bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3526: Beta-oxidation inhibition as a novel therapy for cisplatin-resistant ovarian cancer
Authors: Rada Miran , Cha Jennifer , Sage Jessica , Zhou Bo , Yang Wei , Ashkavand Zahra , Norman Kenneth , Orsulic Sandra , Cheon Dong-Joo 
Published: August 2018

Abstract
Ovarian cancer is the most lethal gynecological cancer and affects one in 70 females in the United States during their lifetime. Cisplatin resistance is the major challenge in the treatment of ovarian cancer but the underlying mechanisms are not fully understood. The purpose of this study is to develop novel therapeutic strategies to treat cisplatin-resistant ovarian cancer. We identified collagen type XI alpha 1 (COL11A1) as a novel biomarker associated with cisplatin resistance in ovarian cancer. COL11A1 is highly expressed by cancer-associated fibroblasts adjacent to cancer cells as well as A2780CIS cisplatin-resistant ovarian cancer cell line. Our data show that COL11A1 binds to DDR2 in ovarian cancer cells and inhibits cisplatin-induced apoptosis in ovarian cancer cells. To obtain mechanistic insights underlying COL11A1-driven cisplatin resistance, we performed Tandem Mass Tag proteomic analysis of A2780CIS ovarian cancer cells before and after COL11A1 knockdown. Our proteomics data revealed that mitochondrial fatty acid β-oxidation was the most upregulated pathway by COL11A1 in ovarian cancer cells. Mitochondrial fatty acid β-oxidation is the major pathway that breaks down fatty acids to produce excess ATP and NADPH to support cell survival. Several studies suggested the association of β-oxidation with tumor cell proliferation in various cancers. However, the role of β-oxidation in ovarian cancer chemoresistance is largely unknown. Our results show that COL11A1 enhances the expression of not only fatty acid receptor CD36, but also key enzymes of fatty acid β-oxidation, such as CPT1A, HADHB, ACSL1 and ACAA2. Significantly, COL11A1-mediated overexpression of these proteins was diminished in the presence of shRNA against DDR2.We also confirmed that ovarian cancer cells increase both fatty acid uptake and oxygen consumption rate in response to palmitate in the presence of COL11A1. Importantly, inhibition of fatty acid β-oxidation using shRNA against CPT1A attenuated the function of COL11A1 in cisplatin resistance. Taken together, our results suggest that COL11A1 confers cisplatin resistance by increasing fatty acid β-oxidation in ovarian cancer cells. Our study uncovers fatty acid β-oxidation as a promising therapeutic target to treat cisplatin-resistant ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.
Citation Format: Miran Rada, Jennifer Cha, Jessica Sage, Bo Zhou, Wei Yang, Zahra Ashkavand, Kenneth Norman, Sandra Orsulic, Dong-Joo Cheon. Beta-oxidation inhibition as a novel therapy for cisplatin-resistant 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 3526.
Abstract 3527: Inhibition of mitochondrial pyruvate transport selectively sensitizes cancer cells to metabolic oxidative stress
Authors: Solst Shane R. , Rodman Samuel N. , Fath Melissa A. , Taylor Eric B. , Spitz Douglas R. 
Published: August 2018

