bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3793: Understanding the function of LMP1 CTAR3 in EBV-associated lymphomas
Authors: Ross Tabithia , Bentz Gretchen L. 
Published: August 2019

Abstract
Background: Our present study aims to determine the function of the repetitive elements in the biology of Epstein-Barr virus (EBV) Latent Membrane Protein-1 (LMP1). Latent EBV infection is associated with distinct lymphoid and epithelial malignancies, and LMP1 is the principal oncoprotein of the virus. LMP1 has three C-terminal activating regions (CTARs) that induce multiple signal transduction pathways resulting in sustained cellular proliferation, increased cellular survival, and its oncogenic nature. CTAR1 and CTAR2 have been extensively characterized, but CTAR3 is much less studied. CTAR3 contains the LMP1 repetitive elements, which consist of 11-amino acid repeats and PxxPxP/Jak-interacting motifs. Analysis of over 200 clinical isolates revealed that there is significant variability in the number of 11-aaR (1.5-7.5 repeats) and PxxPxP-motives (1-2 repeats), but the exact function of these elements in oncogenesis is unknown. The findings of the study will greatly add to the understanding of the oncogenic nature of LMP1 and help to elucidate a specific purpose for the repetitive elements found within CTAR3.
Methods: Using EBV B95.8 as our wild type strain, we constructed GFP-tagged LMP1 expression constructs that contain (1) wild type CTAR3; (2) PxxPxP only (no 11-aaR); (3) 11-aaR only (no PxxPxP); and (4) ΔCTAR3 (no 11-aaR or PxxPxP). These expression constructs were transfected into HEK 293 cells to assess the effect of the repeats on the trafficking and oncogenic potential of LMP1.
Results: Findings suggest that the 11-aaR are necessary for correct intracellular and extracellular trafficking of LMP1. Loss of the 11-aaRs results in decreased plasma membrane-expressed LMP1 and the accumulation of LMP1 in intracellular membranes. Further, loss of the 11-aaR inhibits LMP1-induced cell migration, which suggests that the 11-aaR contribute to the oncogenic nature of LMP1.
Conclusions: The number of 11-aaR found in LMP1 CTAR3 is variable in nature. Here we show that loss of the 11-aaR inhibits the normal biology of the oncoprotein, in that LMP1 trafficking is altered and the ability of the oncoprotein in promote cell migration is abrogated. Therefore, we propose that the CTAR3 11-aaR are essential to the oncogenic nature of LMP1. The role of these repeats during the transformation process and during tumorigenesis will be determined. Ultimately, further appreciation of the role of LMP1 CTAR3 in the biology of the virus may help identify potential targets for therapeutic interventions for EBV-associated malignancies.
Citation Format: Tabithia Ross, Gretchen L. Bentz. Understanding the function of LMP1 CTAR3 in EBV-associated lymphomas [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 3793.
Abstract 3795: Antibiotics induce mitochondrial dysfunction, DNA damage and aerobic glycolysis of human mammary epithelia and fibroblast
Authors: Elliott Robert L. , Jiang Xianpeng 
Published: August 2019

Abstract
Mitochondria evolved from free-living bacteria after being endocytosed by eukaryotic host cells millions of year ago. We hypothesized that antibiotics could cause mammalian mitochondrial damage while causing bacterial lethality. Mitochondrial toxicity of three antibiotics, azithromycin, doxycycline and ciprofloxacin, were tested in human mammary epithelia MCF-12A and fibroblast by fluorescent and transmission electron microscopy. Gene expression and DNA damage were tested by real time polymerase chain reaction (qPCR) and ELISA. We found antibiotics suppressed the mitochondrial membrane potential gradient of MCF-12A and fibroblast. Ultrastructural studies showed that antibiotics caused vacuolated swollen mitochondria with disrupted cristae in MCF-12A and fibroblast, compared to the ultrastructure of mitochondria in the cells without antibiotic treatment. Fluorescent microscopy revealed antibiotics induce mitochondrial reactive oxygen species (ROS), superoxide, after 3 hours of culture. The DNA oxidative damage product, 8-OHdG, was significantly increased in the media after MCF-12A and fibroblast were cultured in antibiotic media for 24 hours. Antibiotics upregulated gene expression of hypoxia inducible factor 1 alpha (HIF1a), 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) in MCF-12A and fibroblast. Lactate production was also increased in the culture media of healthy cells MCF-12A and fibroblast cells, confirming aerobic glycolysis, or “the Warburg effect”, the method to generate energy after cells are treated with antibiotics. In summary, antibiotics caused mitochondrial toxicity, ROS overproduction, DNA oxidant damage, upregulation of HIF1a gene and aerobic glycolysis in healthy mammalian cells. Over-usage of antibiotics could contribute to tumorigenesis and neurodegeneration and aggravate existing mitochondria-associated diseases.
Citation Format: Robert L. Elliott, Xianpeng Jiang. Antibiotics induce mitochondrial dysfunction, DNA damage and aerobic glycolysis of human mammary epithelia and fibroblast [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 3795.
Abstract 3796: Selonsertib, an ASK1 inhibitor, antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance
Authors: Ji Ning , Yang Yuqi , Cai Chao-Yun , Lei Zi-Ning , Wang Jing-Quan , Gupta Pranav , Shukla Suneet , Ambudkar Suresh V. , Kong Dexin , Chen Zhe-Sheng 
Published: August 2019

