bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5484: Pyruvate kinase isozymes M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer
Authors: Yashiro Masakazu , Kitayama Kishu 
Published: August 2018

Abstract
Glycolysis is the primary mode of glucose metabolism, not only in normal cells but also in cancer cells. The Warburg effect, known as anaerobic glycolysis even in the presence of ample oxygen, might contribute to tumor development in such hypoxic environments. It has been suggested that some kinds of glucose metabolism-related enzymes—including pyruvate kinase isozyme M2 (PKM2), PKM1, enolase 1 (ENO1), and glucose-6-phosphate dehydrogenase (G6PDH)—might be associated with the anaerobic glycolysis of cancer cells. Glutamine is also associated with the proliferation of cancer cells by an alternate source of biosynthesis from the TCA cycle, namely glutaminolysis. In the present study we evaluated the significance of the enzymes for glycolysis and glutaminolysis in relation to the proliferation of gastric cancer cells in hypoxic environments. The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and 4 parent cell lines were used. RT-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: PKM2, GLS, ENO1, G6PDH, and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, Shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo. Levels of both PKM2 and GLS mRNA were significantly high in all hypoxia-resistant cell lines, compared with those of their parent cells. Knockdown of PKM2 and GLS significantly decreased the proliferation of all of hypoxia-resistant cells. The combination of siPKM2 and siGLS significantly decreased proliferation compared with treatment by siPKM2 or siGLS alone. The knockdown of ENO1, G6PDH, or PKM1 did not decrease the proliferation of all hypoxia-resistant cells. Combination treatment by Shikonin and BPTES inhibited the proliferation of all hypoxia-resistant cancer cells more than that by either one of the two agents. The in vivo study indicated that the tumor size treated by the combination of Shikonin and BPTES was significantly smaller than that of vehicle-treated group. These findings suggested that PKM2 and GLS might play important roles in the proliferation of hypoxic gastric cancer cells. A combination of PKM2 and GLS inhibitors might be therapeutically promising for the treatment of gastric cancer.
Citation Format: Masakazu Yashiro, Kishu Kitayama. Pyruvate kinase isozymes M2 and glutaminase might be promising molecular targets for the treatment of gastric 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 5484.
Abstract 5488: Serine racemase is a new therapeutic target for colon cancer
Authors: Ohshima Kenji , Nojima Satoshi , Wada Naoki , Hori Yumiko , Tahara Shinichiro , Kurashige Masako , Kawasaki Keisuke , Ikeda Junichiro , Morii Eiichi 
Published: August 2018

Abstract
Cancer cells have an altered metabolic state to meet the requirements of rapid proliferation, and altered amino acid metabolism is known to be significant for cancer cell growth. Amino acids consist of L- and D-amino acids, and humans are known to metabolize L-amino acids. D-amino acids have been considered not to exist in human body except in intestinal flora. Recently, D-serine was reported to be synthesized and catabolized by serine racemase (SRR) and D-amino acid oxidase, respectively, and it has an important function as co-activator of the N-methyl-D-aspartate receptor in the human brain. However, whether D-amino acids function in other human organs has not been elucidated. Moreover, the role of enzymes metabolizing D-amino acids in the context of cancer metabolism has not been studied. Here, we present a novel role for SRR in colon cancer. First, we analyzed SRR expression levels in colon adenoma, colon adenocarcinoma, and normal colon mucosa in ONCOMINE datasets. We found that SRR expression levels were significantly elevated in colon adenoma and colon adenocarcinoma compared to normal colon mucosa in several datasets, including that of the Cancer Genome Atlas (TCGA). To determine whether SRR has a functional role in colon cancer cells, we disrupted its expression using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9) system in two colon cancer cell lines, HCT116 and DLD-1, using two distinct targets of short guide RNAs and examined the effects on cell proliferation. We found that SRR knockout resulted in reduced cell proliferation in both HCT116 and DLD-1 cells, which was recovered by exogenous SRR expression. In addition, a positive correlation was found between SRR expression levels and cell proliferation rate in four colon cancer cell lines, HCT116, DLD-1, WiDr, and Lovo. Moreover, phenazine methosulfate and L-aspartic acid β-hydroxamate, which have been previously reported to inhibit SRR, suppressed in vitro colon cancer cell proliferation. In conclusion, SRR is highly expressed in colon adenoma and colon adenocarcinoma compared to normal colon mucosa, and it enhances colon cancer cell proliferation. SRR is expected to be a potential new target for the development of novel therapies for colon cancer.
