bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 260: Identification of the role of linker histone H1 in estrogen receptor binding and activity
Authors: Cato Laura , Brown Myles 
Published: June 2012

Abstract
The activity of estrogen receptor (ER) in the nucleus is a highly dynamic process, which is tightly regulated by many factors. Among the molecules proposed to facilitate ER activity are proteasome components, chromatin-remodeling complexes, heat shock proteins and histones. Particularly the linker histone H1 seems important, as it is essential to the stability of the higher-order chromatin structure and has been associated with the regulation of gene expression for many years. Eleven linker histones have been identified in humans to date, differing in their timing of expression, extent of post-translational modification and affinity to DNA in chromatin. However, their exact function and ability to differentially affect gene expression are not as clearly understood. It seems probable that linker histones need to be removed, reduced in amount or somehow modified during transcription in order to allow access to the transcription machinery and that these processes are different for the different linker histone subtypes. Here we show that removal of linker histone H1 is a prerequisite for the full activation of ER-regulated target genes in ER positive breast cancer cells. This process is mediated through the activity of the cyclin-dependent kinase 2 (CDK2), which phosphorylates H1 in a hormone-dependent manner, and thereby loosens the interaction of the linker histone with DNA in chromatin. The extent of phosphorylation differs significantly between the different subtypes, suggesting a differential involvement of the H1s in ER-mediated gene expression. Collectively, our results show that H1 dissociation is required for ER-mediated gene expression in breast cancer and that the H1 subtypes may play distinct functional roles in the transcriptional regulation of ER target genes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 260. doi:10.1158/1538-7445.AM2011-260
Abstract 2602: FoxM1 is an attractive therapeutic target in a subset of papillary thyroid cancers
Authors: Ahmed Maqbool , Bavi Prashant , Hussain Azhar R. , Jehan Zeenath , Olyan Aishah S. , Bu Tiezheng R. , Al-Nuaim Abdulrehman , Al-Sobhi Saif , Amin Tarek , Uddin Shahab , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
The FoxM1 transcription factor promotes the pathogenesis of several malignancies. However, little is known about its expression and function in papillary thyroid cancers (PTC). In the present study we investigated the role of FoxM1 in the pathogenesis of PTC in a large series of PTC in a tissue micro array (TMA) format followed by studies using PTC cell lines and nude mice. Our data showed that expression of FoxM1 was over expressed in 28.4 % (141/496) of PTC and significantly associated with activated AKT (p&lt;0.0001) and matrix metalloproteinase-9 (MMP-9) expression (p=0.0004). FoxM1 over expression was also strongly associated with antiapoptotic markers, XIAP (p=0.0024), and Bcl-Xl (p=0.0014). In vitro data using PTC cell lines showed that inhibition of FoxM1 by thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose dependent manner. In addition, thiostrepton treatment caused downregulation of SKP2, and consequent increase expression of p21 in PTC cell lines. We also found that down-regulation of FoxM1 reduced the expression of MMP-2, MMP-9 and vascular endothelial growth factor, resulting in the inhibition of migration, invasion, and angiogenesis in PTC cells. Furthermore, pharmacological inhibition of FoxM1 or siRNA targeted against FoxM1 triggered caspase dependent apoptosis in PTC cells. Finally, treatment of PTC cell line xenografts with thiostrepton resulted in growth inhibition of tumors in nude mice via downregulation of FoxM1 and MMP9. Altogether, our results suggest that FoxM1 and its associated signaling pathway may be a potential target for therapeutic intervention for treatment of PTC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2602. doi:10.1158/1538-7445.AM2011-2602
Abstract 2605: Identification and development of NVP-HSP990, a potent and orally active Hsp90 inhibitor for cancer treatment
Authors: Gao Zhenhai , Machajewski Timothy , Menezes Daniel , Jensen Michael Rugaard , Yu Karen , Guy Chantale 
Published: June 2012

Abstract
