bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2889: Aitongxiao (ATX) induces apoptosis and blocks exosomes release in human liver carcinoma cells
Authors: Huang Ming B. , Leng Jiang 
Published: August 2018

Abstract
Background: The role of exosomes in cancer development has become the focus of much
research, due to the many emerging roles possessed by exosomes. These contents of exosomes
could contribute to tumorigenesis. We discovered Aitongxiao (ATX), a group of 80% alcohol
extracts from 15 plants, has been shown to have an anti-tumor effect on liver carcinoma; however,
the mechanism for the anti-cancer effect of ATX on human liver carcinoma cells is still unclear.
Objective: Due its inhibitory effects on chemical carcinogenesis and inflammation, Aitongxiao
(ATX) has been proposed as an effective agent for the prevention or treatment of human
carcinoma. In this study, we aimed to explore the effect of ATX on human liver carcinoma cells.
Methods: The inhibitory effect of Aitongxiao (ATX) on proliferation of HepG2 and HKCL-C3 cells
was assessed by CCK-8 assay. The cell cycle distribution and cell apoptosis were determined by
flow cytometry. The expression of Alix and CD63 exosomes marker proteins, were detected by
Western Blotting. The exosomes protein concentration was measured by and fluorescent
antibody assays. Exosomes size and particle number were measured by NanoSight analysis.
Results: Aitongxiao (TAX) inhibited the growth of human liver carcinoma cells in a dose and time-
dependent manner. Flow cytometry analysis showed that ATX induced G2/M phase arrest and
cell apoptosis. ATX treatment promoted the cleavage of caspase 3. In addition, the ATX reduced
exosomes release from HepG2 cells, and lose-dose ATX significantly enhanced the growth
inhibition induced by 5-Fu.
Conclusions: Aitongxiao (ATX) could inhibit the growth of human liver carcinoma cells in vitro.
ATX induced both apoptosis and cell cycle arrest and blocked exosomes release, probably
through the inhibition of STAT3 function. Lose-dose ATX significantly enhanced the growth
inhibitory effect of 5-FU on breast cancer cells, further indicating the potential clinical values of
ATX for the prevention or treatment of human liver carcinoma.
Keywords: Aitongxiao, liver carcinoma, HepG2 cells, apoptosis, exosomes
Citation Format: Ming B. Huang, Jiang Leng. Aitongxiao (ATX) induces apoptosis and blocks exosomes release in human liver carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2889.
Abstract 2896: A genome-wide CRISPR/Cas9 pooled screen identifies EML4-ALK variant-specific synthetic lethal partners of HSP90 inhibitors
Authors: Licciardello Marco P. , Clarke Paul A. , Workman Paul 
Published: August 2018

Abstract
The chromosomal rearrangement generating the EML4-ALK fusion protein occurs in 5–7% of patients with non-small-cell lung cancer (NSCLC). Distinct breakpoints give rise to variants with different EML4 fragments and an invariable ALK kinase domain. Patients treated with ALK tyrosine kinase inhibitors, such as crizotinib or alectinib, inevitably develop resistance to the drugs and need alternative therapies. EML4-ALK v1 and v3a/b, the most common variants of the fusion oncogene, display distinct cellular localization and different sensitivity to the inhibition of HSP90 chaperoning activity. In the clinic, HSP90 inhibitors have shown encouraging results in EML4-ALK+ NSCLC patients, but the responses have been heterogeneous. Currently, there is no EML4-ALK variant-based classification of patients and this might have contributed to confounding results in clinical trials. Moreover, the identification of additional biomarkers of sensitivity could further improve patient stratification and suggest potential combinatorial regimes. As chaperones are molecular hubs enriched for synthetic lethal partners, we performed a CRISPR/Cas9-based pooled screen in human NSCLC cell lines carrying different EML4-ALK variants in the presence of non-lethal concentrations of an HSP90 inhibitor. In the screen, we found already described as well as previously unreported EML4-ALK variant-specific synthetic lethal interactions. We are currently dissecting the mechanism behind these interactions, and evaluating their therapeutic potential for EML4-ALK+ NSCLC patients.
Citation Format: Marco P. Licciardello, Paul A. Clarke, Paul Workman. A genome-wide CRISPR/Cas9 pooled screen identifies EML4-ALK variant-specific synthetic lethal partners of HSP90 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2896.
Abstract 2906: eEF1A2 interacts with and inhibits PKR to enhance cancer cell survival
Authors: Martínez-Leal Juan F. , Losada Alejandro , Muñoz Maria Jose , Martinez-Diez Marta , Dominguez Juan Manuel , Galmarini Carlos M. 
Published: August 2018

