bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3567: A novel E2F1-regulated lncRNA, XLOC_000190, is required for S phase progression and cell proliferation
Authors: Ginsberg Doron , Nizri-Megnaji Tali , Baruch Esther 
Published: August 2019

Abstract
Long non-coding RNAs (lncRNAs) are major regulators of many cellular processes including cell cycle progression and cell proliferation. The pivotal transcription factor E2F1 induces both proliferation and cell death and is a critical downstream target of the tumor suppressor RB. The RB/E2F pathway is often inactivated in human tumors resulting in deregulated E2F activity. Here, we report that the human lncRNA XLOC_000190 is an E2F1- regulated lncRNA that plays a role in S phase progression. XLOC_000190 levels are elevated upon activation of E2F1. Furthermore, knockdown of E2F1 and E2F3 reduce XLOC_000190 levels and endogenous E2F1 binds the XLOC_000190 promoter. Moreover, expression of XLOC_000190 is cell cycle regulated and peaks near G1/S transition and in early S. Inhibition of XLOC_000190 expression increases percentage of S phase cells, suggesting that XLOC_000190 plays a role in S phase progression. Also, silencing of XLOC_000190 in cells that are synchronized at the G1/S delays progression of cells through S phase. In agreement with its suggested role in S phase, prolonged silencing of XLOC_000190 inhibits proliferation of human cancer cells in culture. XLOC_000190 is a nuclear lncRNA and its gene is localized downstream to the protein-coding gene CDKN2C that encodes the p18ink4c CDK inhibitor. In search for XLOC_000190 mode of action we do not detect any changes in the expression of this neighbor upon XLOC_000190 silencing. However, XLOC_000190 silencing leads to a significant decrease in the level of Ribonucleotide Reductase Regulatory Subunit M2 (RRM2), which is a critical player in S phase progression. Additional data indicate that RRM2 mediates, at least in part, the effect of XLOC_000190 on S phase progression. Importantly, low levels of XLOC_000190 are associated with increased survival of kidney cancer patients.
In conclusions, our data identify XLOC_000190 as a novel E2F-regulated lncRNA that has a potential role in human cancer and regulates cell-cycle progression and cell proliferation, at least in part, via regulation of RRM2.
Citation Format: Doron Ginsberg, Tali Nizri-Megnaji, Esther Baruch. A novel E2F1-regulated lncRNA, XLOC_000190, is required for S phase progression and cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3567.
Abstract 3568: Metastasis-promoting role of H19 long non-coding RNA in pancreatic cancer cells
Authors: Sasaki Norihiko , Toyoda Masashi , Yoshimura Hisashi , Matsuda Yoko , Arai Tomio , Itakura Yoko , Gomi Fujiya , Aida Junko , Ishiwata Toshiyuki 
Published: August 2019