Abstract
The overexpression of ATP-binding cassette (ABC) transporters has known to be one of the most important mechanisms responsible for the development of multidrug resistance (MDR). Selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, is in phase III clinical trial for the treatment of non-alcoholic steatohepatitis (NASH). In this study, we investigated whether selonsertib could antagonize MDR mediated by ABC transporters, involving in ABCB1, ABCG2, ABCC1 and ABCC10. The results showed that selonsertib significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR-mediated by ABCC1 or ABCC10. Mechanistically, our studies indicated that the reversal effect of selonsertib was related to the attenuation of the efflux function of ABCB1 and ABCG2 transporters, consequently enhancing intracellular accumulation of substrate drugs. Meanwhile, selonsertib, at reversal concentration, affected neither the expression level of ABCB1 and ABCG2 nor the localization of corresponding proteins in subcellular level. Selonsertib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Our in silico docking study showed that selonsertib could interact with the substrate-binding sites of both ABCB1 and ABCG2. This study provides a clue into a novel treatment strategy, which includes a combination of selonsertib with antineoplastic drugs to circumvent ABCB1- or ABCG2- mediated MDR.
Citation Format: Ning Ji, Yuqi Yang, Chao-Yun Cai, Zi-Ning Lei, Jing-Quan Wang, Pranav Gupta, Suneet Shukla, Suresh V. Ambudkar, Dexin Kong, Zhe-Sheng Chen. Selonsertib, an ASK1 inhibitor, antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance [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 3796.
Abstract 3798: Acetate supplementation eliminates hypoxia mediated resistance to differentiation therapy in neuroblastoma cells
Authors: Li Yang , Zhou Yiren , Maris John M. , Giaccia Amato J. , Ye Jiangbin 
Published: August 2019

Abstract
Neuroblastoma is the most common extracranial solid tumor in childhood. Retinoic acid (RA) leads to cell cycle arrest and induces cell differentiation in neuroblastoma cells, thus it has been used to treat neuroblastoma as differentiating agent for decades. However, therapy resistance often occurs and the overall survival remains low. Hypoxia, a common metabolic stress existing in tumor microenvironment, increases tumor resistance to RA by promoting dedifferentiation of neuroblastoma cells. The aim of this study was to elucidate the mechanisms underlying hypoxia-mediated therapy resistance and develop therapeutic approach to improve the response to differentiation therapy. By RNA-Seq analysis, we identified a group of neuron-specific differentiation markers that induced by RA treatment, while the induction was diminished under hypoxia. Associated with the silencing of differentiation markers expression, a significant loss of histone acetylation of H3K9, H3K27 and total H3 was observed under hypoxia. Metabolomics analysis indicated hypoxia inhibited mitochondrial oxidative phosphorylation to decrease intracellular acetyl-CoA and citrate, which provides acetyl-CoA for histone acetyltransferase. Importantly, acetate supplementation restored cellular acetyl-CoA level, histone acetylation, and the expression of differentiation markers under hypoxia. Differentiation morphology was also restored by acetate supplementation under hypoxia. In conclusion, our finding suggested hypoxia contributed to the resistance to RA-induced differentiation by reprogramming cellular metabolism and inducing histone hypoacetylation. Acetate supplementation is an efficacious therapeutic approach to improve the sensitivity of hypoxic tumor to RA-based differentiation therapy.
Citation Format: Yang Li, Yiren Zhou, John M. Maris, Amato J. Giaccia, Jiangbin Ye. Acetate supplementation eliminates hypoxia mediated resistance to differentiation therapy in neuroblastoma 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 3798.
Abstract 3805: Artesunate reduces tumor growth in sunitinb-resistant renal cell carcinoma cells
Authors: Juengel Eva , Markowitsch Sascha , Erb Holger H. , Efferth Thomas , Haferkamp Axel 
Published: August 2019