Citation Format: Kenji Ohshima, Satoshi Nojima, Naoki Wada, Yumiko Hori, Shinichiro Tahara, Masako Kurashige, Keisuke Kawasaki, Junichiro Ikeda, Eiichi Morii. Serine racemase is a new therapeutic target for colon 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 5488.
Abstract 5492: Inhibition of ERK MAPK signaling increases pancreatic cancer dependency on autophagy
Authors: Bryant Kirsten , Peng Sen , Tikunov Andrey , Pierobon Mariaelena , Gunda Venugopal , Tomar Garima , Singh Pankaj , Petricoin Emanuel , Macdonald Jeffrey , Tran Nhan , Kimmelman Alec , Der Channing 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) cell growth is dependent on altered biochemical and cellular activities that facilitate increased metabolic dependencies. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression, which blocks proliferation, was associated with increased rather than decreased autophagic flux. Similarly, KRAS transformation of immortalized human pancreatic epithelial cells showed decreased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and also increased autophagic flux. Addressing a mechanism for ERK suppression increased autophagy, we found increased AMPK activity, decreased mTOR activity, and increased expression of autophagic proteins. We speculated that increased autophagy may be a compensatory mechanism caused by the loss of KRAS- and ERK-dependent metabolic processes. To address this possibility, we performed RNA-seq analyses to monitor gene expression changes in response to ERK inhibition. We observed increased transcription of genes responsible for the metabolic processes of autophagy and β-oxidation, with concurrent decreased transcription of glycolysis and mitochondrial-associated genes. These changes were validated in metabolomic analyses following either genetic silencing of KRAS or ERK inhibition. Thus, the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine synergistically enhanced ERK inhibitor mediated antiproliferative activity. Similarly, genetic or pharmacologic inhibition of specific regulators of autophagy also enhanced ERK inhibitor activity. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment.
Citation Format: Kirsten Bryant, Sen Peng, Andrey Tikunov, Mariaelena Pierobon, Venugopal Gunda, Garima Tomar, Pankaj Singh, Emanuel Petricoin, Jeffrey Macdonald, Nhan Tran, Alec Kimmelman, Channing Der. Inhibition of ERK MAPK signaling increases pancreatic cancer dependency on autophagy [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 5492.
Abstract 5494: Targeting deregulated expression and function of Mitofusin 1 in glioblastoma
Authors: Guda Maheedhara Reddy , Asuthkar Swapna , Labak Collin M. , Smith Chase P. , Tsung Andrew J. , Velpula Kiran 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most common form of adult primary malignant brain tumor with a poor prognosis. Despite advances in standard treatments, such as surgery, radiation, and adjuvant chemotherapy, outcome remains poor. To further develop effective therapeutic approaches, it is essential to garner a better understanding of GBM progression. Substantial research has shown that GBM's progression is associated with metabolic remodeling, that includes the use of aerobic glycolysis as the main source of energy. Here, we report the novel role of Mitofusin 1 (MFN1), a key regulator of mitochondrial outer membrane fusion in glycolysis. We first established that MFN1 is highly expressed in GBM when compared to its isoform MFN2 using TCGA (The Cancer Genome Atlas) and OncomineTM glioma datasets. Silencing MFN1 using MFN1-shRNA in GBM10 cells showed decreased expression levels of PDK1 and HIF1-alpha as observed in western blotting and RT-PCR analysis. Interestingly, c-myc expression was significantly reduced in the shMFN1 treated GBM 10 cell. In addition, RNASeq analysis conducted on shPDK1 treated GBM-10 cells revealed reduced MFN1 levels. Further silencing of MFN1 showed increased OCR and decreased ECAR using seahorse XFp bio analyzer. Collectively, our preliminary data points to MFN1 as a candidate metabolic oncogene in GBM, and targeting MFN1 will be a novel GBM treatment.