Abstract
Human translation elongation factor 1α2, encoded by the eEF1A2 gene, is a pro-oncogenic protein absent from the majority of body tissues (with exception of brain, heart and skeletal muscle1), but expressed in many cancers1-3, where it provides tumor cells with improved fitness and survival. Though its canonical function is delivering aminoacyl-tRNAs to the ribosome, other “moonlighting” functions such as enhancing sphingosine kinase4,5 or antioxidant (most probably through peroxiredoxin-1 stimulation) activities6 have been described for the elongation factor. Recently, we have reported that eEF1A2 is the target for plitidepsin, a marine-derived cyclic depsipeptide currently under development for the treatment of relapsed or refractory multiple myeloma patients7. We have also confirmed that eEF1A2 interacted with previously described partners as PRDX1 and SPHK and enhanced their pro-survival activities8. Here we investigated the role of new “moonlighting functions” of eEF1A2 in the maintenance of the tumor phenotype and survival of cancer cells. Through co-immunoprecipitation and HPLC/MS we have uncovered the interaction between eEF1A2 and dsRNA-activated protein kinase (PKR, EIF2AK2). We have analyzed the kinase activity of PKR in the presence of eEF1A2, demonstrating that PKR activity is inhibited when complexed with eEF1A2. This complex is disrupted after plitidepsin binding to eEF1A2, rendering PKR active. Once activated, the kinase triggers a MAPK cascade and the NF-κB signaling pathway, leading to the activation of the extrinsic apoptotic pathway and the death of the tumor cell. Taken together, these results show that the fitness boost that the moonlighting functions of eEF1A2 provide to cancer cells, which are important for their growth and survival, constitutes an Achilles heel that can be purposely exploited in anticancer therapy. 1 Abbas, W., Kumar, A. & Herbein, G. Front Oncol 5, 75 (2015). 2 Anand, N. et al. Nature genetics 31, 301-305 (2002). 3 Li, Z. et al. PloS one 5, e10755 (2010). 4 Leclercq, T. M., Moretti, P. A., Vadas, M. A. & Pitson, S. M. J Biol Chem 283, 9606-9614 (2008). 5 Leclercq, T. M., Moretti, P. A. & Pitson, S. M. Oncogene 30, 372-378 (2011). 6 Chang, R. & Wang, E. J Cell Biochem 100, 267-278 (2007). 7 Losada, A. et al. Sci Rep 6, 35100 (2016) 8 Losada, A. et al. Abstract #1165, AACR Annual Meeting (2017)
Citation Format: Juan F. Martínez-Leal, Alejandro Losada, Maria Jose Muñoz, Marta Martinez-Diez, Juan Manuel Dominguez, Carlos M. Galmarini. eEF1A2 interacts with and inhibits PKR to enhance cancer cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2906.
Abstract 2910: Identification of URST1 as a novel prognostic biomarker and therapeutic target for various subtypes of breast cancer
Authors: Nakamura Masako , Takano Atsushi , Thang Phung Manh , Miyagi Yohei , Daigo Yataro 
Published: August 2018