Abstract
The H19 long non-coding RNA is highly expressed and carries out various functions in different types of cancers. Recently, we reported that H19 contributes to the metastasis of pancreatic ductal adenocarcinoma (PDAC) cells and its inhibition reduces metastasis in vivo. However, the molecular mechanisms underlying the metastasis-promoting role of H19 in PDAC cells remain unclear. With a focus on cancer stem cells (CSCs), we elucidated the mechanisms by which H19 regulates PDAC metastasis through the overexpression and knockdown of H19 in PDAC cells. To determine whether H19 is expressed heterogeneously or homogeneously in human PDAC cells, we examined its expression in PANC-1 cells using a highly sensitive in situ hybridization technique. Under 2D-culture conditions, PANC-1 cells showed heterogeneous H19 expression and the presence of small populations of H19-expressing cells. In contrast, numerous H19-expressing PANC-1 cells were detected in 3D-cultured spheres. These results suggest that H19 is expressed in CSC-like cells among PANC-1 cells. To investigate the involvement of H19 in the development of CSC characteristics, we examined self-renewal ability, anti-cancer drug resistance, and CSC-marker expression. Sphere formation of PDAC cells depended on H19expression. However, other CSC characteristics of the cells, including CSC-marker expression and anticancer-drug resistance were unaffected by H19 levels. In addition to its role in the development of CSC characteristics, we investigated the involvement of H19 in stromal invasion, which is a key step in the metastatic cascade. Although the invasion ability of PDAC cells was dependent on H19 expression, metalloproteinase activity, a key mediator of invasion, was independent of H19 expression. During the process of invasion, a critical event is the adhesion of cancer cells to the extracellular matrix. Therefore, we investigated whether H19 contributes to this cell-to-matrix adhesion step. We found that H19 promoted cell adhesion by regulating the expression of integrins and CD24. Notably, the increased adhesion of H19-overexpressing cells was blocked by an anti-β1-integrin antibody, which resulted in the inhibition of sphere formation and invasion. Taken together, H19 plays critical roles in CSC self-renewal and cell adhesion of PDAC cells that lead to invasion and metastasis. Our findings suggest that H19 represents a novel therapeutic target for the metastasis of pancreatic cancer.
Citation Format: Norihiko Sasaki, Masashi Toyoda, Hisashi Yoshimura, Yoko Matsuda, Tomio Arai, Yoko Itakura, Fujiya Gomi, Junko Aida, Toshiyuki Ishiwata. Metastasis-promoting role of H19 long non-coding RNA in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3568.
Abstract 3579: Long non-coding RNA ADAMTS9-AS2 inhibits ovarian tumor growth via Annexin A1
Authors: Rodriguez-Aguayo Cristian , Bayraktar Emine , Mangala Lingegowda S. , Ivan Cristina , Lopez-Berestein Gabriel , Sood Anil K. 
Published: August 2019

Abstract
Non-coding RNAs (ncRNA), which account for more than 75% genome transcripts, have unique functions in regulating cancer pathogenesis. Long non-coding RNAs (lncRNAs) are key regulators of gene expression and are involved in cancer progression and metastasis. However, the role of long non-coding RNAs (lncRNAs) in high-grade serous ovarian cancer (HGSC) is not well understood. We used the NCode™ non-coding RNA array to screen downregulated lncRNAs in HGSCs. After analyzing the array data of lncRNAs in HGSCs (n=29) and normal ovarian (n=11) samples, the probes mapping to the top 25 most down-regulated non-coding RNAs were analyzed. Two lncRNAs (ADAMTS9-AS1 and ADAMTS9-AS2) were identified as the antisense of gene ADAMTS9, and we validate by in vitro translation assay, q-RT-PCR, in-situ hybridization and the biological functions of ADAMTS9-AS2 in ovarian cancer cells. Moreover, using A2780-CP20 orthotopic mouse models of ovarian cancer, we further demonstrated restoring ADAMTS9-AS2 resulted in profound reduction of tumor growth and metastasis. Here, we demonstrate that ADAMTS9-AS2 is highly down-regulated (5.01x10-13 and 1.6x10-19) in ovarian cancers. Overexpression of ADAMTS9-AS2 leads to significantly increased apoptosis (7.5% control and 19.5% AS2OE) and decreased proliferation (49.5% control and 37.0% AS2OE) compared with controls. Consistently, increased expression of ADAMTS9-AS2 led to significantly reduced tumor burden in A2780-CP20 orthotopic ovarian cancer mouse models. We identified the promoter region of Annexin A1 as the major target of ADAMTS9-AS2. The binding of lncRNA ADAMTS9-AS2 to the promoter region can facilitate the expression of tumor suppressor Annexin A1 thereby decrease the proliferation and increase apoptosis of cancer cells. Collectively, our data point to an important role for ADAMTS9-AS2 as a tumor suppressor in ovarian cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Cristian Rodriguez-Aguayo, Emine Bayraktar, Lingegowda S. Mangala, Cristina Ivan, Gabriel Lopez-Berestein, Anil K. Sood. Long non-coding RNA ADAMTS9-AS2 inhibits ovarian tumor growth via Annexin A1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3579.
Abstract 358: Inhibition of AKT phosphorylation in acute myeloid leukemia by ISC 4
Authors: Thakur Shreya , Annageldiyev Charyguly , Ramisetti Srinivasa , Patel Trupti , Iyer Saumya , Dhanyamraju Pavan , Amiin Shantu , Sharma Arun , Claxton David , Sharma Arati 
Published: August 2019

Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with percent remission of 35-40% for younger patients and 5-15% for older patients and a survival of 5-10 months if left untreated. This emphasizes the urgent unmet need for new therapeutics in AML. The activation of PI3K/AKT signaling pathway plays an important role in cellular survival, proliferation and regulation of apoptosis in cancer cells including leukemia. Recent studies showed that activation of AKT may correlate with poor prognosis in AML. Furthermore, mutations such as FLT3-ITD in the PI3K-AKT pathway causing constitutive activation of AKT, are very common in AML, therefore, it remains as an important target for AML treatment. Phenylbutyl isoselenocyanate (ISC-4), a small drug-like molecule that is developed by our group through optimization of naturally occurring isothiocyanates, targets the P13K-AKT pathway in melanoma and other gastrointestinal malignancies. In this study, we demonstrated potent activity of ISC-4 against AML. We tested the cytotoxicity of ISC-4 in various human AML cell lines (n=6) and in samples collected from AML patients (n=8). AML cell lines exhibited dose-dependent sensitivity to ISC-4 in the low micromolar range (IC50: 2-5 uM) as did most primary AML cases. Western blotting showed a dose dependent decrease in AKT phosphorylation in MV-4-11 and AML-OCI3 cell lines, and lead to an increase in cleaved PARP levels, indicating the induction of apoptosis. Furthermore, ISC-4 treatment reduced the clonogenicity of primary AML cells at relatively low concentrations. Future studies will aim to further develop ISC-4 as a single agent and in combination with anti-leukemic agents and demonstrate the preclinical efficacy in AML animal models including AML patient derived xenografts (PDXs). Together, these data demonstrates the therapeutic potential of ISC-4 that can be a promising drug candidate for further development as a novel therapy for AML.
Citation Format: Shreya Thakur, Charyguly Annageldiyev, Srinivasa Ramisetti, Trupti Patel, Saumya Iyer, Pavan Dhanyamraju, Shantu Amiin, Arun Sharma, David Claxton, Arati Sharma. Inhibition of AKT phosphorylation in acute myeloid leukemia by ISC 4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 358.
Abstract 3587: Targeting cancer metabolism: A novel approach for improved radiotherapy
Authors: Taori Suchet , Naz Sarwat , Gamson Janet , Mathias Askale , Cook John , Mitchell James B. 
Published: August 2019

Abstract
One key distinguishing hallmark of cancer cells includes a deregulated cellular metabolism that can be reprogrammed to preferentially exhibit dependence on glycolysis over oxidative phosphorylation (OXPHOS) even in the presence of oxygen (commonly known as “Aerobic Glycolysis” or the Warburg Effect). The bi-directional conversion of glucose to lactate in the presence of oxygen is mainly driven by the activity of the lactate dehydrogenase enzyme (LDH), of which, its A isoform is highly overexpressed in a variety of tumors. In the present study we characterized two novel LDH inhibitors (NCI-006 and NCI-737) in combination with ionizing radiation (IR) for their anti-cancer and radio-sensitization effects across tumor types. This study primarily examined effects of this novel combination therapy in cell lines of Pancreatic (MiaPaca, Hs766T, Panc-1), Lung (H460, A549), Head and Neck (FaDU, UMSCC-1), and Prostate (DU145, PC3) origin. Our preliminary results indicated that targeting LDH in conjunction with IR can enhance radiosensitivity under both hypoxic and normoxic conditions across glycolytic tumor cell lines while not affecting non-glycolytic/normal cells (1522, skin fibroblast) in vitro. Further we established that this enhanced radiosensitivity could be attributed to reduced DNA repair as seen by enhanced expression of y-H2AX and reduced ATP generation. Our results also indicated that increased expression of lactate and glucose transporters, combined with cellular bioenergetics changes, leads to a reprogramming of cells to OXPHOS. Lastly, we found that inhibition of OXPHOS and NAD+ in conjunction with these novel LDH inhibitors promotes metabolic synthetic lethality in vitro. As cancer patients continue to receive radiation for local tumor control, we hope that future studies targeting cancer metabolic vulnerabilities in combination with IR in vivo will enhance the therapeutic ratio of radiotherapy.
*The LDH inhibitors used in this study were provided by the NCI Experimental Therapeutics (NExT) Program
Citation Format: Suchet Taori, Sarwat Naz, Janet Gamson, Askale Mathias, John Cook, James B. Mitchell. Targeting cancer metabolism: A novel approach for improved radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3587.
Abstract 3594: GLUT1 as a metabolic target in glioblastoma therapy
Authors: Labak Collin M. , Guda Maheedhara R. , Jain Neha , Smith Chase P. , Cain Charles P. , Tsung Andrew J. , Velpula Kiran K. 
Published: August 2019