Hsp90 is recognized as a potential target for the treatment of cancer, due to its chaperone functions that are required for maintaining the stability and/or active conformation of signalling molecules essential for tumorigenesis. The development of small molecule Hsp90 inhibitors has become an extremely competitive field of research. Here for the first time we present biological and pharmacological properties of NVP-HSP990, a potent oral Hsp90 inhibitor discovered by Novartis. In vitro, NVP-HSP990 potently inhibits all 4 isoforms of Hsp90 (Hsp90α, Hsp90β, TRAP-1 and GRP94) and has no major activities in a safety pharmacology panel of kinases, receptors and enzymes evaluated. NVP-HSP990 demonstrates broad-spectrum anti-tumor activities in tumor cell lines (IC 50s ranging from 4-35 nM) and primary patient samples (mean IC50 =49 nM). In vivo, NVP-HSP990 is highly bioavailable across species and a single oral administration of 15 mg/kg induces sustained target inhibition up to 7 days as indicated by downregulation of client protein (c-Met) and upregulation of Hsp70 in a cMet overexpressing gastric GTL16 xenograft tumor model. Weekly administration of NVP-HSP990 was efficacious in a broad range of mouse and rat human tumor xenograft models driven by well defined oncogenic Hsp90 client proteins. In summary, NVP-HSP990 represents a novel class of oral Hsp90 inhibitors with unique and superior pharmacological and drug-like properties. NVP-HSP990 is currently being evaluated in Phase I clinical trial in advanced solid tumors. In addition, we will present multiple secreted biomarkers for Hsp90 that were identified through a novel in-silico data mining approach. Several of these biomarkers have been validated both in vitro and in vivo, and have the potential to be utilized as clinical pharmaco-dynamic markers in the development of Hsp90 inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2605. doi:10.1158/1538-7445.AM2011-2605
Abstract 261: Emerging roles for the CREB regulated transcription coactivators (CRTCs) in oncogenesis
Authors: Amelio Antonio L. , Dorsey Frank C. , Steeves Meredith A. , Southern Mark R. , Young Brandon M. , Lawani Mariam B. , Prater Stephanie M. , Alperstein Adam S. , Cleveland John L. , Conkright Michael D. 
Published: June 2012

Abstract
Oncogenesis is a complex, multi-factorial process of cellular transformation that leads to the development of many types of cancers. The factors that contribute to this process reprogram normal cellular functions, including metabolic pathways, and allow uncontrolled cell growth. The CRTC family of CREB coactivators, in conjunction with CBP/p300, cooperate in the regulation of cAMP-inducible genes involved in cell survival, proliferation, glucose metabolism, and adaptive mitochondrial biogenesis. A subset of tumors share a common t(11;19)(q21;p13.1) translocation that forms a chimeric oncogene by fusing CRTC1 to the NOTCH coactivator MAML2. Consequently, the CRTC1/MAML2 translocation induces the aberrant expression of genes regulated by CREB and NOTCH and the deregulation of these target genes is believed to cause tumorigenesis. We demonstrate that a gain-of-function activity by the CRTC1/MAML2 oncoprotein promotes interactions with the MYC:MAX network. This interaction is specific as neither CRTC1 or MAML2 parental proteins activate MYC:MAX complexes. Specifically, RNA-seq analysis revealed that a significant proporation of genes involved in key aspects of cell growth, survival, and metabolism within the MYC:MAX and CREB transcription networks are induced by CRTC1/MAML2. Analysis of cellular transformation by RK3E foci formation assays identified a synergistic effect of MYC expression on CRTC1/MAML2-induced transformation and this can be blocked by a dominant negative MYC molecule. Furthermore, in-frame deletions of CRTC1/MAML2 that lack transforming activity are unable to induce the expression of MYC-responsive reporters revealing a critical role for MYC target genes in CRTC1/MAML2-induced cell growth and transformation. Collectively, these studies indicate that CRTC1/MAML2 promotes cellular transformation through cooperative activation of MYC and CREB pathways thereby challenging current paradigms which suggest that translocations function through aberrant activation of parental pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 261. doi:10.1158/1538-7445.AM2011-261
Abstract 2617: MPC-3100, a synthetic Hsp90 inhibitor, induces biomarker changes in vitro and in vivo
Authors: Baichwal Vijay R. , Brown Brita , Robinson Rosann , Cimbora Daniel , Wettstein Daniel , Beelen Andrew P. , Mather Gary G. , Carlson Robert O. 
