bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1868: Upregulation of p62/Nrf2 and downregulation of p-eIF2a provide more susceptible to docosahexaenoic acid-induced cell death in LMP-1 expressing nasopnaryngeal carcinoma cells
Authors: Jing Kaipeng , Shin Soyeon , Han Seung-Hyeon , Wu Tong , Lim Kyu 
Published: August 2018

Abstract
Docosahexaenoic acid (DHA) induces apoptotic cell death through several mechanisms in cancer cells. We have previously demonstrated that DHA triggers apoptosis by increasing reactive oxygen species (ROS) accumulation and the ROS-mediated apoptosis caused by DHA is associated with Nrf2 signaling activation. Here we report that DHA-induced cell death is more susceptible through upregulation of p62-Nrf2 and downregulation of p-eIF2α in LMP-1-expressing nasopharygeal carcinoma (NPC) cells. Treatment of four human NPC cells (CNE, CNE-LMP1, HONE, HONE-EBV) with DHA for 24 hr resulted in a dose-dependent inhibition of cell growth. The DHA effect was due to the induction of apoptosis, given that DHA increased the cleaved form of PARP as well as the number of TUNEL-positive cells. The inhibition of CNE-LMP1 and HONE-EBV cells after DHA treatment is more susceptible compared with CNE and HONE cells without LMP1 by MTT assay. The level of p62 and Nrf2 of LMP1-NPC cells were increased after DHA pretreatment compared to control NPC cells. On the other hand, the level of p-eIF2α produced reverse result. The activation of Nrf2 signal seems to result from decreased Nrf2 inhibitor, Keap1, because DHA remarkably attenuated Keap1 expression levels. Moreover, silencing Nrf2 by small interfering RNAs inhibited the cytotoxic effect of DHA, indicating that Nrf2 activation plays a positive role in the process of DHA-induced apoptosis. Increased staining for LMP1 and p62 was observed in NPC tissues when compared with the nonneplastic (chronic inflammation) tissues. These results suggest that differential regulation of p62/p-eIF2α/NRF2 contributes to susceptible cell death by DHA in LMP-1-expressing NPC cells. Thus, utilization of DHA may represent a promising therapeutic approach for chemoprevention and treatment of human NPC. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2015R1D1A1A01056887) and by the framework of international cooperation program managed by National Research Foundation of Korea (2015K2A2A6002008)].
Citation Format: Kaipeng Jing, Soyeon Shin, Seung-Hyeon Han, Tong Wu, Kyu Lim. Upregulation of p62/Nrf2 and downregulation of p-eIF2a provide more susceptible to docosahexaenoic acid-induced cell death in LMP-1 expressing nasopnaryngeal carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1868.
Abstract 1870: The anti-proliferative and pro-apoptotic effect of MDM2-p53 antagonists evaluated in human tumor cells lines and chronic lymphocytic leukemia patient samples
Authors: Willmore Elaine , Zhao Yan , Ciardullo Carmela , Woodhouse Laura , Thomas Huw D. , Ahn Maria , Fazal Lynsey , Noble Martin E. , Hardcastle Ian , Howard Steven , Chessari Gianni , Lunec John , Wedge Steve 
Published: August 2018