Abstract
To determine if mitochondrial pyruvate transport could represent a therapeutic target for sensitizing cancer cells to oxidative stress, lung and breast cancer cells were treated with 5 µM UK5099 to inhibit the mitochondrial pyruvate carrier (MPC). Treatment with UK5099 selectively sensitized lung and breast cancer cells to clonogenic cell killing when combined with depletion of glutathione using 1 mM buthionine sulfoximine (BSO; a glutathione synthesis inhibitor) for 48 h and 72 h, relative to normal lung and breast epithelial cells. Furthermore, cancer cell killing mediated by UK5099 combined with BSO was inhibited by the thiol antioxidant, N-acetylcysteine (NAC; 20 mM), independent of GSH levels, indicating a mechanism of toxicity involving reduced thiols and metabolic oxidative stress. In addition, treatment with UK5099 alone for 48 h also decreased levels of total glutathione in cancer cells that could be reversed by NAC. Using oxidation-sensitive fluorescent dyes (CDCFH2 and MitoSOX), treatment of lung and breast cancer cells for 24 h and 48 h with UK5099 induced increases in steady state levels of pro-oxidants (presumably hydroperoxides and mitochondrial superoxide), which were further increased with BSO. Finally, treatment of breast cancer cells with UK5099 for 24 and 48 hours significantly sensitized breast cancer cells to clonogenic cell killing mediated by paclitaxel. These data support the hypothesis that inhibition of the MPC selectively causes an impairment of antioxidant capability in cancer cells that is enhanced by depletion of glutathione. Furthermore, these results also support the hypothesis that inhibition of the MPC represents a significant target for sensitizing human breast cancer cells to chemotherapy agents thought to induce oxidative stress.
Supported by R01CA182804.
Citation Format: Shane R. Solst, Samuel N. Rodman, Melissa A. Fath, Eric B. Taylor, Douglas R. Spitz. Inhibition of mitochondrial pyruvate transport selectively sensitizes cancer cells to metabolic oxidative stress [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 3527.
Abstract 3538: Targeting the E3 ubiquitin ligase RNF20 in ovarian cancer
Authors: Cole Alexander J. , Dickson Kristie-Ann , Clifton-Bligh Roderick , Marsh Deborah J. 
Published: August 2018

Abstract
E3 ubiquitin ligases are responsible for the final stage of the enzymatic ubiquitination cascade, where they transfer ubiquitin from an E2 conjugating enzyme to a lysine on the recognized substrate. The most common family of E3 ligases are RING (Really Interesting New Gene) domain proteins. Using immunohistochemistry, we have shown that the ring finger protein RNF20 is strongly expressed in 87% (379 of 424) of high-grade serous ovarian cancer (HGSOC) (1). In contrast, other tumors, including breast, metastatic prostate and colorectal cancer, have been reported to show a decrease in RNF20 transcript levels. The Cancer Genome Atlas has reported &lt; 1% (3 of 316) HGSOCs with RNF20 missense variants of unknown pathogenicity. Given the high level of RNF20 expression in HGSOC, it is unlikely that RNF20 transcript levels are reduced in these tumors.
RNF20 functioning in a heterodimer with RNF40 is the main E3 ligase complex responsible for monoubiquitination of histone H2B at lysine 120 (H2Bub1) (2). This active histone mark leads to an open chromatin configuration favouring DNA access by transcriptional complexes and DNA repair proteins. The RNF20/RNF40 complex also monoubiquitinates and stabilizes the Eg5 motor protein that functions in spindle assembly during mitosis, preventing spindle assembly defects, cell cycle arrest and apoptosis. RNF20 has also been implicated in polyubiquitination of the tumor suppressor Ebp1, promoting its degradation via the 26S proteasome in malignant cells.
We have down-regulated RNF20 in ovarian cancer cell lines to investigate the potential of targeting this E3 ligase to overcome resistance to platinum therapies that is a major problem for the clinical management of women with ovarian cancer. Cell lines studied included the HGSOC lines; COV318, OVCAR-3, OVCAR-4, CaOV3, HEY and OVSAHO, as well as the endometrioid line A2780. Cells were studied as monolayers and spheroid cultures. We have shown that down-regulation of RNF20 leads to lower levels of H2Bub1, consistent with a more closed chromatin configuration. Clonogenic cell survival assays following the treatment of ovarian cancer cell lines with cisplatin showed an impaired ability of cells in which RNF20 had been down-regulated to form colonies. This work provides preliminary evidence that developing strategies to therapeutically down-regulate RNF20 may increase the efficacy of standard-of-care chemotherapy for women with ovarian cancer.
(1) Dickson KA et al., Hum Mol Genet (2016)
(2) Cole AJ et al., Endocr Relat Cancer (2015)
Citation Format: Alexander J. Cole, Kristie-Ann Dickson, Roderick Clifton-Bligh, Deborah J. Marsh. Targeting the E3 ubiquitin ligase RNF20 in 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 3538.
Abstract 3540: Ubiquitin code: Accelerating the discovery of poly-ubiquitylated proteins by novel chain-selective affinity matrices
Authors: Chaturvedi Apurva , Foote Peter , Julius Sarah , Abed Essam , Singh Rajesh K. 
Published: August 2018

