin inhibitor Tenovin 6 resulted in massive cell death. Immunohistochemical analysis of more than 310 Ewing's sarcoma samples identified moderate (25%-50% positive nuclei) to strong (&gt;50% positive nuclei) SIRT1 expression in 35% of cases. Additional 20% showed sporadic positivity (between 10-25% positive nuclei). The involvement of SIRT1 in tumor suppressive NOTCH signaling is not restricted to Ewing's sarcoma, but also relevant at least to B-cell malignancies and some normal tissues, since we found that in several B-cell leukemia and lymphoma cell lines and in keratinocytes HEY1 was able to lead to activating p53 acetylation in a SIRT1 suppression-dependent manner. Supported by grants from the Austrian Science Fund (P22328-B09) and the European Comission (EU-FP7 STREP 259348).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1190. doi:1538-7445.AM2012-1190
Abstract 1199: Sorting nexin 2 (SNX2) controls drug sensitivity to molecular targeted anticancer agents through membrane trafficking of c-Met protein in cancer cell
Authors: Ono Mayumi , Ogi Sayaka , Yamamoto Chizuko , Fujita Hideaki , Kuwano Michihiko 
Published: August 2012

Abstract
Various molecular targeted anticancer drugs are often developed by targeting activated growth factor receptors that are expressed on plasma membrane of cancer cells. Expression of such active receptors on the cell surface is essential to limit the drug sensitivity to molecular targeted drugs in lung cancer cells and others. The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. Human SNX family proteins comprise about 34 proteins with wide range of biological functions, which play specialized and/or generalized roles in the regulation of protein trafficking, including endosomal trafficking of membrane receptors and transporters. SNX1 and SNX2 are components of the mammalian retromer complex. In this study, we show that the small-interfering RNA (siRNA)-mediated knockdown of SNX2 decreased the cell-surface localization of c-Met, but not that of EGFR, resulting in degradation of the c-Met protein. Knockdown of SNX2 markedly altered sensitivity to anticancer drugs targeting c-Met and EGFR through promotion of compensatory activation of the EGFR pathway in lung cancer cells. Furthermore, SNX2 knockdown also specifically decreased c-Met expression, and altered drug sensitivity to c-Met-targeted drug in gastric cancer cells. These findings suggest that SNX2 is a key protein that regulates c-Met-driven growth-signalling pathways, affecting the therapeutic efficacy of growth factor receptor-targeted drugs in lung and gastric cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1199. doi:1538-7445.AM2012-1199
Abstract 12: Bcr/Abl induces expression of Aurora kinase A via Akt signaling
Authors: Jang Jing , Ikezoe Takayuki , Nishioka Chie , Yokoyama Akihito 
Published: August 2012

Abstract
Aurora kinase A (AURKA) plays a pivotal role in the mitotic processes during cell division. We previously showed that AURKA was aberrantly expressed in hematological malignant cells including those from chronic myeloid leukemia (CML) compared to CD34+ hematopoietic stem/progenitor cells isolated from healthy volunteers. This study explored molecular mechanisms by which bcr-abl induced expression of AURKA; Lentiviral transduction of p210 bcr-abl into murine lymphoid Ba/F3 as well as human CD34+ hematopoietic stem/progenitor cells potently increased levels of AURKA in association with phosphorylation of AURKA and Akt, as assessed by real time RT-PCR and Western blot analysis. On the other hand, exposure of CML K562 cells which constitutively expressed phosphorylated forms of Akt and AURKA to imatinib, an inhibitor of bcr-abl kinase, de-phosphorylated both Akt and AURKA. In addition, the capability of bcr-abl to induce expression of AURKA in human CD34+ hematopoietic stem/progenitor cells was blunted when Akt was inactivated by a short hairpin RNA. These observations suggested that p210 bcr-abl activated AURKA at least in part via Akt signaling. Moreover, we found that lentiviral transduction of imatinib-resistant T315I mutant of bcr-abl into Ba/F3 cells also activated both Akt and AURKA. Importantly, exposure of p210 T315I bcr-abl-expressing Ba/F3 cells to a specific inhibitor of AURKA effectively inhibited their proliferation in vitro. Taken together, AURKA may be a promising molecular target in bcr-abl driven hematological malignancies and inhibition of AURKA could be useful to overcome imatinib-resistance mediated by bcr-abl mutants.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 12. doi:1538-7445.AM2012-12
Abstract 1207: Opposite effects on proliferation and bone metastasis genes by Estrogen Receptor B1 and Estrogen Receptor B2 in the prostate cancer cell line PC3
Authors: Dey Prasenjit , Jonsson Philip , Hartman Johan , Williams Cecilia , Gustafsson Jan-Åke , Ström Anders 
Published: August 2012