Abstract
We investigated the cellular response to two MDM2-p53 antagonists (RG7388 and Cpd 1) in a panel of 19 tumor cell lines and in patient-derived chronic lymphocytic leukemia (CLL) cells. RG7388 (Idasanutlin) is an MDM2-p53 antagonist developed by Roche and Cpd1 a novel potent and selective MDM2-p53 antagonist developed as part of an ongoing Alliance between Newcastle University, Cancer Research UK and Astex Pharmaceuticals. RG7388 and Cpd1 potently inhibited the proliferation of many cell lines, with MDM2-amplified SJSA-1 osteosarcoma cells and cells from haematological malignancies being the most sensitive (e.g. GI50 values in the acute myeloid leukemia cell line MOLM13 were 33 + 16 nM for RG7388 and 8 + 1 nM for Cpd 1). We also examined induction of apoptosis by measuring caspase 3/7 activation (24 h treatment). SJSA-1 cells showed a 20-fold increase in caspase activation and Molm13 cells a 6-fold increase (measured at 300nM with RG7388). However, cell lines from solid tumours such as the colorectal carcinoma HCT116 or the hepatocellular carcinoma HepG2 did not show any induction of apoptosis, even at concentrations up to 1µM RG3788. In primary CLL cells, Cpd 1 reduced cell viability (48 h) with an average LC50 of 131 + 46 nM (n = 4), compared to 400 + 55 nM for RG7388 (n =23). We also quantified mRNA levels in 25 primary CLL samples and found that RG7388 induced a predominantly pro-apoptotic gene signature: following 6h treatment, 1µM RG7388 resulted in an average 8-fold induction of PUMA and 3.5-fold increase in BAX compared to a 1.6-fold induction of CDKN1A (p21). Our data confirm that targeting the MDM2-p53 interaction is an effective strategy to inhibit growth and viability of tumor cells, and that some cells, including those expressing high levels of MDM2 or those derived from hematological malignancies, display a striking apoptotic response.
Citation Format: Elaine Willmore, Yan Zhao, Carmela Ciardullo, Laura Woodhouse, Huw D. Thomas, Maria Ahn, Lynsey Fazal, Martin E. Noble, Ian Hardcastle, Steven Howard, Gianni Chessari, John Lunec, Steve Wedge. The anti-proliferative and pro-apoptotic effect of MDM2-p53 antagonists evaluated in human tumor cells lines and chronic lymphocytic leukemia patient samples [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 1870.
Abstract 188: Regulation of breast cancer progression by stromal DDR1
Authors: Sun Xiujie 
Published: August 2018

Abstract
Adipose stromal cells (ASC) constitute a significant component of breast stroma. Emerging evidence demonstrates a functional interaction between ASC and breast cancer (BC) cells. Here, we report that stromal discoidin domain receptor 1 (DDR1) is important for ASC-BC communication. Using a DDR1 knockout mouse model, we find that syngeneic mammary tumors grow more slowly in KO mice than wild-type littermate controls. In vitro, loss of DDR1 in stromal vascular fraction (SVF) impairs its ability to stimulate migration and invasion of tumor cells. Furthermore, we show that DDR1-dependent IL-6 production in SVF is responsible for the SVF effect on tumor cells. These results uncover a previously unrecognized role of stromal DDR1 in BC progression and a potential therapeutic target for BC treatment.
Citation Format: Xiujie Sun. Regulation of breast cancer progression by stromal DDR1 [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 188.
Abstract 1886: A novel inhibitor of eIF4F protein translation complex sensitizes DLBCL cells to BCL-2 targeted therapy
Authors: Herzog Lee-or , Nguyen Nancy , Chiu Honyin , Mallya Sharmila , Ronai Ze'ev A. , Fruman David A. 
Published: August 2018

