bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1482: Triptolide inhibits the growth of osteosarcoma by regulating microRNA-181a via targeting PTEN gene in vivo and in vitro
Authors: Jiang Chunming , Fang Xiang , Wang Xuepeng , Li Maoqiang , Jiang Wu , Zhu Liulong , Bian Zhenyu 
Published: July 2017

Abstract
Objective: We aimed to study the effect of triptolide on OS and the related molecular mechanism.
Methods: The cell viability, apoptosis portion, tumor size, tumor weight and invasion of OS cells were determined. The relative level of miR-181 in OS tissues and the adjacent tissues was determined by qRT-PCR. The target gene of miR-181a was determined and verified by luciferase report assay. At last, OS cells were treated with triptolide and triptolide + miR-181a mimics to verify the relationship between triptolide and miRN-181a.
Results: Triptolide inhibited the cell viability, promoted the apoptosis, decreased the tumor size and weight, and reduced the invasion of OS cells. The level of miR-181a in OS cells decreased significantly after treating with triptolide, and the relative level of miR-181a in OS tissues was markedly higher than that in the adjacent tissues. PTEN was reported and verified the direct target gene of miR-181a. The overexpression of miR-181a decreased the inhibition of triptolide on OS proliferation and promotion on OS apoptosis.
Conclusion: Triptolide inhibited the proliferation of OS by regulating miR-181a via targeting PTEN gene in vivo and vitro.
Note: This abstract was not presented at the meeting.
Citation Format: Chunming Jiang, Xiang Fang, Xuepeng Wang, Maoqiang Li, Wu Jiang, Liulong Zhu, Zhenyu Bian. Triptolide inhibits the growth of osteosarcoma by regulating microRNA-181a via targeting PTEN gene in vivo and in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1482. doi:10.1158/1538-7445.AM2017-1482
Abstract 1491: Mitochondrial dysfunction from defective Cytochrome oxidase complex induces tumorigenic phenotype
Authors: Srinivasan Satish , Guha Manti , Ruthel Gordon , Nakagawa Hiroshi , Avadhani Narayan 
Published: July 2017

Abstract
Mitochondrial defects that affect activity of the electron transport chain (ETC) complexes are associated with several diseases including cancer. Dysfunctional mitochondria resulting from mitochondrial DNA (mtDNA) alterations or exposure to xenobiotics have been shown to initiate retrograde signaling pathway characterized by disrupted membrane potential, elevated cytosolic calcium and activation of Calcineurin, a calcium dependent phosphatase. In some cell types these events form the basis for triggering transcriptional reprogramming that converts non tumorigenic cells to tumorigenic phenotype. Cytochrome oxidase (CcO) is the terminal enzyme of the ETC that catalyzes the transfer of electrons from reduced cytochrome C to oxygen. All the mutations of CcO subunits identified as prevalent in various cancers like prostrate, pancreatic, colon and ovarian cancers have been found in mtDNA encoded subunits. Effect of loss of nuclear subunits leading to reduced Cytochrome oxidase activity on tumor progression are not well studied. Nuclear subunits IVi1 and Vb of CcO are susceptible to various stress conditions like exposure to long term hypoxia, ischemia-reperfusion and treatment with ethanol resulting in selective degradation and loss of activity. Here we report the activation of retrograde signaling by loss of these subunits. Genetic silencing of the subunits IVi1 and Vb, and loss of activity resulted in metabolic shift to glycolysis and was accompanied by increased glucose utilization. Disruption of the CcO complex activated many of the hallmark factors of Ca2+/Calcineurin mediated retrograde signaling. Importantly, rescue of the CcO deficiency by overexpressing CcO subunits or by inhibitors of retrograde signaling pathway attenuated the phenotypic changes such as anchorage independent growth and increased invasive potential. Further, esophageal tumor sections from human patients revealed reduced CcO subunits IVi1 and Vb in the center of the tumor mass suggesting a pathological significance of these findings. Our results show that mitochondrial ETC defect initiates a retrograde signaling and induces genes with major roles in tumor development. (Supported by NIH grants CA-22762 and GM-34883)
Note: This abstract was not presented at the meeting.
Citation Format: Satish Srinivasan, Manti Guha, Gordon Ruthel, Hiroshi Nakagawa, Narayan Avadhani. Mitochondrial dysfunction from defective Cytochrome oxidase complex induces tumorigenic phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1491. doi:10.1158/1538-7445.AM2017-1491
Abstract 1493: LonP1 is required for tumor maintenance and growth
Authors: Amidon Benjamin S. , Wu Dongyun , Bradley John , Ma Jingya , Tsu Christopher , Carideo-Cunniff Elizabeth , Kolev Vihren , Garnsey James , Shah Pooja , Koenig Erik , Liao Hua , Cullis Courtney 
Published: July 2017