Abstract
The estrogen receptor β1 (ERα1) is successively lost during cancer progression while its splice variant estrogen receptor β2 (ERα2) is still expressed in advanced prostate cancer. The latter cancer often metastases to bone. We wanted to investigate, if the loss of ERα1 and/or expression of its splice variant ERα2 affect signaling pathways involved in bone metastasis of prostate cancer. ERα2 is a 495 amino acid long splice variant of estrogen receptor ERα1, which is 530 amino acids long. Using PC3 cells stably expressing ERα1, we found that ERα1 represses expression of the bone metastasis regulator Runx2 and its target gene Slug. On the other hand, using PC3 cells stably expressing ERα2 we found that the same factors are up-regulated. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade of prostate carcinoma is increased by ERα2. In agreement with increased Twist1 expression we find increased expression of DKK1, a factor which has been shown to increase the RANKL/OPG ratio and enhance osteoclastogenesis indicating that expression of ERα2 can cause a cancer to be osteolytic. Furthermore, we found that only ERα1 and not ERα2 inhibits proliferation and expression of the proliferation markers ki67, cyclin E, c-Myc and p45Skp2. In addition, nuclear β-catenin and its mRNA levels are reduced by ERα1 expression. In conclusion we find that ERα1 inhibits proliferation and factors known to be involved in bone metastasis while ERα2 increases proliferation and up-regulates factors involved in bone metastasis. Thus, ERα2 has oncogenic abilities in strong contrast to the tumor suppressor effect of ERα1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1207. doi:1538-7445.AM2012-1207
Abstract 1210: Tetraspanin CD63 interacts with extranuclear estrogen receptor alpha and regulates non-genomic signaling pathways in breast cancer
Authors: Huang Jian , Mackinnon Alexander Craig , Jiang Liying 
Published: August 2012

Abstract
Tetraspanin is a four transmembrane protein family whose members are regarded as molecular linkers. They also serve as scaffold proteins for many signaling processes. CD63 is a member of the tetraspanin family that serves as a lysosomal protein. Estrogen receptor alpha (ERα) plays critical roles in breast carcinogenesis. Extranuclear ERα could initiate rapid estrogen responses by forming protein complexes with many signaling molecules. Here, we report a novel protein complex formed between tetraspanin CD63 and extranuclear ERα. Immunoprecepitation (IP) experiments in MCF-7 and BT474 cells showed that CD63 interacts with ERα at endogenous levels. IP experiments using extracts from different cellular compartments (nucleus, cytoplasm and plasma membrane) showed that the interaction between CD63 and ERα is mainly located on the plasma membrane. Moreover, using co-immunofluorescence (IF) staining, we found CD63 co-localized with ERα on plasma membrane and/or in the cytoplasm. To further explore the effects of CD63 on ERα signaling pathways, we stably knocked down CD63 by shRNA in MCF-7 and BT474 cells. Interestingly, the expression of ERα was increased with lower expression of CD63. We further examined ERα from extracts of nucleus, cytoplasm, and membrane by western blots, and found that ERα in cytoplasm and/or membrane was increased by knocking down CD63 whereas the ERα level in the nucleus was not changed. IF staining showed similar results. Furthermore, P-MAPK level was up-regulated in both MCF-7 and BT474 cell lines with suppressed expression of CD63. These data suggest that the tetraspanin CD63 may facilitate the transport of ERα between plasma membrane and/or cytoplasm and nucleus, an important new function. CD63 may play a key role on organizing and regulating non-genomic ERα signaling pathways in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1210. doi:1538-7445.AM2012-1210
Abstract 1228: Interleukin 8 (IL8) is a modulator of tumorigenicity in colon cancer initiating cells
Authors: LoGuidice Amanda , Huang Emina 
Published: August 2012