Published: June 2012

Abstract
Introduction: MPC-3100 is a fully synthetic, orally bioavailable, Hsp90 inhibitor in clinical development. It is broadly active in xenograft models with anti-tumor activity ranging from tumor regression to tumor growth inhibition in many cancer types including colon, gastric, ovarian, prostate, breast, lung and myeloid leukemia. Here we evaluate the effect of MPC-3100 on stability of client proteins in cells and xenograft tumors. We also determine the effect on Hsp70 protein levels, a biomarker of Hsp90 inhibition, in peripheral blood mononuclear cells (PBMCs) from cancer patients receiving MPC-3100.
Methods: Her2, Akt, Cdk4, c-Raf and Hsp70 client protein levels were monitored in cell culture with protein immunoblots. Formalin-fixed, paraffin-embedded sections of xenograft tumors from mice dosed orally with MPC-3100 were analyzed by immunohistochemistry (IHC) to monitor changes in Her2, Akt and Hsp70 protein levels. To monitor changes in Hsp70 in cancer patients treated with MPC-3100, PBMCs were collected prior to drug administration, 8 and 24 hours post-dose on Day 1 and 24 hours post-dose on Days 7 and 21 of the first treatment cycle. Hsp70 protein levels were determined by ELISA.
Results: Exposure of HCT-116, NCI-N87 and DU-145 cells to MPC-3100 in vitro resulted in a time-dependent reduction in client protein levels with maximal reduction by 24 hours. The IC50 values for client protein reduction ranged from 0.1 μM to 0.5 μM, comparable to the cellular cytotoxicity values of MPC-3100 at 72 hours for the various cell lines. IHC revealed reduction in Her2 and Akt protein in N87 xenografts in mice given a single oral dose of 200 mg/kg MPC-3100 relative to tumors from animals dosed with vehicle. Healthy volunteer PBMCs exposed to 1 μM MPC-3100 for 24 hours ex vivo revealed a reduction in Akt, c-Raf and Cdk4 protein levels ranging from 50% to 90%. PBMCs from cancer patients receiving MPC-3100 showed an increase of 28 to 589 ng of Hsp70 protein per mg total protein over baseline by Day 8. The increase in Hsp70 expression was seen as early as 8 hours after the first dose and sustained through at least Day 22.
Conclusions: The changes in client proteins and biomarkers observed in cells and tumor xenografts exposed to MPC-3100 confirm that the cellular cytotoxic activity and anti-tumor activity in xenografts are a result of Hsp90 inhibition. The consistent increase in Hsp70 expression in PBMCs from cancer patients receiving MPC-3100 indicates that Hsp90 function is inhibited in patients at doses that have been well tolerated in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2617. doi:10.1158/1538-7445.AM2011-2617
Abstract 2638: Association between Adriamycin-induced autophagy and senescence in breast cancer cells
Authors: Di Xu , Bristol Molly L. , Valerie Kristoffer , Hawkins Amy J. , Gewirtz David A. 
Published: June 2012

Abstract
Previous studies from this laboratory demonstrated that the topoisomerase II poison, Doxorubicin, at a clinically relevant concentration of 1µM, induced a pronounced senescence response in breast cancer cells. Doxorubicin was also observed to generate a time-dependent increase of autophagy within 72 hrs by multiple approaches, including acridine orange staining (AOS), downregulation of p62 (indicative of autophagic flux), LC3 puncta formation and electron microscopy. The current studies were designed to investigate the potential relationship between senescence and autophagy in response to Doxorubicin in breast cancer cells.