Abstract
Proper mitochondrial function is critical for energy production and the cycling of metabolites required for tumor establishment and growth. LonP1 is an ATP-dependent serine protease that is critical for maintaining mitochondrial protein homeostasis by degrading misfolded and damaged proteins in the mitochondrial matrix. Knockdown of LonP1 has been shown to reduce tumorogenesis and is consistent with the model that requires properly functioning mitochondria for tumor establishment. It is unclear what the role of LonP1 is in tumor maintenance and growth from an established tumor, therefore the LonP1 gene was mutated and complemented by a doxycycline-inducible copy of LonP1. These complementation clones have the ability to establish tumors in vivo in the presence of doxycycline, however upon doxycycline withdrawal the tumors regress and show evidence of apoptosis. These xenograft lines permit unique insight into not only potential LonP1 substrates but also the direct and indirect effects from loss of mitochondrial matrix protein homeostasis. Comparison and contrast of these complemented cell lines in vitro and in vivo by expression and proteomic analysis will be discussed.
Citation Format: Benjamin S. Amidon, Dongyun Wu, John Bradley, Jingya Ma, Christopher Tsu, Elizabeth Carideo-Cunniff, Vihren Kolev, James Garnsey, Pooja Shah, Erik Koenig, Hua Liao, Courtney Cullis. LonP1 is required for tumor maintenance and growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1493. doi:10.1158/1538-7445.AM2017-1493
Abstract 1496: Connecting the metallome with metabolism in ovarian cancer
Authors: Shide Eric D. , Amable Lauren 
Published: July 2017

Abstract
Ovarian cancer has historically been diagnosed late stage and lacks effective biomarkers for detection and prognosis. The deregulation of metabolism and signaling cascades inherent of cancer may contribute to aberrant levels of metal within cells. Biological processes essential for cell proliferation require metals for enzyme cofactors, signaling molecules, and structural components. Metallomics is the study of the comprehensive, dynamic metal profile within cells. The goal of our study was to characterize the ovarian cancer metallome at the level of whole cell and mitochondria in comparison to non-cancer. Additionally, cellular metabolism was analyzed to connect the mitochondrial (mito-)metallome to mitochondrial function. Ten human ovarian cancer cell lines were used for experiments: A2780, CAOV3, A2780/CIS, A2780/CP70, ES2, OVCAR3, OVCAR5, SKOV3, TOV112, and TOV21. Three non-cancer human ovarian cell lines of epithelial and fibroblast origin served as controls. Inductively coupled mass spectrometry (ICP-MS) was used to evaluate the metallome by measuring the following metals: calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), phosphorous (P), sulfur (S), selenium (Se), and zinc (Zn). An XF24 Seahorse analyzer was used to measure cellular metabolism and mitochondrial function in the ovarian cancer and non-cancer cell lines. Our results demonstrated that there was a distinct metal profile at the level of the whole cell and mitochondria in ovarian cancer cells compared to non-cancer ovarian cells. The whole cell ovarian cancer metallome consisted of increased Mg, P, and Cu, and decreased Fe, Mn, and Se in comparison to non-cancer. The cancer mito-metallome consisted of increased Mg, P, Cu, Zn, Se, and Ca. Referencing established literature of the known metals that serve as cofactors for mitochondrial proteins, the relationship between the mito-metallome and functional metabolic pathways was established. Changes in cellular metabolism were reflected by changes in the mito-metallome. Our study was the first to evaluate an extensive panel of metals simultaneously in the mitochondria and bridge the unique metal signature of ovarian cancer to cell metabolism. Future proteomics studies will be used to further validate the connection of metals to cellular function. Metallomics and the ovarian cancer cell metallome provide further understanding of how cancer deregulates the metallome and how metallomics may provide an avenue for identifying new cancer biomarkers and allow for effective targeting of cancer with chemotherapy.
Citation Format: Eric D. Shide, Lauren Amable. Connecting the metallome with metabolism in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1496. doi:10.1158/1538-7445.AM2017-1496
Abstract 1504: Tumor-treating fields (TTFields) interfere with biological key properties of glioma cells in vitro
Authors: Silginer Manuela , Weller Michael , Stupp Roger , Roth Patrick 
Published: July 2017

