bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3590: Mechanisms and inhibition RIOK2 for obesity-driven prostate cancer
Authors: Macias Everardo , Cho Jiyoon , Rosowicz Drew , Heidari Zahra , You Sungyong , Maravilla Erick J. , Chi Jen-Tsan , Freedland Stephen J. 
Published: August 2019

Abstract
Obesity is associated with greater risk of high-grade prostate cancer (PC), recurrence after therapy, metastases, and PC specific mortality. The fact that obesity is a PC risk factor creates an opportunity to identify and target the mechanisms underlying obesity-enhanced lethal PC. We exploited this link by performing an shRNA in vivo screen in obese mice targeting the entire kinome, which found Right Open Reading Frame Kinase 2 (RIOK2) as essential for PCs in obese mice. We found RIOK2 gene signature is correlated with a 56% increased risk of metastatic PC. Moreover, when we queried only men with a BMI ≥ 30 kg/m2 we found that high levels of RIOK2 gene signature increased the risk of metastasis by an additional 50%. RIOK2, a serine/threonine kinase, is critical for de novo ribosome maturation and assembly, which is essential to maintain the high proliferation rates in cancer cells. Indeed, we found that RIOK2 loss reduced de novo protein synthesis in PC cells and decreased cell viability. Conversely, RIOK2 overexpression enhanced PC cell growth. As our goal is to find actionable PC targets to reduce obesity effects on PC, we conducted a protein structure based compound screen in silico and identified a lead kinase inhibitor of RIOK2 (kiRIOK2). Our lead kiRIOK2 inhibits cell proliferation, protein synthesis, anchorage-independent growth and invasion of multiple PC lines in the µM range. SAR optimized kiRIOK2 have increased efficacy and bioavailability. Our studies are providing probes and mechanistic insights to further investigate the role of RIOK2 in PC biology. In the long-term, this may help mitigate the added risk of obesity on PC metastasis and PC-specific mortality.
Citation Format: Everardo Macias, Jiyoon Cho, Drew Rosowicz, Zahra Heidari, Sungyong You, Erick J. Maravilla, Jen-Tsan Chi, Stephen J. Freedland. Mechanisms and inhibition RIOK2 for obesity-driven prostate 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 3590.
Abstract 3593: PDK1 is a preferential metabolic target in glioblastoma
Authors: Guda Maheedhara R. , Asuthkar Swapna , Tsung Andrew J. , Velpula Kiran K. 
Published: August 2019

Abstract
Glioblastoma (GBM), the most common adult primary malignant brain tumor, carries a high morbidity and mortality despite therapeutic advances. GBM’s progression is associated with a transition from oxidative phosphorylation to aerobic glycolysis as its main source of energy. Our laboratory recently confirmed that overexpression of pyruvate dehydrogenase kinase isoform 1 (PDK1) positively contributes to GBM progression. Here we report a novel role of mitofusin 1 (MFN1), a mitochondrial outer membrane GTPase that is a key regulator of mitochondrial fusion associated with glycolysis. We have shown that both PDK1 and MFN1 are highly co-expressed in glioblastoma patient specimens. Data obtained from The Cancer Genome Atlas demonstrated a positive correlation between PDK1 and MFN1 mRNA levels and the survival of GBM patients. The data obtained from the subtyped glioma stem cells corroborated with the datamining studies. To directly explore the potential MFN1-PDK1 interplay, we used CRISPR/Cas9 to suppress MFN1 expression in proneural, classical and mesenchymal subtypes of GBM stem cells (CSC). In another experiment, using ChIP assay, we showed that both PDK1 and MFN1 are under the transcriptional control of Myc oncogene. We present evidence that silencing MFN1 regulates altered metabolism in GBM CSC by increasing ROS levels, altering mitochondrial membrane potential, reduced lactate metabolites via NMR spectroscopy. Taken together, our results indicate that combined targeting of PDK1 and MFN1 shift Warburg effect towards oxidative phosphorylation, and may have increased therapeutic potential for glioblastoma patients.
Citation Format: Maheedhara R. Guda, Swapna Asuthkar, Andrew J. Tsung, Kiran K. Velpula. PDK1 is a preferential metabolic target in glioblastoma [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 3593.
Abstract 3598: Phosphoglycerate mutase 1 inhibitor causes metabolic disadvantages in glioblastoma by rescue of FBP1 repression
Authors: Lee Sungmin , Kim Hyunwoo , Kang Hyunkoo , Youn BuHyun 
Published: August 2019