Abstract
The purpose of this project is to investigate the feasibility of using small molecules targeting cap-dependent translation to sensitize B cell lymphoma cells to killing by BCL-2 inhibitors (venetoclax/ ABT-199). We hypothesized that diffuse large B-cell lymphoma (DLBCL) cell survival requires cap-dependent translation, which is facilitated by eukaryotic translation initiation factor 4E (eIF4E)-eIF4G interaction and is promoted by mTOR complex 1 (mTORC1). We used the compound SBI-756, a novel inhibitor targeting the scaffolding protein eIF4G (1). SBI-756 is more potent and selective than previously reported compounds targeting the eIF4E cap-binding protein, or compounds targeting eIF4A helicase. By treating DLBCL cells (germinal center B-cell subtype) with SBI-756 (sub μM concentrations), we discovered profound synergistic induction of apoptosis when combined with venetoclax. Cell viability was reduced even more compared to mTOR kinase inhibitor (TOR-KI) treatment combination. Moreover, SBI-756 was found to reduce the viability (IC50 = 653nM) of VAL lymphoma cells lacking 4E-BP1, while VAL were insensitive to TOR-KI treatment. By using Proximity Ligation Assay (PLA) we showed that SBI-756 treatment prevents eIF4E-eIF4G association in intact lymphoma cells. Dual luciferase assays validated this and indicated a dose-dependent reduction in cap-dependent translation following SBI-756 treatment. Also, Western blot analyses confirmed that SBI-756 treatment did not change mTOR substrates' phosphorylation, indicating that the SBI-756 effect is specific to preventing the eIF4E-eIF4G interaction. Furthermore, SBI-756 treatment reduced polysome formation with a corresponding increase in abundance of monosomes. Lastly, induced expression of 4E-BP1 mutant, which irreversibly binds eIF4E, sensitized DLBCL cells to venetoclax treatment to a similar extent as TOR-KI treatment. Ongoing studies will investigate: (1) The molecular mechanism by which translation inhibition by SBI-756 synergizes with venetoclax to prime DLBCL cells toward apoptosis, and (2) pharmacokinetic and pharmacodynamic effects of venetoclax and SBI-756 treatment on DLBCL progression in vivo. Hence, this project highlights a novel combination for treatment of aggressive lymphomas, and establishes its efficacy using preclinical models.
Reference: 1. Feng Y., et al. SBI-0640756 attenuates the growth of clinically unresponsive melanomas by disrupting the eIF4F translation initiation complex. Cancer Res 2015;75(24):OF1-8.
Citation Format: Lee-or Herzog, Nancy Nguyen, Honyin Chiu, Sharmila Mallya, Ze'ev A. Ronai, David A. Fruman. A novel inhibitor of eIF4F protein translation complex sensitizes DLBCL cells to BCL-2 targeted therapy [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 1886.
Abstract 1898: Regulation of cysteine supply for survival in hepatocellular carcinoma an breast cancer cell lines
Authors: Kim Do Hyung , Lee Seung Jin 
Published: August 2018

Abstract
Several types of tumor highly rely on extracellular cystine to supply cysteine for essential biological processes, therefore, cystine transporter, system xc-, has been suggested as a potential target for cancer therapy. However, it has not been known about cellular heterogeneity and regulatory mechanisms for cystine-dependency. Cystine dependency of 9 hepatocellular carcinoma cell lines and 6 breast cancer cell lines was measured using cystine-deprived medium or sulfasalazine, an inhibitor of system xc-. Cultivation with cystine-deficient media significantly reduced the growth in 9 cell lines, moderately in 3 cell lines, but in 2 cell lines including SNU398 cells. Sulfasalazine dose-dependently decreased the growth of cystine-dependent cell lines, which was prevented by the addition of 2-mercaptoethanol which reduces cystine to be shuttled via L-type transporter system. To identify regulatory mechanisms to render cells to be less dependent on extracellular cystine, siRNA kinase library was screened in SNU387 cells. The siRNAs to decrease viability of SNU387 cells in cystine-deficient media were identified. These research suggest cellular heterogeneity for the dependency on extracellular L-cystine and the kinase which may support cysteine supply in the absence of extracellular cystine could be a potential candidate for targeting cysteine metabolism.
Citation Format: Do Hyung Kim, Seung Jin Lee. Regulation of cysteine supply for survival in hepatocellular carcinoma an breast cancer cell lines [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 1898.
Abstract 1901: Structural basis for selective therapeutic targeting of BFL-1 in cancer by a covalent stapled peptide inhibitor
Authors: Harvey Edward P. , Seo Hyuk-Soo , Guerra Rachel M. , Bird Gregory H. , Dhe-Paganon Sirano , Walensky Loren D. 
Published: August 2018