Citation Format: Maheedhara Reddy Guda, Swapna Asuthkar, Collin M. Labak, Chase P. Smith, Andrew J. Tsung, Kiran Velpula. Targeting deregulated expression and function of Mitofusin 1 in glioblastoma [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 5494.
Abstract 550: One enhancer stimulates cancer cells proliferation and metastasis via the regulation of PDL1 expression
Authors: Li Chunyan , Chen Han , Liang Han 
Published: August 2018

Abstract
Cancer cells employ multiple mechanisms to evade the recognition by the host immune system, including the expression of the negative T cell regulatory molecule PD-L1. PD-1/PD-L1-mediated immune escape plays key role during cancer development. It is crucial to unravel the regulatory mechanism of PD-1/PD-L1. In this study, we seek one enhancer (we named “enh9”) that regulates the transcription of PD-L1 by systematic exploration. First, we found that PD-L1 and enh9 were co-expressed in multiple cancer types, including both lung adenocarcinoma and lung squamous cell carcinoma, which was further validated in a cohort of 130 lung cancer cell lines from the Cancer Cell Line Encyclopedia database. Then the direct interaction between PD-L1 and enh9 was further confirmed by Hi-C dataset. To validate the transcriptional regulation of PD-L1 by enh9, we knocked out enh9 using CRISPRi (CRISPR/ clustered regularly interspaced short palindromic repeats interference) in lung adenocarcinoma cell line A549, and single cell clones with double-copy deletion of enh9 were screened out. The expression of PD-L1 was dramatically reduced at both mRNA and protein level in enh9 knockout cells. Furthermore, we found that the cell proliferation and metastasis of enh9 knockout cells were significantly decreased compared to the control cells. Based on the previous studies that PD-L1 intrinsically regulated cancer cells' proliferation in ovarian and melanoma cancer cells, ongoing work is to determine whether enh9 regulates the cancer cell hallmarks by direct regulation of the expression of PD-L1 in lung cancer cells. The regulatory mechanisms will be deeply studied. In conclusion, we found an enhancer regulated the expression of PD-L1, which was one famous immune checkpoint, and it may play key roles in the cancer cell hallmarks.
Citation Format: Chunyan Li, Han Chen, Han Liang. One enhancer stimulates cancer cells proliferation and metastasis via the regulation of PDL1 expression [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 550.
Abstract 5503: Loss of MED12 induces tumor dormancy in human ovarian cancer
Authors: Luo Xiao-Lin , Deng Cheng-Cheng , Liu Ji-Hong , Fu Li-Wu 
Published: August 2018

Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological malignancies due to high rate of disease relapse. Disease relapse in cancer patients after clinical remission are often referred to tumor dormancy. Here we identify MED12 as an important molecular regulator of tumor dormancy. We found that MED12 knock-out could induce dormancy of EOC cells in vitro and in vivo. Mechanistically, microarray analysis showed that MED12 knock-out decreased the expression of EGFR. Restoration of EGFR expression in MED12 knock-out cells restored the proliferation ability. Additionally, we found that MED12 could bind to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with the level of EGFR. Clinical data demonstrated that chemotherapy-resistant patients showed a lower expression of MED12. In conclusion, MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR.
Citation Format: Xiao-Lin Luo, Cheng-Cheng Deng, Ji-Hong Liu, Li-Wu Fu. Loss of MED12 induces tumor dormancy in human ovarian 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 5503.