Abstract
Breast cancer is one of the most common causes of cancer death for women worldwide. To identify diagnostic and therapeutic targets for breast cancer, we screened molecules that were highly expressed in the majority of breast cancers by our gene expression profile database. During this process, we identified URST1 (up-regulated in solid tumor 1) as a candidate. Immunohistochemical analysis showed that URST1 was expressed in 195 of 257 (75%) breast cancer cases (69% in luminal type, 88% in HER2-positive cancer, 86% in Triple-negative cancer) that had undergone curative surgery, whereas no staining was observed in adjacent normal breast tissues. URST1 expression was significantly related to poor clinical outcome for breast cancer patients (P = 0.01, Log-rank test) and multivariate analysis showed that it was an independent prognostic factor. Knockdown of endogenous URST1 expression by siRNAs against URST1 or treatment with URST1 inhibitor significantly inhibited the growth of breast cancer cells through cell cycle arrest at G2/M phase. Our data suggest that URST1 is likely to be a prognostic biomarker and therapeutic target for various subtypes of breast cancers.
Citation Format: Masako Nakamura, Atsushi Takano, Phung Manh Thang, Yohei Miyagi, Yataro Daigo. Identification of URST1 as a novel prognostic biomarker and therapeutic target for various subtypes of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2910.
Abstract 2918: Decursin from Angelica gigas Nakai regulates CXCR7 expression and its downstream signaling in gastric cancer cells
Authors: Kim Solbi , Kim Nayoung , Ryu Hyewon , Song Gyu-Yong , Lee Hyo Jin 
Published: August 2018

Abstract
Background: C-X-C motif chemokine receptor 7 (CXCR7) is a member of the G protein-coupled receptor family and is reported to be involved in the invasion, migration and tumor progression of various cancers. However, few compounds regulate CXCR7 expression. Therefore, compounds that negatively regulate CXCR7 may inhibit tumor progression and thus serve as candidates for effective anti-cancer drugs. In this study, we investigated the regulation of CXCR7 by decursin derived from Angelica gigas and its downstream signaling.
Methods: A CXCR7-overexpressing stable cell line was established in gastric cancer cells, and the expression of membrane CXCR7 was confirmed by flow cytometry and immunocytochemistry. Cell viability was examined using the CCK-8 assay. We investigated the potential of decursin to inhibit cell migration and invasion using a Transwell system. We also examined the mechanism of CXCR7 regulation by decursin by performing Western blot analysis of downstream proteins using phospho-specific antibodies.
Results: CXCR7 overexpression significantly increased the proliferation, invasion and migration of gastric cancer cells. In addition, spheres were well formed under anchorage-independent conditions in CXCR7-expressing gastric cancer cells. Levels of phospho-Stat3 and -Akt, positive regulators of cancer progression, were significantly increased. Decursin treatment reduced CXCR7 expression at the cellular membrane, and significantly decreased cancer cell invasion and migration. When treated with decursin, the sphere formation capacity decreased in a dose-dependent manner. In addition, decursin decreased the phosphorylation of Stat3 and its downstream target, c-Myc; however, it had no effect on Akt phosphorylation.
Conclusion: Decursin reduces the invasion, migration and tumor progression of cancer cells by inhibiting CXCR7. Decursin could be proposed as a new anti-cancer drug by decreasing the expression of CXCR7, which is believed to be a therapeutic target in gastric cancer.
Citation Format: Solbi Kim, Nayoung Kim, Hyewon Ryu, Gyu-Yong Song, Hyo Jin Lee. Decursin from Angelica gigas Nakai regulates CXCR7 expression and its downstream signaling in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2918.
Abstract 2919: Discovery of small-molecule compounds targeting c-MYC using a novel cell-based screen
Authors: Mangatt Biju , Pietra Anthony D. , Waszkiewicz Anna , Jaworski Jon-Paul , Ghidelli-Disse Sonja , Berrodin Thomas J. , Sherk Christian S. , Meinhold Derrick W. , Rutkowska-Klute Anna , Sundaram Shanker K. , Ganji Gopinath , Halsey Wendy S. , Livi George P. , Li William , Mack James , Romeril Stuart P. , Minthorn Elisabeth A. , Kumar Rakesh , Drewes Gerard C. , Heerding Dirk A. , Kallal Lorena A. , Buser Carolyn A. , Medina Jesus R. 
Published: August 2018