Abstract
Tumor-treating fields (TTFields) are low amplitude alternating electric fields which are supposed to exert anti-tumor effects by targeting dividing tumor cells while sparing cells in the brain not undergoing cell division. Although this novel therapeutic approach has shown encouraging results in phase III trials in glioblastoma, its biological effects on tumor cells have only been poorly understood.
Here, we investigated the effects of TTFields on glioma cells in vitro using the inovitroTM system that allows the application of TTFields to cell cultures. Exposure to TTFields potently induce autophagy and necroptosis and interfere with the migration and invasion of long-term glioma cell lines, but also of glioma-initiating. The combination of TTFields with irradiation or temozolomide (TMZ) reduced viability and clonogenic survival in an additive or synergistic manner. Further studies suggest that the O6-methyl-guanine DNA methyltransferase (MGMT) status does not influence the efficacy of TTFields and TMZ-resistant glioma cells remain responsive to TTFields application, thus making TTFields particularly attractive for the majority of glioblastoma patients with tumors that are unlikely to benefit from TMZ treatment.
In summary, these findings demonstrate that the application of TTFields may interfere with various biological key properties of glioma cells and may allow for a more detailed clinical evaluation of TTFields beyond the clinical data available so far.
Citation Format: Manuela Silginer, Michael Weller, Roger Stupp, Patrick Roth. Tumor-treating fields (TTFields) interfere with biological key properties of glioma cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1504. doi:10.1158/1538-7445.AM2017-1504
Abstract 1514: A novel approach for targeting androgen receptor signaling axis in prostate cancer
Authors: Kaochar Salma , Foley Christopher , Coarfa Cristian , Mitsiades Nicholas 
Published: July 2017