Abstract 5508: ANKRD52 inhibited tumor metastasis in lung adenocarcinoma
Authors: Lee Ting-Fang , Lin Yen-Fan , Liu Ying-Pu , Wu Cheng-Wen 
Published: August 2018

Abstract
Cancer metastasis is an ultimate challenge in our effort to fight cancer as a life-threatening disease. A member of ankyrin repeat proteins, ankyrin repeat domain 52 (ANKRD52), is studied here to be involved in the regulation of lung adenocarcinoma metastasis. Ankyrin repeat proteins are known to function as a platform for protein-protein interactions, and ANKRD52 was shown to interact with protein phosphatase 6 (PP6). Immunohistochemistry staining in lung adenocarcinomas tissues revealed low ANKRD52 expressing in stage-IV patients compared to those in stages I to III. Overexpressed ANKRD52 prevented lung cancer formation in the xenograft model. Using lung cancer cell lines, ANKRD52 knockdowns showed significantly increased cell mobility while forced expression decreased cell mobility. Using mass spectrometry analysis, p21-activated kinases (PAK1) was identified to interact with ANKRD52. The regulation of PAK1 phosphorylation by the ANKRD52-PP6 complex is essential to cell mobility. Our model demonstrated a novel anti-metastatic protein, ANKRD52, that regulates cell mobility through interacting with PP6 leading to PAK1 dephosphorylation.
Citation Format: Ting-Fang Lee, Yen-Fan Lin, Ying-Pu Liu, Cheng-Wen Wu. ANKRD52 inhibited tumor metastasis in lung adenocarcinoma [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 5508.
Abstract 551: Discovering the co-drivers of mutant TP53 that promote breast cancer progression
Authors: Pal Anasuya , Park Jin , LaBaer Joshua 
Published: August 2018

Abstract
Breast cancer is a heterogeneous disease and has different subtypes. Genetically 30% of all breast tumors and 80% of basal-like breast tumors harbor mutations in TP53 and numerous somatic mutations in other genes. This molecular heterogeneity has posed a challenge in developing effective therapeutic regimens and targeted therapies. Different TP53 missense mutations co-exist with other mutations in tumors and we hypothesize that tumor heterogeneity results from combinatorial effects of neo-morphic functions of specific TP53 driver mutations and a distinct subset of functionally important co-mutations (or ‘co-drivers'). We ectopically expressed the ten most prevalent missense TP53 mutants found in breast cancer tumors in non-transformed mammary epithelial cells and examined their phenotypes associated with the hallmarks of cancer. The results showed wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell invasion and cell polarity. As a proof of concept for the ‘co-driver', we knocked-out PTEN in a non-invasive TP53 Y234C mutant using the CRISPR system and observed increased cell invasion. A subsequent genome-wide CRISPR library-based screen on non-invasive TP53 Y234C expressing cells identified co-driver candidates that were highly enriched in the invasive population of Y234C cells. The top candidates included several known mutated genes in breast cancer patients with TP53 mutations, and were associated with signaling and cytoskeletal pathways that play crucial role in regulating cell invasion. These results demonstrate that this approach can pinpoint the key loss-of-function mutations in clinically important TP53 mutant backgrounds that can promote cancer-like behavior, and identify the combinations of ‘TP53 mutant and co-driver pathways' that can be targeted by specific inhibitors.
Citation Format: Anasuya Pal, Jin Park, Joshua LaBaer. Discovering the co-drivers of mutant TP53 that promote breast cancer progression [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 551.