Silencing of ATM by the pharmacological inhibitors, caffeine or KU55933, or by small interfering RNA abrogated doxorubicin-induced senescence, as demonstrated by decreased β -galactosidase staining as well as down-regulation of p21 expression. At the same time, silencing/attenuation of ATM suppressed autophagy, based on decreased conversion of LC3-I to LC3-II by Western blotting, and reduced acridine orange staining.
Free radicals are well-established to induce senescence, and Doxorubicin-induced senescence has been shown to be associated with free radical generation. We demonstrate that the antioxidants, glutathione (GSH) or N-acetyl cysteine (NAC), were able to collaterally suppress Doxorubicin-induced senescence and autophagy, based on reduced β-Gal staining, LC3-I to II conversion and activation of ATG5, respectively. Similarly, both senescence and autophagy induced by the topoisomerase I inhibitor, camptothecin, were suppressed by GSH or NAC.
Silencing of p53 or p21 expression inhibited both Doxorubicin-induced senescence and autophagy in both breast and colon cancer cells. In contrast, a blockade of autophagy either by the pharmacological inhibitors, 3-methyl adenine or chloroquine, or genetic silencing of ATG5 or ATG7 expression, only served to delay the onset of Doxorubicin-induced senescence. Similarly, a delayed senescence response was observed when autophagy induced by camptothecin or H2O2 was blocked by chloroquine or bafilomycin in MCF-7 cells.
Our studies suggest that: 1. Free radicals, ATM, p53 and p21 are involved in the signaling pathways that promote the autophagic and senescence responses to chemotherapeutic agents; 2. autophagy acts to accelerate senescence; and 3) while chemotherapy induced autophagy and senescence are closely associated, senescence can likely occur in the absence of autophagy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2638. doi:10.1158/1538-7445.AM2011-2638
Abstract 2649: Attenuation of JNK phosphorylation by 4-phenyl-3-butenoic acid in tumorigenic cells
Authors: Burns Timothy J. , Matesic Diane F. 
Published: June 2012

Abstract
The c-Jun N-terminal kinase (JNK) signaling pathway controls many cellular processes such as cell growth, differentiation, and apoptosis. Aberrant JNK activity has been implicated in various cancer types including but not limited to hepatocellular carcinoma, glioblastoma, leukemia, and lung cancer, presumably through activation of the transcription factor activator protein-1 (AP-1). When activated by JNKs, AP-1 is a positive regulator of cell proliferation and many tumorigenic cell types are found to have increased JNK activity. Phosphorylated mitogen-activated protein kinase kinase 4 (pMKK4) and phosphorylated mitogen-activated protein kinase kinase 7 (pMKK7) are known to activate JNKs via phosphorylation. The purpose of this study was to determine the effects of 4-phenyl-3-butenoic acid (PBA) on JNK pathway proteins. PBA is a small molecule anti-inflammatory agent which was previously shown to inhibit growth, increase gap junction intercellular communication, and increase phosphorylation of p38 mitogen activated protein kinase (p38 MAPK) in tumorigenic cells at concentrations that do not similarly affect non-tumorigenic cells. Our studies utilized tumorigenic ras-transformed rat liver epithelial cells (WB-ras) and human lung carcinoma (H2009) cells. Cells were grown to confluence and were subjected to treatment with PBA (0.1 mg/ml) or vehicle for 48 hours. Whole cell lysates were extracted and individual proteins were separated by SDS-PAGE, followed by western blotting using phosphorylation site-specific antibodies to JNK pathway proteins. Quantitative analysis of western blots was performed utilizing densitometry software. PBA attenuated phosphorylation of JNK approximately two-fold in both WB-ras and H2009 lung carcinoma cells. PBA also attenuated phosphorylation of the JNK downstream effector, activating transcription factor 2 (ATF-2). Phosphorylation of MKK4 was decreased following treatment with PBA, while phosphorylation of MKK7 was unaffected. This data suggests that PBA may inhibit growth of tumorigenic cells in part through decreased activation of the JNK pathway via a MKK4 mechanism.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2649. doi:10.1158/1538-7445.AM2011-2649