Abstract
Background and Objectives: The androgen receptor (AR) is a ligand-activated transcription factor (TF) that plays critical oncogenic roles. Medical castration therapy is the mainstay treatment for advanced PrCa, but the AR signaling axis frequently remains active in castration-resistant PrCa (CRPC). Despite advances in AR targeting with abiraterone and enzalutamide, disease progression re-occurs in the form of CRPCs that still express AR-dependent genes. This highlights the need for novel approaches to block AR signaling and CRPC growth.
The GATA family of TFs contains six members in mammals, all of which bind a consensus DNA sequence (A/T)GATA(A/G) to regulate gene expression. GATA2 is the predominant family member in prostate luminal epithelial cells. In a search for TFs that control AR expression, we found that GATA2 induces AR gene expression as well as promotes the recruitment of coactivators to the AR transcriptional complex. We found that GATA2 protein expression was strongly correlated with AR protein expression (Spearman's correlation coefficient: 0.323, p-value &lt;0.0001) in our PrCa specimens (n=383). The intensity of GATA2 immunostaining in our BCM patient cohort positively correlated with Gleason score (R=0.37, p-value &lt;0.01) and was a significant predictor of biochemical recurrence (p-value &lt;0.001). We also demonstrated that GATA2 directly promotes expression of both full-length and AR splice-variant, resulting in a strong positive correlation between GATA2 and AR expression in both PrCa cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and AR splice-variants. Using ChIP-Seq we found that GATA2 colocalizes with AR and Forkhead box protein A1 (FOXA1) on chromatin to enhance recruitment of steroid receptor coactivators (SRC1, SRC2, and SRC3) and formation of the transcriptional holocomplex. Lastly, we identified a GATA2 small molecule inhibitor (SMI) that can suppress the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PrCa cell lines. We propose that the inhibition of GATA2 is a ‘first-in-field’ approach to target AR expression and function, including ligand-independent AR, for the treatment of CRPC.
Citation Format: Salma Kaochar, Christopher Foley, Cristian Coarfa, Nicholas Mitsiades. A novel approach for targeting androgen receptor signaling axis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1514. doi:10.1158/1538-7445.AM2017-1514
Abstract 1523: The mechanism of action of BCL6 in glioblastoma
Authors: Jones Nicole M. , Fabre Marie-Sophie , Senanayake Dinindu Sachindra , Hatzi Katerina , Melnick Ari M. , McConnell Melanie J. 
Published: July 2017

Abstract
Glioblastoma (GBM) is the most common and most deadly brain tumor to occur in adults. Initially patients respond to radiation and chemotherapy, which primarily work by causing large amounts of DNA damage, causing apoptosis of the cells. However, this process does not happen effectively in GBM and understanding how these cells resist cell death in response to therapy is key to improving the efficacy of treatment. BCL6 is a transcription factor that stops cell death in response to DNA damage. Recent work in our lab has shown BCL6 to be present in untreated GBM tumors and up-regulated in treated GBM cells. This evidence indicates that BCL6 may be used as a mechanism of therapy resistance by GBM cells. In this study, the objective was to determine the mechanism of action of BCL6 in GBM cells using luciferase reporter assays, quantitative chromatin immunoprecipitation (qChIP) and RNA sequencing. We observed that BCL6 was transcriptionally active in GBM as shown by a reduction in luciferase activity when BCL6 was present. qChIP experiments revealed that BCL6 binding changed over time and was different with different types of DNA-damaging treatment. Preliminary analysis of our RNA sequencing data has identified a unique subset of genes which are upregulated when BCL6 is inhibited and downregulated in response to chemotherapy. These changes indicate that these genes may be regulated by BCL6 in chemotherapy treated cells. All of these results illustrate that BCL6 appears to have an active and relevant function in GBM cells, which demonstrates that BCL6 is an attractive therapeutic target in GBM.
Citation Format: Nicole M. Jones, Marie-Sophie Fabre, Dinindu Sachindra Senanayake, Katerina Hatzi, Ari M. Melnick, Melanie J. McConnell. The mechanism of action of BCL6 in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1523. doi:10.1158/1538-7445.AM2017-1523
Abstract 1525: Chemically induced degradation of the oncogenic transcription factor BCL6
Authors: Kerres Nina , Steurer Steffen , Schlager Stefanie , Bader Gerd , Berger Helmut , Blake Sophia , Caligiuri Maureen , Engen John , Ettmayer Peter , Gerstberger Thomas , Gerlach Daniel , Jacob Roxana , Lucas Simon , Mayer Moriz , Nikolai Mischerikow , Klaus Rumpel , Dirk Scharn , Renate Schnitzer , Voss Tilman , Andreas Zoephel , Kraut Norbert , McConnell Darryl , Mark Pearson , Koegl Manfred 
Published: July 2017