Abstract
Elevated expression of the c-MYC oncogene (either due to gene amplification, translocation, abnormality in upstream signaling pathways and/or protein stabilization) is one of the most common abnormalities in human cancers. Efforts to identify direct pharmacological inhibitors of c-MYC function have not yet yielded drug-like molecules. Therefore, we sought to pursue alternative screening strategies for this classically “undruggable” transcription factor. We developed a novel antibody-based high-throughput HTRF screening assay that specifically detects endogenous c-MYC protein levels in a MYC amplified cancer cell line. Taking advantage of the short half-life of c-MYC, both at the protein and mRNA level, we conducted a cell-based screen of the GSK screening collection to identify compounds that can rapidly decrease c-MYC protein levels. Elimination of false positive hits using stringent triage assays successfully identified two valid hit series exemplified by GSK970 and GSK417. Molecular mode of action studies revealed these molecules inhibit MYC transcription by binding to the minor groove of DNA with AT sequence specificity. Unfortunately, this mechanism of c-MYC inhibition demonstrated poor in vivo translatability as tissue DNA acts as a molecular sink, effectively sequestering compound, and limiting its pharmacodnyamic response.
Citation Format: Biju Mangatt, Anthony D. Pietra, Anna Waszkiewicz, Jon-Paul Jaworski, Sonja Ghidelli-Disse, Thomas J. Berrodin, Christian S. Sherk, Derrick W. Meinhold, Anna Rutkowska-Klute, Shanker K. Sundaram, Gopinath Ganji, Wendy S. Halsey, George P. Livi, William Li, James Mack, Stuart P. Romeril, Elisabeth A. Minthorn, Rakesh Kumar, Gerard C. Drewes, Dirk A. Heerding, Lorena A. Kallal, Carolyn A. Buser, Jesus R. Medina. Discovery of small-molecule compounds targeting c-MYC using a novel cell-based screen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2919.
Abstract 2921: Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy
Authors: Qian Guoqing , Yao Weilong , Hall Williams D. , Shanmugam Mala , Lonial Sagar , Sun Shi-Yong 
Published: August 2018

Abstract
Background: Agents that inhibit bromodomain and extra-terminal domain (BET) protein, a promising cancer therapeutic target which imposes epigenetic modulation of gene expression, have been actively tested in the clinic as potential anticancer drugs. Some proteasome inhibitors such as carfilzomib (CFZ) are FDA-approved drugs for the treatment of patients with advanced multiple myeloma. The current study focuses on studying the combination of a BET inhibitor (e.g., JQ1) and a proteasome inhibitor (e.g., CFZ) as a novel cancer therapeutic strategy.
Methods: Diverse solid and hematologic cancer cell lines were used to test the effects of the combinations on cell survival and apoptosis via SRB assay, colony formation assay, flow cytometric analysis, and Western blotting. Bim knockout cell lines were generated using a CRISPR-based method for mechanistic study. Transcriptional regulation of target genes was examined by quantitative RT-PCR. The anti-tumor effects were also examined in a xenograft tumor model.
Results: The tested combinations (e.g., JQ1 with CFZ) synergistically decreased cancer cell survival and enhanced apoptosis in vitro and inhibited tumor growth in vivo. The combinations dramatically induced apoptosis accompanying with enhanced elevation of Bim and several ER stress marker proteins. Bim knockout significantly blocked apoptosis induced by the combinations in both HCT116 and L363 cells. Transcriptional upregulation of Bim by the combinations was observed.
Conclusions: The enhanced anti-tumor effects of dual inhibition of BET and proteasome is likely due to augmented induction of ER stress and Bim-dependent apoptosis. Our findings warrant further investigation of this combinatorial strategy as an effective regimen against cancer in the clinic.
Citation Format: Guoqing Qian, Weilong Yao, Williams D. Hall, Mala Shanmugam, Sagar Lonial, Shi-Yong Sun. Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2921.
Abstract 2981: Clonal deletion of tumor-specific T cells by combination checkpoint blockade compromises antitumor efficacy in low tumor burden states
Authors: Pai Chien-Chun Steven , Lu Xiaoqing , Simons Donald , DuPage Michel , Roybal Kole T. , Chen Mingyi , Kwek Serena , Casbon Amy-Jo , Kinsbury Gillian A. , Fong Lawrence 
Published: August 2018