Abstract
Radiotherapy is a primary treatment for patients with glioblastoma (GBM). Despite high therapeutic efficacy, the tumor cells that survive after radiotherapy may cause side effects. In this study, we found that fructose 1,6-bisphosphatase 1 (FBP1) which is a rate-limiting enzyme in gluconeogenesis was downregulated upon treatment with ionizing radiation (IR). IR-induced infiltrating GBM has overexpressed Ets1 which was suggested to be a transcriptional repressor of FBP1. Besides, glucose uptake and extracellular acidification rates were increased upon FBP1 downregulation, which indicated an elevated glycolysis level. We found that emodin, an inhibitor of phosphoglycerate mutase 1 derived from natural substances, significantly suppressed the glycolysis rate and the IR-induced GBM aggressiveness in the in vivo orthotopic xenograft mouse models. We propose that the downregulation of FBP1 level reprogrammed the metabolic state of GBM, and thus, FBP1 is a promising therapeutic target regulating GBM metabolism following radiotherapy.
Note: This abstract was not presented at the meeting.
Citation Format: Sungmin Lee, Hyunwoo Kim, Hyunkoo Kang, BuHyun Youn. Phosphoglycerate mutase 1 inhibitor causes metabolic disadvantages in glioblastoma by rescue of FBP1 repression [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 3598.
Abstract 3600: Antibiotics suppress growth of breast cancer cells and synergize cytotoxicity of 2-Deoxy-D-glucose: Treating cancer like an infection
Authors: Jiang Xianpeng , Benoit Amanda , Jiang Toby , Elliott Robert L. 
Published: August 2019

Abstract
Mitochondria evolved from free-living bacteria via endocytosis within a eukaryotic host cell millions of year ago. We hypothesized that antibiotics might damage mitochondria of human cancer cells and lead to oxidative damage of cancer cells. We examined three classes of antibiotics, azithromycin, doxycycline and ciprofloxacin in the human breast cancer cell lines MCF-7 and MDA-MB-231. The combination of antibiotics and the anti-glycolytic agent, 2-Deoxy-D-glucose (2-DG) was also tested in the cells. Cell growth was measured by MTT [3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide] assay. Mitochondrial membrane potential and reactive oxygen species were tested by fluorescent microscopy. Gene expression and DNA damage were measured by real time polymerase chain reaction (qPCR) and ELISA. All antibiotics suppressed mitochondrial membrane potential and growth of MCF-7 and MDA-MB-231 cells in a dose dependent pattern. The IC50of all three antibiotics were less than clinical patient’s maximum serum concentration (Cmax) or concentrations in tissues. The IC50 of ciprofloxacin in MCF-7 (1.25-2.5µM) and MDA-MB-231 (2.5-3.5µM) are much lower than the Cmax 7.7µM while patients take 500mg every 12 hours orally in clinical practice. The DNA oxidative damage metabolite, 8-OHdG, in the media was significantly increased after cancer cells were cultured in the media containing antibiotics for 24 hours. Three antibiotics upregulated gene expression of glycolytic enzymes including hexokinase 2(HK2), phosphofructokinase 1 (PFKM) and pyruvate kinase muscle isozyme M2 (PKM2), lactate dehydrogenase A (LDHA), and glucose transporters 1 (SLC2A1) and 3 (SLC2A3). The antibiotics increased uptake of 3[H]-2-DG of MCF-7 and MDA-MB-231. These results suggest that cancer cells increase aerobic glycolysis to produce ATP after antibiotic treatment. Thus, we combined 2-DG and antibiotics to treat the breast cancer cell lines. The antibiotics and 2-DG synergistically inhibited growth of the breast cancer cells. MDA-MB-231, a chemo-drug resistant cell line, has similar sensitivity to antibiotics and 2-DG as the MCF-7, a drug sensitive cell line. In summary, azithromycin, doxycycline and ciprofloxacin suppress the growth of breast cancer cells and augment the cytotoxicity of 2-DG to breast cancer cells. These findings suggest we can treat cancer with antibiotics similar to treating an infection.
Citation Format: Xianpeng Jiang, Amanda Benoit, Toby Jiang, Robert L. Elliott. Antibiotics suppress growth of breast cancer cells and synergize cytotoxicity of 2-Deoxy-D-glucose: Treating cancer like an infection [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 3600.
Abstract 3603: Sphingomyelin synthase inhibition in sarcomas results in ceramide accumulation and apoptosis
Authors: Barrott Jared J. , Meldrum Trevor , Afrin Farjana , Pashikanti Srinath 
Published: August 2019