Abstract
Ubiquitin (Ub) is attached via isopeptide bonds to lysine residues in the target protein or to another Ub to form poly-Ub chains. The reversibility, heterogeneity, and diversity of these modifications combined with the lack of suitable tools have made it difficult to properly isolate and characterize poly-ubiquitylated cellular proteins. However, in 2009, a novel technology called TUBEs (Tandem-repeated Ub-Binding Entities) was developed. TUBEs have revolutionized the Ub field by allowing poly-ubiquitylated proteins to be enriched/purified from cellular extracts. Development of TUBEs that selectively bind K48-, K63-, and M1-linked poly-ubiquitylated proteins has helped understand the role of modified proteins in cell physiology. However, the roles of other Ub-linkages remain obscured mainly due to the lack of tools that specifically recognize them. Structure-based approach to engineer unique high affinity Ub binding domains(UBDs) for rare Ub-linkages has been implemented to design highly selective affinity matrices. Biochemical and biophysical experiments demonstrate highly selective interactions of the matrices to distinct lysine-linked poly-Ub chains. Power of these highly selective affinity matrices has made it possible to perform Ub proteomics bypassing SILAC mass spectrometry. Application of these affinity matrices in Far Western detection, pull-down and imaging will be described in the poster. To conclude, we have identified unique binding partners for K6-, K11-, K27-, K29-, K33- and K48-linked poly-Ub chains. Development of chain selective affinity matrices (TUBEs) that selectively bind to poly-ubiquitylated proteins will dramatically accelerate the pace of discovery in this important area of biology.
Citation Format: Apurva Chaturvedi, Peter Foote, Sarah Julius, Essam Abed, Rajesh K. Singh. Ubiquitin code: Accelerating the discovery of poly-ubiquitylated proteins by novel chain-selective affinity matrices [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 3540.
Abstract 355: Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding
Authors: Lv Deguan , Jia Feng , Hou Yanli , Sang Youzhou , Alvarez Angel A. , Zhang Weiwei , Hu Bo , Cheng Shi-Yuan , Ge Jianwei , Li Yanxin , Feng Haizhong 
Published: August 2018

Abstract
Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM) where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity- deficient mutants or TRIM24 mutants lacking H3K23ac binding sites promoted PIK3CA expression, AKT phosphorylation and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.
Citation Format: Deguan Lv, Feng Jia, Yanli Hou, Youzhou Sang, Angel A. Alvarez, Weiwei Zhang, Bo Hu, Shi-Yuan Cheng, Jianwei Ge, Yanxin Li, Haizhong Feng. Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding [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 355.
Abstract 3554: The role of P2RY14 in acute leukemia
Authors: Shah Kinjal , Kazi Julhash 
Published: August 2018

Abstract
Leukemia is a group of blood cancers that originate in the bone marrow and involves uncontrolled proliferation of different types of blood cells. The PI3K/mTOR pathway is the second most frequently deregulated pathway in a majority of cancers such as breast cancer, lung cancer and melanomas as well as leukemia. There are several promising drugs targeting this pathway for use in the clinic. However, acquired resistance to the drugs remains a major challenge to overcome. Mutations in the genes coding for receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) are quite common in all forms of acute leukemia. This can be a major cause of deregulation of the PI3K-mTOR pathway. To understand how cells display resistance to the dual PI3K/mTOR inhibitor, we used a panel of acute leukemic cell lines. We observed that while a number of cell lines displayed sensitivity to the dual PI3K/mTOR pathway inhibitor PKI-587, many cells displayed substantial resistance. Cells sensitive to PKI-587 also showed aberrant activation of the PI3K/mTOR pathway and also displayed sensitivity to a panel of various other PI3K/mTOR inhibitors. Using RNA sequencing data from the COSMIC database, we compared gene expression between the cell lines that are either resistant or sensitive to PKI-587. We found that the expression of P2RY14 was around 9-fold upregulated in cells showing resistance to PKI-587. Thus, we identified Purinergic receptor 14, P2RY14, as the target gene. P2RY14 is a G protein-coupled receptor that has not been much studied in hematologic malignancies. However, this receptor seems to have a role in the localization of Hematopoietic Stem Cells (HSCs) and in promoting regenerative capabilities following injury. Acute lymphoblastic leukemia patients with higher expression of P2RY14 mRNA displayed relatively poor survival compared to patients carrying the lower expression of P2RY14. To understand the role of this receptor in leukemia, we stably transfected the murine pro B cell line Ba/F3 with P2RY14. Activation of P2RY14 by its ligand, UDP glucose, resulted in selective induction of ERK1/2 phosphorylation. Taken together, our data suggest that the GPCR P2RY14 couples to ERK signaling which probably has a significant role in acute leukemia. Nevertheless, further in vitro testing of the receptor functionality with various biochemical and molecular biology techniques is required before this receptor, P2RY14, can be utilized as a therapeutic target in the future treatment of acute leukemia.
Citation Format: Kinjal Shah, Julhash Kazi. The role of P2RY14 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 3554.
Abstract 3555: TREM2 is upregulated and plays oncogenic role in gastric cancer
Authors: Zheng Yulong , Jiang Lihua , Xiao Cheng , Xu Nong , Gao Qiqi , Yao Yinan , Hu Yongxian , Sun Yun , Xu Xin 
Published: August 2018