Abstract
Glioblastoma (GBM) is an aggressive diffuse glioma with poor prognosis due to lack of sound therapeutic options. As in many aggressive tumors, GBMs create a hypoxic microenvironment and switch to glycolytic metabolism from oxidative phosphorylation in what is known as the Warburg Effect. Here, we hypothesize that strategically inhibiting influx of glucose via targeting GLUT1 may reverse the Warburg Effect and selectively slow tumor progression. Nanostring data suggests an aberrant metabolic clincial profile in our cohort of GBM patients. Datamining studies and immunoblot analysis were conducted on these same human GBM specimens to demonstrate upregulated GLUT1. Mass spectrometric analysis was performed on GLUT1 precipitated from mesenchymal subtype patient-derived xenograft (PDX). Zonula Occludens adhesion studies were carried out to determine GLUT1 inhibition's effects on cell-cell adhesion structures. Finally, ATP, lactate release, and glucose uptake assays were performed on PDX and GLUT1-silenced PDX to demonstrate a normalized metabolic phenotype when GLUT1 is silenced. Our work suggests that GLUT1 overexpression plays a major role in the metabolic profile of mesenchymal subtype GBM, and that targeting its overexpression could prove effective in reversing the Warburg Effect in GBM cells and ultimately improving patient outcomes.
Citation Format: Collin M. Labak, Maheedhara R. Guda, Neha Jain, Chase P. Smith, Charles P. Cain, Andrew J. Tsung, Kiran K. Velpula. GLUT1 as a metabolic target in glioblastoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3594.
Abstract 36: Application of patients derived organoids as co-clinical model
Authors: Cho Young-Won , Kim Hwang-Phill , Min Dong Wook , Lim Yoojoo , Song Sang-Hyun , Han Sae-Won , Kim Tae-You 
Published: August 2019

Abstract
Organoids are known to best in vitro model system which mostly mimic genetic, phenotypic feature of its origin. And it is expected and suitable to variable disease modeling and study. For cancer modeling using organoids as co-clinical model, our group derived organoids from 40 colorectal tumor including lymph node, terminal ileum metastatic tumor and ascites. Whole exome sequencing of matched tumor organoids and tissues was performed and their somatic mutation concordance was analyzed. As a results, Organoids reflect their genetic statues of the original tumor tissue and their phenotypic features are maintained. In order to prove the appliance of these organoids as a co-clinical model, clinical drugs on colorectal cancer such as 5-Fluorouracil, oxaliplatin, SN38 and cetuximab were tested. The drug results reflected the actual clinical outcome of the corresponding patients. To find the precise drug treatment option for conventional chemo-refractory patients, we performed 134 anti-cancer drug library screening. Organoids with specific mutations were sensitive to drugs which target these corresponding mutations. For instance, organoid with RNF43 mutation was sensitive to porcupine inhibitor which suppresses auto- and paracrine WNT- driven growth. In conclusion, we suggest that patient derived organoids can be applied in cancer treatment as a co-clinical model, due to their highly correlated genetic information and drug sensitivity with those of the patients themselves.
Citation Format: Young-Won Cho, Hwang-Phill Kim, Dong Wook Min, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim. Application of patients derived organoids as co-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 36.
Abstract 3604: Synthetic lethality therapy for lung cancers with compromised glutathione homeostasis
Authors: Yan Xiang , Fang Bingliang 
Published: August 2019