Abstract 5510: Loss of epithelial membrane protein 2 enhances Kras-driven lung tumorigenesis via FAK/AKT pathways
Authors: Jang Ji Yun , Park Mi Kyung , Lee Chang Hoon , Lee Ho 
Published: August 2018

Abstract
Epithelial membrane protein-2 (EMP2) belongs to the growth arrest specific-3 (GAS3)/PMP22 family of tetraspan proteins. These family members are involved in the pathogenesis of human diseases, including malignancy. EMP2 is highly expressed in normal lung alveoli; however, its functional role in lung tumor is largely unknown. In this study, we focus a novel function for EMP2 in lung tumor progression. To investigate this possibility, EMP2 knock-out mice were crossed with KrasG12Dmice that carry an oncogenic mutation of the Kras gene (G12D) and develop lung adenocarcinoma. Incidence of lung tumor in KrasG12DEMP2-/- mice was higher than that in KrasG12DEMP2+/+ mice. We also found that loss of EMP2 accelerated lung tumor progression. Then, we investigated the role of EMP2 in lung cancer cell line. Expression of EMP2 was knocked out by CRISPR/Cas9 editing system in H1299 (KrasWT), H358 (KrasMut) and A549 cells (KrasMut). Loss of EMP2 induced that expression of integrin α5 is increased but expression of integrin α6 is decreased. Alteration of integrin expression activated FAK/AKT pathway. These results support the role of EMP2 loss in the control of lung cancer progression with oncogenic Kras. Taken together, these findings establish that EMP2 is a potent suppressor of Kras-driven lung tumorigenesis via FAK/AKT pathway.
Citation Format: Ji Yun Jang, Mi Kyung Park, Chang Hoon Lee, Ho Lee. Loss of epithelial membrane protein 2 enhances Kras-driven lung tumorigenesis via FAK/AKT pathways [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 5510.
Abstract 5515: Ras-like estrogen-regulated growth-inhibitory gene (RERG): A novel biomarker and potential therapeutic target for women with lung cancer
Authors: Scoyk Michelle Van , Avasarala Sreedevi , Wu Pei-Ying , Su Yanlin , Lerner Lane , Hulbert Alicia , Bikkavilli Kamesh , Winn Robert A. 
Published: August 2018

Abstract
Background: Lung cancer is the second most common cancer diagnosed in women. In fact, twice as many women will die from lung cancer compared to breast cancer, the key risk factor being tobacco use. Hence, there is a need to identify new molecular biomarkers to aid in early detection and develop new therapeutic strategies in tobacco-related lung cancer. Ras-like Estrogen-Regulated Growth-Inhibitory Gene (RERG) is a member of the Ras superfamily of GTPases that play an important role in cellular processes such as proliferation, differentiation, and apoptosis. Unlike other members of the Ras superfamily members of proto-oncogenes, RERG functions as a tumor suppressor.
Objective: To investigate the utility of RERG expression as a novel biomarker and a potential therapeutic target in lung cancer.
Results: In silico analysis of The Cancer Genome Atlas (TCGA) lung cancer datasets revealed a significant downregulation of RERG expression in lung tumors. Furthermore, reduced expression of RERG in lung tumors was also observed to be correlated with poor prognosis as determined by Kaplan-Meier survival analysis. Evaluation of formalin-fixed, paraffin-embedded (FFPE) human lung cancer tissues and fresh frozen lung tumor tissues corroborated our in silico observations. Most notably, tobacco smoke was identified to be associated with decreased RERG expression in lung tumors. The most intriguing observation from this study is the significant decrease of RERG expression in female smokers as a result of promoter hypermethylation.
Conclusion: Taken together, these findings suggest that RERG may represent a potential biomarker in lung cancer, particularly among smokers. Further investigation would focus on the mechanism of RERG loss and its influence on lung tumor development, particularly in female smokers.
Citation Format: Michelle Van Scoyk, Sreedevi Avasarala, Pei-Ying Wu, Yanlin Su, Lane Lerner, Alicia Hulbert, Kamesh Bikkavilli, Robert A. Winn. Ras-like estrogen-regulated growth-inhibitory gene (RERG): A novel biomarker and potential therapeutic target for women with lung 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 5515.