Abstract
Sphingolipid metabolism is critical to cellular homeostasis especially as cells undergo mitosis. It is, therefore, unsurprising that the sphingolipid pathway is upregulated in a number of a cancers. Sphingoid bases such as sphingosine and ceramide are rapidly synthesized to provide the building blocks of other sphingolipids. Inhibition of downstream enzymes that convert sphingosine and ceramide into sphingolipids can lead to an increase of ceramide, which results in cellular toxicity and initiation of apoptosis. Using the marine natural product Jaspine B and chemically synthesized analogues, we investigated the potency of inhibiting sphingomyelin synthase in sarcoma cell lines. Sphingomyelin synthase is a downstream enzyme that converts ceramide into sphingomyelin by adding the polar head group phosphorylcholine to ceramide. Jaspine B and its analogues exhibited submicromolar potency against several human sarcoma cell lines. It was determined that the inhibition of sphingomyelin synthase resulted in an increase in ceramide and sphingosine levels and that sphingomyelinase enzymatic activity increased. While the mitochondria mass remained the same, the membrane potential of the mitochondria was significantly affected by the presence of the inhibitors. In conclusion, inhibitors of sphingolipid metabolism are viable therapeutic options with high untapped potential to treat cancer.
Citation Format: Jared J. Barrott, Trevor Meldrum, Farjana Afrin, Srinath Pashikanti. Sphingomyelin synthase inhibition in sarcomas results in ceramide accumulation and apoptosis [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 3603.
Abstract 3607: Inhibition of mutant IDH enzymes reduces production of 2-HG but does not restore wild type IDH activity in vitro or in vivo
Authors: Sellers Katie , Sleger Taryn , Ronseaux Sebastien , Narayanaswamy Rohini , Hudson Christine , Roddy Thomas , Nicolay Brandon 
Published: August 2019