Abstract
A myriad of combination immunotherapies is being developed as cancer treatments with the goal of enhancing antitumor immunity. We found that depending on the disease setting, combined immune checkpoint blockade may not always lead to synergistic antitumor effects. While combined anti-CTLA-4 and anti-PD-1 improves control of established tumors, this combination can paradoxically compromise antitumor immunity in the low tumor burden state in preclinical models as well as in melanoma patients. This paradoxical outcome results from treatment-induced apoptosis of tumor-specific T cells. These changes further alter the overall T-cell receptor repertoire. Activated tumor-specific T cells express higher levels of IFN-γ receptor and are more susceptible to apoptosis. Deficiency of IFN-γ receptor on immune cells rescues this phenotype and restores antitumor activity. Additionally, tumor-specific T cells lacking the IFN-γ receptor demonstrate a significant survival advantage compared to their wild-type counterparts in tumor-bearing mice receiving combination therapy. Finally, combination therapy induces significantly higher levels of IFN-γ in the low versus high tumor burden state on a per cell basis, reflecting their less exhausted immune status. Thus, the optimal immunotherapy strategy may depend on disease context, and may not always favor more potent combination immunotherapies.
Citation Format: Chien-Chun Steven Pai, Xiaoqing Lu, Donald Simons, Michel DuPage, Kole T. Roybal, Mingyi Chen, Serena Kwek, Amy-Jo Casbon, Gillian A. Kinsbury, Lawrence Fong. Clonal deletion of tumor-specific T cells by combination checkpoint blockade compromises antitumor efficacy in low tumor burden states [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2981.
Abstract 2998: Dynamic 3d chromosomal landscapes in acute leukemia
Authors: Thandapani Palaniraja , Kloetgen Andreas , Lazaris Charalampos , Chen Xufeng , Ntziachristos Panagiotis , Tsirigos Aristotelis , Aifantis Iannis 
Published: August 2018

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 10-15% of pediatric and 25% of adult ALL cases. Despite improved prognosis driven by the significant advances in the molecular understanding of T-ALL, the outcome of T-ALL patients with primary resistant and relapsed leukemia remains poor. Recent evidences have highlighted a role for changes in 3D chromatin architecture in cancer progression. Herein, for the first time we explored genomewide changes in chromatin organization in primary T-ALL samples relative to T cells from healthy donors. We show how the organization of topologically associated domains (TADs) influences key oncogenic and tumor-suppressive loci by modifying the promoter-enhancer landscape, deregulating the transcriptional program and ultimately causing disease progression.
To comprehensively characterize the chromatin landscape of clinically relevant loci in T-ALL, we sought to identify changes in intra-TAD activity and TAD disruptions on a genome-wide scale. We developed and implemented new computational approaches for Hi-C data analysis with a focus on Hi-C data integration with ChIP-Seq and RNA-Seq. We found significant correlations of TAD activity with CTCF occupancy, super-enhancer activity and gene expression of leukemia relevant loci. Furthermore, among the dozens of TAD disruptions we identified, we found a novel TAD “fusion” event around the MYC locus, which allows for chromatin interactions between a recently reported Notch-dependent MYC super-enhancer and promoter to drive overexpression of MYC. This particular TAD fusion is accompanied by a complete CTCF loss in the TAD boundary and increased MYC expression in T-ALL samples. Overall, this study sheds new light into how changes in chromatin architecture influence disease progression by restructuring oncogene and tumor suppressor landscapes.
Citation Format: Palaniraja Thandapani, Andreas Kloetgen, Charalampos Lazaris, Xufeng Chen, Panagiotis Ntziachristos, Aristotelis Tsirigos, Iannis Aifantis. Dynamic 3d chromosomal landscapes in acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2998.