Abstract
Introduction: At least 20% of patients with ulcerative colitis (UC) will develop colitis associated cancer (CAC) within 30 years of disease onset. Furthermore, patients with UC have a 5 fold greater risk of developing CAC than the incidence of CRC in the general population. Recently, we isolated and propagated colon cancer initiating cells (CCICs) from UC and CRC patients, and showed that these cells generated tumors in mice and propagated as spheres in vitro. IL8 is a pro-inflammatory chemokine with known proliferation and migration properties. Previously, we showed that inhibition of IL8 inhibited the growth of CCIC-derived tumors in vivo. We hypothesize that IL8 modulates several cancer processes and potentiates the progression from colitis to cancer. Methods: Conditioned media from UC and CRC patient sphere cell isolate cultures were used for measurement of secreted IL8. Exogenous IL8 (10 ng/mL) was added to sphere cultures and proliferation was evaluated. In addition, we knocked down IL8 and IL8 receptor (CXCR1) expression in CRC cell line by short hairpin RNA (shRNA) and measured proliferation in vitro and tumor growth in vivo. We then monitored CCICs from UC or CRC patients, either in the presence or absence of IL8, for symmetric vs. asymmetric division via time lapse video. Results: The chemokine array showed an increase in IL8 in both UC and CRC spheres. Spheres treated with IL8 proliferated faster than controls. Sphere numbers increased with increased exposure to IL8 on days 5 and 7. Conditioned media concentrations of IL8 were increased in both CRC (361-2446 pg/mL) and colitic spheres (208-599 pg/mL) when compared to commercial CRC cell lines (HT29-20.8 and SW480-74.6, respectively). In vitro, knockdown of IL8 or CXCR1 decreased proliferation 1.8-fold compared to the non-targeting controls. Similarly, in vivo xenografts of IL8 or CXCR1 knockdown cells showed 80% decreased tumor growth. UC-derived CCICs exposed to exogenous IL8 exhibited an increase in proliferation starting as early as 16 hrs. We also observed that IL8 treated cells showed a higher percentage of symmetric cellular divisions (68%) when compared to untreated cells (42%). Conclusions: Our findings demonstrate that IL8 potentiates proliferation and symmetric cell division, which is thought to be associated with tumorigenicity. This indicates that IL8 may contribute to the progression of colitis-associated cancer through a modulation of tumorigenic processes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1228. doi:1538-7445.AM2012-1228
Abstract 1244: Differential requirements for the receptor tyrosine kinase c-Met in scirrhous gastric carcinoma cell lines
Authors: Yoshida Nachi , Yamaguchi Hideki , Muroi Emi , Takanashi Miho , Fukami Kiyoko , Sakai Ryuichi 
Published: August 2012

Abstract
The prognosis of patients with scirrhous gastric carcinoma (SGC) has been very poor. SGC cells do not form obvious tumor mass, but cause diffuse infiltration and eventually rigid thickening of the gastric wall. Furthermore, SGC cells frequently infiltrate through gastric serosa and cause peritoneal dissemination. However, the mechanisms underlying the progression of SGC have not yet been fully elucidated. In the present study, we performed immunoblotting and proteomic analyses of tyrosine-phosphorylated proteins in differentiated non-SGC cell lines (MKN7, MKN1, and MKN74) and poorly differentiated or SGC cell lines (MKN45, NUGC-4, KATO III, HSC59, 58As9, HSC44-PE, and 44As3) to identify signaling pathways and molecules that are characteristics of SGC. We found that the tyrosine kinase receptor c-Met is overexpressed and highly phosphorylated in SGC cell lines. c-Met is a cell surface receptor for HGF and implicated in the growth, survival, invasion, and metastasis of various human cancers. Amplification of c-Met gene in SGC was also previously reported. We analyzed the downstream signaling pathways of c-Met in SGC cells by using two c-Met inhibitors PHA-665752 and JNJ-38877605. Treatment of 58As9 cells with the c-Met inhibitors markedly inhibited phosphorylation of Erk, Akt, and Stat3, but promoted phosphorylation of Src. In contrast, 44As3 cells treated with the c-Met inhibitors showed no significant changes in phosphorylation of these molecules, in spite of successful inhibition of c-Met phosphorylation. Reflecting these observations, c-Met inhibitors blocked cell proliferation and caused morphological alterations in 58As9 cells but not in 44As3 cells. Similar results were obtained when MKN45 and NUGC-4 cells were analyzed in the same manner: MKN45 cells but not NUGC-4 cells were sensitive to c-Met inhibition. These results suggest that SGC can be classified into two subtypes according to their dependencies on the c-Met signaling pathway. Further studies are now conducted to identify therapeutic targets in c-Met-independent SGC cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1244. doi:1538-7445.AM2012-1244