Abstract
Background
Triggering receptor expressed on myeloid cells-2 (TREM2) is thought to be invovled in innate immunity and inflammation regulation. More recently, the importance of TREM2 has been highlighted by identification in several kinds of solid tumors. Nonetheless, the oncogenic roles and potential molecular mechanisms of TREM2 in gastric cancer (GC) remain unknown.
Methods
The expression levels of TREM2 were determined by quantitative PCR (qPCR) and immunohistochemistry (IHC). MTT, colony formation, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, and in vivo tumorigenicity assays were performed to determine the pro-proliferative role of TREM2 in GC cells. mRNA sequencing, qPCR, and Western blotting were used to explore the underlying molecular mechanism of pro-proliferative role of TREM2 in GC cells.
Results
The mRNA expression of TREM2 was markedly up-regulated in tumor tissues (n=16) in comparison with that in corresponding non-tumorous tissues. Immunohistochemical study were performed to determine the protein expression in 108 patients with surgically resected GC. Its expression was positively associated with TNM stage (P=0.023) and T classification (P=0.021), and was inversly correlated with the poor clinical outcome of the patients.
The human GC cell lines MGC-803 and BGC-823 were used for proliferation analysis. The transfected GC cell lines with stable overexpression of TREM2 were established. Ectopic overexpression of TREM2 in GC cells promoted cell proliferation,
whereas loss of TREM2 function inhibited proliferation. In vivo animal experiments further validated the pro-proliferative role of TREM2. Deep sequencing to profile global gene expression of MGC-803 cells with TREM2 overexpression. In the biological process analysis, these differentially expressed genes were mainly involved in the MAPK signaling. Molecular mechanistic investigations explored that TREM2 upregulated GREM1 expression, thereby activating ERK1/2 signaling via VEGFR2-PLC-γ-PKC axis and promoting GC cell proliferation.
Conclusion
High TREM2 expression predicts poor prognosis in GC and TREM2 promotes GC cells proliferation. Our findings suggest that GREM1-VEGFR2-PLC-γ-PKC-ERK1/2 signaling axis contributes to the oncogenic roles of TREM2 on GC cells. TREM2 could be an effective prognostic biomarker and a potential therapeutic target.
Citation Format: Yulong Zheng, Lihua Jiang, Cheng Xiao, Nong Xu, Qiqi Gao, Yinan Yao, Yongxian Hu, Yun Sun, Xin Xu. TREM2 is upregulated and plays oncogenic role in 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 3555.
Abstract 356: Polyadenyaltion of canonical histone mRNA: A potential mechanism of arsenic-induced carcinogenesis
Authors: Chen Qiao Yi , Chen Danqi , Kluz Thomas , Wu Feng , Zhu Yusha , Marais Thomas Des , Li Jinquan , Zhang Xiaoru , Jordan Ashley , Sun Hong , Jin Chunyuan , Costa Max 
Published: August 2018