Abstract
BCL-2 family proteins are master regulators of the mitochondrial apoptotic pathway and dictate whether a cell will live or die in response to stress. Cancer cells hijack the anti-apoptotic arm of this signaling network, overexpressing BCL-2, MCL-1, and BFL-1, to enforce cellular immortality. Whereas BCL-2 has been drugged by the selective small-molecule inhibitor, venetoclax, and new MCL-1 inhibitor molecules have just entered phase I clinical testing, anti-apoptotic BFL-1 remains undrugged. Importantly, the expression of BFL-1 can cause resistance to these molecules and has been independently linked to the pathogenesis and chemoresistance of human cancers, including melanomas and hematologic malignancies. Given the emergence of BCL-2 family proteins as high-priority cancer targets, solving their structures, alone and in complex with their natural BH3 domain ligands, yields important blueprints for drug design. Whereas the structures of numerous “BH3-in-groove” complexes have been solved, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69 Å resolution, revealing similarities and key differences among unliganded anti-apoptotic targets. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by BH3-based stapled peptide inhibitors. The crystal structure of a complex between BFL-1 and a cysteine-reactive and stapled NOXA BH3 α-helix demonstrated the sulfhydryl bond and fortuitous interactions between the acrylamide-bearing moiety and a newly formed hydrophobic cavity. Comparison of the apo and BH3-liganded structures further revealed an induced conformational change. The two BFL-1 structures expand our understanding of the surface landscapes available for selective targeting of BFL-1, and inform a new therapeutic strategy for overcoming BFL-1-dependent apoptotic blockades in human cancer.
Citation Format: Edward P. Harvey, Hyuk-Soo Seo, Rachel M. Guerra, Gregory H. Bird, Sirano Dhe-Paganon, Loren D. Walensky. Structural basis for selective therapeutic targeting of BFL-1 in cancer by a covalent stapled peptide inhibitor [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 1901.
Abstract 1906: PFKFB4, much more than just a glycolytic gene
Authors: Phillips Emma L. , Bethke Frederic , Balss Jörg , Pusch Stefan , Christen Stefan , Schnölzer Martina , Habel Antje , Capper David , Deimling Andreas Von , Fendt Sarah-Maria , Lichter Peter , Goidts Violaine 
Published: August 2018

Abstract
Glioblastoma is one of the most aggressive primary brain tumors in adults, with a dismal median overall survival of only 14 months after diagnosis. Glioblastoma stem-like cells (GSCs) are particularly resistant to current therapies, capable of self-renewal and tumour initiation and are hence thought to be major contributors to patient relapse. A kinome and phosphatome wide screen revealed glycolysis gene 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) as an important candidate gene for GSC survival. Notably, silencing PFKFB4 in an orthotopic xenograft mouse model of glioblastoma completely rid the mice of the tumor. Here we show a brand new function of PFKFB4, independent of its role in glycolysis - namely in the regulation of HIF1α, which is upregulated in GSCs. Gene expression profiling revealed a downregulation in HIF1α target genes in PFKFB4-silenced GSCs, and HIF1α protein levels are also dramatically reduced upon silencing. Mass spectrometric analysis of immunoprecipitated PFKFB4 protein revealed a novel interaction partner, F-box only protein 28 (FBXO28), an E3 ubiqutin ligase. Co-immunoprecipation assays show that FBXO28 forms an SCF multi-protein ubiquitin ligase complex with CUL1 and SKP1. Ubiquitylation studies of HIF1α show that PFKFB4 stabilizes this crucial protein in GSCs by preventing its targeting by FBXO28 for proteasomal degradation. These new findings, coupled with its cancer specific expression in a variety of tumor entities, makes PFKFB4 a compelling target.
Citation Format: Emma L. Phillips, Frederic Bethke, Jörg Balss, Stefan Pusch, Stefan Christen, Martina Schnölzer, Antje Habel, David Capper, Andreas Von Deimling, Sarah-Maria Fendt, Peter Lichter, Violaine Goidts. PFKFB4, much more than just a glycolytic gene [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 1906.
Abstract 1913: Investigation of targeting SKP2 to improve the treatment response in glioma
Authors: Wang Jing , Su Hong-Kai , Chen Zhong-Ping , Qu Yue , Cai Hai-Ping 
Published: August 2018