Abstract 2650: KRIBB801 modulates STAT3 pathway via binding to JAK3
Authors: Kwon Byoung-Mog , Shin Dae-Seop , Han Dong Cho 
Published: June 2012

Abstract
Constituent activation of STAT3 in human cancers causes abnormal proliferation and survival of cancer cell. Therefore, the small-molecules inhibiting STAT3 activity could be used for therapeutical drug in STAT3 dependent proliferating cancer cells. In this report, we screened small-molecules inhibiting STAT3 activity in chemical library containing 1,333 synthetic compounds obtained from “Korea Chemical Bank” through a cell-based luciferase assay system. KRIBB801 was selected as a novel inhibitor of STAT3 activation. KRIBB801 inhibits STAT3 phosphorylation at 1 hour and the expression of the STAT3-regulated genes at the same time point. Inhibition of STAT3 phosphorylation leads to apoptosis of MDA-MB-468. We postulated that inhibition of JAK family proteins or c-Src result in inhibition of STAT3 phosphorylation. Interestingly, phosphorylation of these kinases was mildly inhibited at 1 hr which phosphorylation of STAT3 was perfectly inhibitied. This result implies that inhibition of STAT3 phosphorylation by KRIBB801 is independent event with phosphorylation of upstream kinases. Co-immunoprecipitation shows that KRIBB101 inhibits the JAK3-STAT3 interaction. Moreover, JAK3 molecules were captured by biotylated KRIBB801. Finally, KRIBB801 inhibits kinase activity of JAK3 about 30% at 10 μM in vitro kinase assay. From these results, we suggest that KRIBB801 binds to JAK3 molecules and disturbs JAK3-STAT3 interaction which leads to inhibition of STAT3 phosphorylation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2650. doi:10.1158/1538-7445.AM2011-2650
Abstract 2652: Effect of selective serotonergic reuptake inhibitors on radiation therapy
Authors: Moran Nicci P. , Romano Michelle A. , Warren Graham W. 
Published: June 2012

Abstract
Introduction: Selective serotonergic reuptake inhibitors (SSRIs) are well-established antidepressants commonly used in cancer patients. Studies suggest that SSRIs may play a role in increased cell death in cancer cells; however, the use of SSRIs as adjunctive agents to be used in combination with conventional cancer treatment is not well established. The purpose of this study was to evaluate the effect of SSRIs on cell survival in combination with radiation therapy (XRT).
Methods: Human lung cancer lines (A-549 and H-460) and squamous oropharyngeal cancer cells (FaDu) were treated with several dose escalated SSRIs (fluoxetine, sertraline, paroxetine) alone or in combination with dose escalated XRT (0,2,4,6 Gy) to evaluate the cytotoxic effects of SSRIs using clonogenic survival assays. Western blot analysis was used to evaluate apoptosis (cleaved Caspase-3 and cleaved PARP) and autophagy (LC3-II) to assess potential mechanisms of the effects of SSRIs on XRT.
Results: Fluoxetine, paroxetine, or sertraline alone had a cytotoxic effect on cancer cells in a concentration dependent manner. Sertraline and paroxetine at 2.5-5uM appeared to have an additive effect on XRT with severe cytotoxicity noted at higher concentrations. In contrast, fluoxetine appeared to have a sensitizing effect on cells at 1-10uM in a tumor cell specific manor. Western blot analysis demonstrated that fluoxetine administration decreased cleaved Caspase-3 and cleaved PARP expression at 24 or 48 hours. Evaluation of autophagy using LC3-II demonstrated no change with XRT; however, treatment with fluoxetine increased the expression of LC3-II at 24 and 48 hours in the presence or absence of XRT.
Conclusions: Most SSRIs appear to have a cytotoxic effect alone or in combination with XRT. Fluoxetine appears to have a unique sensitizing effect on XRT in cancerous cells possibly through an increased induction of autophagy. Data supports further examination of fluoxetine as an adjunctive agent in combination with XRT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2652. doi:10.1158/1538-7445.AM2011-2652