Abstract
Mutations in isocitrate dehydrogenase (IDH) 1 and 2 occur in variety of malignancies, and notably &gt;70% of low grade gliomas. These mutations lead to neomorphic enzymatic activity that results in the production of the oncometabolite (D)-2-hydroxyglutarate (2-HG) through the consumption of NADPH. IDH mutant cells and tumors have been shown to have heightened sensitivity to reactive oxygen species (ROS) and radiation, though it is unclear if this sensitivity is due to a loss of IDH wild type enzymatic NADPH production, the neoenzymatic activity of the mutant enzyme, or a combination of these activities. In support of the hypothesis that sensitivity to ROS and radiation is due to a reduced IDH wild type activity in IDH mutant cells, we previously demonstrated that combined treatment of mutant IDH mouse xenografts with AG-881, a potent orally available mutant IDH inhibitor, and radiation resulted in superior tumor growth inhibition than either modality alone. To extend this investigation, we have now developed a novel assay to read out the wild type activity of IDH1/2 enzymes in both cell-based assays and mouse xenograft models. Using an isotopic labeling approach that allows us to fully differentiate the activity of wild type IDH1/2 from the mutant enzymatic activity in the same cell or tumor, we observed that mutant IDH cells and tumors have a significantly reduced level of wild type IDH1/2 activity compared to normal tissue or IDH wild type tumors. Importantly, pharmacologic inhibition of mutant IDH1/2 that resulted in &gt;90% reduction in 2-HG production in mutant cells and tumors did not restore the IDH1/2 wild type activity. These data support our previous observations and suggest that therapeutic strategies targeting the reduced activity of wild type IDH enzymes, such as modalities that induce ROS or treatment with radiation, would be effective when combined with mutant IDH inhibitors.
Citation Format: Katie Sellers, Taryn Sleger, Sebastien Ronseaux, Rohini Narayanaswamy, Christine Hudson, Thomas Roddy, Brandon Nicolay. Inhibition of mutant IDH enzymes reduces production of 2-HG but does not restore wild type IDH activity in vitro or in vivo [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 3607.
Abstract 3610: Cellular fatty acid uptake is enhanced in tamoxifen-resistant breast cancer cells
Authors: Hwang Sewon , Lee Mi-Ock 
Published: August 2019

Abstract
The most accepted therapeutic regimen for treating ER-alpha breast cancer is Tamoxifen. Yet over 30% of patients gain resistance. Recently, lipid metabolism has been rising as a new mode of cancer drug resistance. In order for a rapid growth, cancer cells show a strong avidity for lipid which they obtain by de novo lipogenesis or increasing the uptake of exogenous lipids. Lipid metabolism may confer drug resistance, but little is known about its association with endocrine resistance. Thus, we aimed to investigate the association of lipid metabolism in the context of tamoxifen resistance. First, fatty acid translocase and membrane-associated fatty acid binding protein, both of which are responsible for fatty acid uptake, were overexpressed in MCF7/TAMR-8 and T47D/TR-1, TR-2 cell lines. Also the mRNA level of fatty acid activating enzyme, long-chain fatty-acid-coenzyme A, were elevated as well. Next, through Oil-red-O staining and Nile red staining followed by FACS analysis, we examined whether tamoxifen-resistant cells actually increase fatty acid uptake. When supplemented with free fatty acids, tamoxifen-resistant cell lines showed higher efficiency in fatty acid uptake compared to the control cell lines. Subsequently when the amount of triglyceride accumulation was measured, more TG were present in resistant cells at the basal level and after free fatty acid treatment. Taken together, these results suggest lipid uptake by cancer cells may play a role in driving tamoxifen-resistance in breast cancer.
Citation Format: Sewon Hwang, Mi-Ock Lee. Cellular fatty acid uptake is enhanced in tamoxifen-resistant breast 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 3610.
Abstract 3612: Decreased vitamin C uptake mediated by SLC2A3 promotes leukemia progression and impedes Tet2 restoration
Authors: Liu Jun , Hong Junshik , Ahn Kwangsung , Yoon Sungsoo 
Published: August 2019