Abstract
Glioma is the most frequent tumor in central nervous system (CNS), constituting about 30% of CNS tumors and 80% of malignant brain tumors. The current standard strategy for glioma treatment is surgery plus adjuvant chemotherapy and concurrent radiotherapy. However, the prognosis of glioma is still poor. It has been proved that the existence of glioma stem cells and the timely repair of DNA damages are the main causes of treatment failure. Skp2 (S-phase kinase associated protein-2), a member of F-box proteins, forms the Skp2 SCF complex with Skp1, Cullin-1, and Rbx1, serves as one of the important E3-ligases in the process of ubiquitination, and is responsible for substrate recognition. Skp2 is overexpressed in a variety of human cancers and promotes cancer progression by inducing p27 degradation. Importantly, Skp2 deficiency profoundly restricts cancer progression in multiple genetic mouse tumor models. Our group has demonstrated that Skp2 is involved in the regulation of pool size and self-renewal ability of hematopoietic stem cells, as well as breast cancer stem cells and nasopharyngeal carcinoma stem cell-like cells. However, the exact role of Skp2 in the regulation of glioma stem cells and DNA damage repair in glioma has not been elucidated yet. We proposed that targeting Skp2 could promote radio- and chemotherapy sensitivity through suppressing function of glioma stem cells. We first detected the expression of SKP2 in glioma tumor tissues and found that SKP2 was highly expressed in glioma and related to the prognosis of glioma patients. We also adopted gene knockdown methods and inhibitor pretreatment with small molecules in order to suppress the level of Skp2, and then checked the sphere formation and self-renewal ability of glioma stem cell upon radio/chemo treatments. In this way we evaluated the role of Skp2 in repressing the glioma cell proliferation and subsequently triggering apoptosis. Our project will clarify the novel mechanisms about how Skp2 is involved in the glioma radio- and chemotherapy resistance, which will provide a potential target to improve the radio/chemo therapeutic effect through targeting one single target.
Citation Format: Jing Wang, Hong-Kai Su, Zhong-Ping Chen, Yue Qu, Hai-Ping Cai. Investigation of targeting SKP2 to improve the treatment response in glioma [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 1913.
Abstract 194: Prognostic implication of stromal hyaluronic acid protein expression in resected oropharynx and oral cavity cancer
Authors: Ko Yoon Ho , Won Hye Sung , Sun Der Sheng , Hong Soon Auck , Hong Ji Hyung 
Published: August 2018

Abstract
Background: Hyaluronic acid (HA) is a well-characterized component of extracellular matrix (ECM), which plays a critical role in a variety of cellular processes and regulates cell adhesion, migration, and proliferation associated with prognosis of various tumor types. However, the clinical prognostic significance in resected head and neck squamous cell carcinoma (HNSCC) is not well identified.
Methods: The resected tissues from oropharynx or oral cavity cancer patients undergoing surgery were made for tissue microarray (TMA) divided into stroma and cancer panels. Including HA protein expression, HA synthases (HAS) and hyaluronidases (HYAL1) was also assessed by immunohistochemistry.
Results: A total of 160 resected oropharynx or oral cavity cancer tissues between 1994 and 2012 were analyzed in this study. Stromal HA expression, positive in 31 (19.4%) of patients, showed a trend favoring for HPV negative tumor. Other clinicopathological characteristics did not differ according to stromal HA protein expression. However, the HA expression in stroma were statistically associated with clinical outcomes. In the multivariate analysis for clinical outcomes, stromal HA expression was found to be an independent indicator for disease recurrence. (HR, 2.716; 95 % CI, 1.323 - 5.575, P = 0.007), and the combined analysis of tumoral and stromal expression of HA showed that patients with a cancer and stroma-positive HA expression showed a significantly worse outcome than those with other combinations (RFS, P = 0.023, OS, P = 0.082). In addition, when using stratification of HPV stastus, the stromal HA expression remained an independent indicator for disease recurrence and survival(HR, 2.712; 95% CI, 1.323 - 5.56; P = 0.006).
Conclusions: The HA expression in stroma could be related with poor prognosis independently in surgically resected HNSCC. Thus, the finding suggested that HA in stroma may serve not only as a prognostic marker but also as a supposed target for HNSCC treatment.
Citation Format: Yoon Ho Ko, Hye Sung Won, Der Sheng Sun, Soon Auck Hong, Ji Hyung Hong. Prognostic implication of stromal hyaluronic acid protein expression in resected oropharynx and oral cavity 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 194.