Abstract
Naturally occurring inorganic arsenic has been identified as a prominent causal agent in lung, bladder, liver, and prostate cancers. Although arsenic (As) has long been known to induce carcinogenicity via epigenetic mechanisms, alteration in histone gene expression has not been explored. The replication-dependent histone genes (also known as canonical histone genes) are the only genes found in multicellular organisms whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3' end. Instead, they contain a conserved 26-nucleotide sequence that forms a stem-loop structure, and serves as the binding site for the Stem-loop binding protein (SLBP). SLBP is critical for canonical histone pre-mRNA processing and histone mRNA translation. Our previous studies demonstrated that arsenic exposure increases polyadenylation of histone H3.1 mRNA (a canonical histone H3) and its presence outside of S phase of the cell cycle due to the loss of SLBP protein and mRNA. Here we report that ectopic expression of polyadenylated H3.1 mRNA induces cell transformation and that the transformed cells are able to form tumors in athymic nude mice. These carcinogenic effects are dependent on the level of polyadenylation of canonical H3.1 mRNA. Notably, transfection of H3.1 cDNA with a stem-loop sequence in the front of the poly(A) signal generates less polyadenylated H3.1 mRNA and thereby attenuates cell transformation. Furthermore, the increase in polyadenylated H3.1 mRNA is able to antagonize histone H3.3 (a non-canonical variant of H3) in the promoter of active genes and perturb expression of cancer-related genes. In addition transfection of H3.1 with a poly(A) tail causes mitotic block in the cell cycle as well as chromosome instability. Furthermore, acute arsenic exposure by inhalation in mice results in the loss of SLBP and gain of polyadenylated H3.1 mRNA in lung tissues. These results suggest that the polyadenylation of canonical histone mRNAs induce by Arsenic is very disruptive to cellular genomic integrity and contributes to development of human cancers.
Citation Format: Qiao Yi Chen, Danqi Chen, Thomas Kluz, Feng Wu, Yusha Zhu, Thomas Des Marais, Jinquan Li, Xiaoru Zhang, Ashley Jordan, Hong Sun, Chunyuan Jin, Max Costa. Polyadenyaltion of canonical histone mRNA: A potential mechanism of arsenic-induced carcinogenesis [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 356.
Abstract 3562: Merkel cell polyomavirus t-antigen regulates aggresome formation and autophagy in merkel cell carcinoma
Authors: Shi Hao 
Published: August 2018

Abstract
Merkel cell carcinoma (MCC) is an aggressive and deadly skin cancer. About 80% of MCCs harbor integrated Merkel cell polyomavirus (MCV) genome with a mutation in the large T (LT) gene, leading to expression of truncated LT and intact small T (sT). The molecular mechanism how the virus contributes to MCC development is still not fully understood. Paranuclear dot-like staining of cytokeratin 20 is a typical characteristic of MCC. However, it is unexplored whether these dot-like structures are functionally important in MCC. In this study, we aimed to characterize the identity of these dot-like structures and to determine whether MCV T-antigens play a role in the formation of these structures. Using immunostaining, we showed that these structures were co-localized with aggresome markers (including intermediate filaments, BAG3 and HSP70) and were localized at the microtubule organization center, as demonstrated by the presence of γ-tubulin. These structures became dispersed to the periphery upon microtubule depolymerization using colcemid. Similarly, silencing of BAG3 in MCV-positive MCC cells resulted in aggresome clearance. Interestingly, we observed that these structures were associated with MCV-positive MCCs and silencing of MCV T-antigens led to dispersion of the aggresome. Additionally, ectopically expressed truncated, but not wild-type, LT could facilitate aggresome formation in MCV-negative cells. We also showed that silencing of MCV T-antigens induced autophagy in MCV-positive MCC cells, while ectopically expressed MCV T-antigens suppressed autophagy in MCV-negative MCC cells. In conclusion, we uncover a novel role of MCV T-antigen in hijacking cellular degradation pathways, suggesting that the autophagy-aggresome pathway plays important roles in MCV infection and MCC tumorigenesis.
Citation Format: Hao Shi. Merkel cell polyomavirus t-antigen regulates aggresome formation and autophagy in merkel cell carcinoma [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 3562.