Abstract
Glutathione (GSH)/GSH reductase (GSR) and thioredoxin/thioredoxin reductase (TXNRD) are two major compensating thiol-dependent antioxidant pathways that maintain protein dithiol/disulfide balance. We hypothesized that functional deficiency in one of these systems will render cells dependent on compensation by the other system for survival, providing a mechanism-based synthetic lethality approach for treatment of cancers. The human GSR gene is located on chromosome 8p12, a region frequently lost in human cancers. GSR deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of GSR sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the GSR gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. The results showed that GSR deficiency sensitized lung cancer cells to this agent. A correlation analysis of auranofin sensitivity and gene expression levels in a panel of 129 NSCLC cell lines revealed that auranofin sensitivity correlated with the expression levels of the GSR, glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. In NSCLC patient-derived xenografts with reduced expression of GSR and/or GCLC, growth was significantly suppressed by treatment with auranofin. Together, these results provide proof-of-concept evidence that cancers with compromised expression of enzymes required for GSH homeostasis or with chromosome 8p deletions that include the GSR gene may be targeted by a synthetic lethality strategy with TXNRD inhibitors.
Citation Format: Xiang Yan, Bingliang Fang. Synthetic lethality therapy for lung cancers with compromised glutathione homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3604.
Abstract 3605: O-linked N-acetylglucosamine transferase as a potential therapeutic target for metastatic gastric cancer
Authors: Hur Joon Young , Lee Jeeyun , Kim Kyoung-Mee , Byeon Sun-Ju , Lee Inkyoung , Kang Won Ki 
Published: August 2019

Abstract
Introduction
Many cancer types display elevated O-GlcNAcylation and aberrant expression of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Here, we describe metabolic reprogramming linked to aberrant increased O-GlcNAcylation, and then inhibition of O-GlcNAcylation as a potential therapeutic target for gastric cancer (GC) treatment.
Methods
We utilized 17 established GC cell lines including 6 primary cell lines (AGS, OCUM-2M, MKN45, SNU1, SNU484, and SNU719), 4 metastatic cell lines (MKN1, MKN28, MKN74, and SNU216), 6 ascite cell lines (SNU5, SNU19, SNU601, SNU620, SNU638, and SNU668), and 1 pleural effusion cell line (KATO III). We collected 21 matched pairs of primary GC and normal gastric tissues and Patient-derived cells (PDCs) (N = 10) at the Samsung Medical Center. PDCs and all cells were grown in RPMI-1640 medium supplemented with 10% FBS. For immunoprecipitation, cells were transfected with pFlag-OGT or siOGT, washed with cold PBS, and lysed in a buffer. Protein extracts (300-500 μg) were incubated with protein G-agarose beads (sc-2002; Santa Cruz)
Results
Cell lines of primary, metastasis and ascites showed expression of O-GlcNAc and OGT. OGT expression is increased in tumor cell and ascites and western blot results showed that OGT expression is more increased in ascites than tumor cell. OGT knockdown inhibited MKN1 cell growth and colony formation. To determine the effect of OGT knockdown on tumor growth in vivo, BALB/c nude mice were injected subcutaneously in the bilateral flank with siC and siOGT transfected MKN1 cells (1 x 107 cells). OGT overexpression enhances O-GlcNAcylation of NFκB p65, c-Myc, and K-Ras. NFκB p65, c-Myc, and K-Ras immunoprecipitates obtained from the cellular extracts were analyzed by immunoblotting for O-GlcNAc. OGT knockdown inhibited PDC (collected from malignant ascites) cell growth. OGT knockdown inhibited GC PDC (1 x 104 cells) cell invasion. Targeting OGT with siRNA in xenograft models decreases the growth of tumors.
Conclusion
Depletion of OGT inhibits cancer cell proliferation and OGT knockdown significantly delays tumor growth in xenograft model. Future work will take advantage of approaches to explain the impact of O-GlcNAc modification on GC.
Citation Format: Joon Young Hur, Jeeyun Lee, Kyoung-Mee Kim, Sun-Ju Byeon, Inkyoung Lee, Won Ki Kang. O-linked N-acetylglucosamine transferase as a potential therapeutic target for metastatic gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3605.