Abstract
The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). It is a DNA-binding protein that represses gene transcription through the recruitment of co-repressor proteins via its BTB domain. Disruption of the interaction of BCL6 with co-repressor proteins interferes with the physiological and oncogenic functions of BCL6. We have used structure-based drug desgin to develop potent compounds that block this interaction with half maximal inhibitory concentration values (IC50s) below 3 nM. In addition to inhibiting co-repressor binding, a subset of the identified inhibitors also caused rapid disappearance of BCL6 protein in cells. This effect was mediated by compound-induced multi-ubiquitylation of BCL6 and degradation by the proteasome and was dependent on the presence of a functional DNA binding domain on BCL6. Compounds that induced BCL6 degradation displayed significantly stronger induction of expression of BCL6-repressed genes than compounds that merely inhibited co-repressor interaction. BCL6-degrading inhibitors had anti-proliferative effects in several DLBCL cell lines, while non-degrading BCL6 inhibitors only had minor effects on proliferation. The fact that the magnitude of effects elicited by this novel class of BCL6 degrading compounds greatly exceeds that of our equipotent classical co-repressor interaction inhibitors offers exciting new opportunities for the development of BCL6-based lymphoma therapeutics.
Citation Format: Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Helmut Berger, Sophia Blake, Maureen Caligiuri, John Engen, Peter Ettmayer, Thomas Gerstberger, Daniel Gerlach, Roxana Jacob, Simon Lucas, Moriz Mayer, Mischerikow Nikolai, Rumpel Klaus, Scharn Dirk, Schnitzer Renate, Tilman Voss, Zoephel Andreas, Norbert Kraut, Darryl McConnell, Pearson Mark, Manfred Koegl. Chemically induced degradation of the oncogenic transcription factor BCL6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1525. doi:10.1158/1538-7445.AM2017-1525
Abstract 1528: Forecasting novel therapies by understanding the role BRD4 in regulating the Notch3 signaling in ovarian cancer
Authors: Villar-Prados Alejandro , Wu Sherry Y. , Roszik Jason , Sood Anil K. , Engelhardt Margaret I. 
Published: July 2017

Abstract
Advances in cancer research have led to the rapid development of novel drug therapies designed for optimal personalized patient care. Despite this surge of treatments, there is still a challenge in accurately predicting the most effective targeted therapy for a specific cancer. Additionally, the potential of systematically identifying and re-purposing currently existing therapeutics designed for one specific cancer to treat other malignancies remains understudied. To address this problem, our group has developed an integrative computational therapy-forecasting algorithm. This algorithm incorporates data from The Cancer Genome Atlas (TCGA) as well as molecular and survival correlations to identify candidate anti-tumor drugs that can be re-purposed for other malignancies by targeting novel pathways. Our computational analysis predicted that bromodomain inhibitors, which inhibit bromodomain-containing proteins such as BRD4, would target the Notch3 pathway in high-grade serous ovarian carcinoma (HGSC). Upregulation of Notch3 plays a crucial role in HGSC tumorigenesis and is associated with worse patient survival. Current Notch3 targeted therapies are not effective, thus designing therapeutic strategies to target Notch3 are critical for HGSC. We hypothesize that inhibition of BRD4 is an effective therapeutic target in HGSC by downregulating the Notch3 pathway. Current in vitro results demonstrated that BRD4 inhibition either by using chemical inhibitors or siRNA results in a decrease in HGSC cell viability by both MTT and 2-D colony formation assays. Furthermore, inhibition of BRD4 resulted in a decrease in both Notch3 transcription and protein levels. Given that BRD4 regulates gene transcription, we performed chromatin immunoprecipitation (ChIP) and observed that BRD4 was present in the Notch3 gene promoter. These findings suggest that by inhibiting BRD4 in HGSC, we can target Notch3 and biologically validates our initial in sillico analysis. The successful completion of this project could have major implications for development of personalized therapies not only for HGSC but for other cancers as well.
Note: This abstract was not presented at the meeting.
Citation Format: Alejandro Villar-Prados, Sherry Y. Wu, Jason Roszik, Anil K. Sood, Margaret I. Engelhardt. Forecasting novel therapies by understanding the role BRD4 in regulating the Notch3 signaling in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1528. doi:10.1158/1538-7445.AM2017-1528