Abstract
Background: Two new studies in Nature and Cell, from Agathocleous et al. (2017) and Cimmino et al. (2017), respectively, showed that vitamin C regulates HSC function and suppresses leukemogenesis by modulating Tet2 activity. However, little is known about the relationship between vitamin C transporter and hematological malignancies.
Purpose: In this study, we investigated the role of SLC2A3, a gene that encode GLUT3 which mainly transport glucose and oxidized form vitamin C, in hematological malignancies. Through this research we identified a set of biomarkers which can predict the effect of vitamin C treatment and develop stagey to improve this putative innovative treatment.
Results: We analyzed gene expression patterns of the major GLUT family genes in primary AML blast cells using previously published microarray datasets (GSE37307) and (GSE9476) and determined that SLC2A3 gene expression was significantly decreased in blast cells compared with normal hematopoietic cells. By contrast, expression of SLC2A1, SLC2A2 and SLC23A2 was not significant different in between primary AML cells and normal hematopoietic cells. Next, we analyzed the relevance of SLC2A3 expression to the survival of AML patients from TCGA and TARGET database and found that below-median SLC2A3 expression was associated with inferior overall survival. Subsequently, we detected the SLC2A3 mRNA expression level on 4 AML cell lines and 3 DLBCL cell lines, there were very low expression level on OCI-AML-3 and OCI-LY1. To check whether decreased expression of SLC2A3 has an impact on the Vitamin C effect, we treated the 7 cell lines with dose dependent vitamin C, up to 500 μM, 48 hours. The cell viability assay showed that OCI-AML-3 and OCI-LY1 have no response to Vitamin C, however the proliferation of NB4, HEL, HL60, OCI-LY19 and Toledo was suppressed by 250 μM Vitamin C.
Conclusions: SLC2A3 expression was decreased in AML blast cell and down regulation of SLC2A3 was closely associated with the poor outcomes of AML patients. In vitro study showed that SLC2A3 was essential for the effect of Vitamin C. Therefore, SLC2A3 could be a potential biomarker to predict the effect of Vitamin C treatment. In addition, through targeting SLC2A3, efficacy of Vitamin C treatment could be improved.
Citation Format: Jun Liu, Junshik Hong, Kwangsung Ahn, Sungsoo Yoon. Decreased vitamin C uptake mediated by SLC2A3 promotes leukemia progression and impedes Tet2 restoration [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 3612.
Abstract 3617: Trastuzumab-conjugated gold nanoparticles as novel HER2-targeted therapeutics against trastuzumab-resistant gastric cancer
Authors: Kumon Kento , Kubota Tetsushi , Kuroda Shinji , Kanaya Nobuhiko , Kakiuchi Yoshihiko , Tsumura Tomoko , Kikuchi Satoru , Kagawa Shunsuke , Tazawa Hiroshi , Fujiwara Toshiyoshi 
Published: August 2019

Abstract
While trastuzumab (Tmab), a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2), has greatly contributed to improve survival outcomes in metastatic gastric cancer, an issue of concern is that no current HER2-targeted therapeutic agent is effective against Tmab-resistant gastric cancer. Nanotechnology, which has progressed rapidly in recent years, greatly contributes to progress in medical fields including cancer therapy, and especially, gold nanoparticles (AuNPs) are attention-grabbing nanomaterials that are promising drug carriers with unique properties of high in vivo stability and a large surface area available for attachment of materials such as antibodies. Methods: We created HER2-targeted AuNPs by conjugating Tmab onto their surface (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines in vitro and in vivo. We also examined T-AuNPs on HER2-negative MKN74 gastric cancer cells with adenoviral vector-mediated overexpression of the HER2 extracellular domain (HER2-ECD). Results: The size of T-AuNPs was 85.39 ± 0.68 nm and the surface was negatively charged with 39.43 ± 0.85 mV. In in vitro assays, T-AuNPs showed 6-fold higher cytotoxic activity than Tmab against NCI-N87 cells. Then, T-AuNPs showed significantly stronger cytotoxic effects than controls against both MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy was proven to play an important role in T-AuNPs cytotoxic mechanisms. This autophagy was considered to be induced by HER2-dependent internalization of T-AuNPs, some of which were interestingly located in the cytoplasm independent of lysosomal encapsulation. Although T-AuNPs were not cytotoxic towards MKN74 cells, they became cytotoxic following HER2-ECD overexpression. Finally, Intratumoral injection of T-AuNPs showed potent antitumor effects, which were mediated by autophagy, against NCI-N87 and MKN7 subcutaneous tumors in vivo mouse models. Conclusion: HER2-targeted AuNPs with conjugated Tmab can be a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.
Citation Format: Kento Kumon, Tetsushi Kubota, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Tomoko Tsumura, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara. Trastuzumab-conjugated gold nanoparticles as novel HER2-targeted therapeutics against trastuzumab-resistant 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 3617.