Abstract
Introduction: Renal cell carcinoma (RCC) is the most common cancer of the kidney. Due to therapy resistance effect of the approved compounds, like the tyrosine kinase inhibitor (TKI) sunitinib, is limited. Thus, new treatment approaches are urgently needed. Artesunate (ART) is derived from Traditional Chinese Medicine (TCM), showing anti-tumor activity, also in urologic tumors. However, little is known about the efficiency of ART on therapy-resistant RCC. Therefore, we investigated the effect of ART on sunitinib-resistant RCC cell lines.
Material and Methods: Parental (=sensitive) and sunitinib-resistant (1 µM) RCC cell lines, KTC-26, A498, and Caki-1, were exposed to ART (1-100 µM) for 24, 48 and 72 hours. ART untreated cells served as controls. Tumor cell growth, proliferation, cell cycling and the expression of cell cycle regulating proteins were then evaluated. Aside, the appearance of apoptotic and necrotic effects was determined.
Results: Exposure to different concentrations of ART significantly reduced the tumor cell growth and proliferation of parental and sunitinib-resistant cells in a time- and dose-dependent manner, compared to the controls. At the same time, exposure to ART resulted in a cell cycle arrest in the G0/G1 phase. Notably, this effect was more prominent in the sunitinib-resistant cells. G0/G1 phase elevation was associated with a decrease in the percentage of S and G2/M phase cells. The observed changes in cell growth and cell cycle phases were accompanied by distinct modulations of the cell cycle regulating proteins, indicating for an inhibitory regulation of ART through cell cycle arrest. Indeed, neither necrotic nor apoptotic effects events were detectable after ART treatment, corroborating this assumption.
Conclusion: Due to our data we conclude that ART has anti-tumor effects not only in parental but also in sunitinib-resistant RCC cells. Thus, adding ART to the standard therapies might be a promising treatment strategy for patients with advanced RCC. Further investigations are necessary to verify our findings.
Citation Format: Eva Juengel, Sascha Markowitsch, Holger H. Erb, Thomas Efferth, Axel Haferkamp. Artesunate reduces tumor growth in sunitinb-resistant renal cell carcinoma 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 3805.
Abstract 3813: PHB2 inactivation by AKAP-BIG3 is required for progression of HER2-overexpressing breast cancer
Authors: Yoshimaru Tetsuro , Matsushita Yosuke , Sasa Mitsunori , Miyoshi Yasuo , Katagiri Toyomasa 
Published: August 2019

Abstract
Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is linked to aggressive tumor behavior and a poorer prognosis. Anti-HER2 monoclonal antibody, trastuzumab extends the overall survival of patients with HER2-overexpressing breast cancer, but resistance to trastuzumab and/or other HER2-targeted therapies remains a serious clinical problem. Our previous studies demonstrated that Brefeldin A-Inhibited Guanine nucleotide-exchange protein 3 (BIG3), which is exclusively overexpressed in the majority of breast cancers, functions as a cancer specific A-kinase anchoring protein that binds protein kinase A (PKA) and protein phosphatase 1 (PP1Cα), thereby inactivating prohibitin2 (PHB2) suppressive activity through its dephosphorylation on Ser39. We further developed dominant-negative stapling peptide (stERAP), which is designed to specifically disrupt binding of BIG3-PHB2 complex and improve duration of their anti-tumor effects. Here we newly report that stERAP has significant suppressive effects on the HER2 signaling network by activating the tumor suppressive ability of PHB2. stERAP resulted in intrinsic PHB2 release from BIG3, followed by rapid phosphorylation on Ser39, Thr42 and Thr169 via PKCα, TTK and MK5, respectively. Importantly, PHB2 released from BIG3 by stERAP treatment translocated into nucleus, followed by acting as a transcriptional co-repressor by recruiting HDAC1 and NcoR through its Ser39-phosphorylation. More importantly, we observed that serine/threonine phosphorylations of PHB2 are necessary for disruption of HER2-HER3 hetero-dimerization and NF-κB signalling activation which are associated with acquired resistance to trastuzumab. We demonstrated that weekly treatment of stERAP completely suppressed the proliferation of trastuzumab-resistant HER2-positive breast cancer cells in vitro and in vivo. We are currently examining the association of both BIG3 overexpression and PHB2 dephosphorylation with poor prognosis of patients with HER2-positive breast cancers by immunohistochemical staining, and will report these results at this meeting. We demonstrated for the first time that PHB2 inactivation by the AKAP-BIG3 (BIG3/PKA/PP1Cα tri-complex) is required for oncogenic HER2 signalling activation in breast cancer cells, and stERAP may be a promising anti-cancer drug for trastuzumab-resistant breast cancer.
Citation Format: Tetsuro Yoshimaru, Yosuke Matsushita, Mitsunori Sasa, Yasuo Miyoshi, Toyomasa Katagiri. PHB2 inactivation by AKAP-BIG3 is required for progression of HER2-overexpressing breast 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 3813.
Abstract 3824: Increased production of endogenous hydrogen sulfide (H2S) induced resistance to 5-FU and Oxaliplatin in colon cancer cells
Authors: Chen Shanwen , Zuo Shuai 
Published: August 2019

Abstract
The combination of 5-FU and Oxaliplatin has been widely adopted as one of the first line chemotherapeutic regimens for colon cancer patients. However, the development of chemoresistance can lead to early recurrence and metastasis to distant organs, thus remaining a leading cause of death from colon cancer. In the present study, the increased production of hydrogen sulfide (H2S) in colon cancer tissues was validated and the effect of inhibition of production of endogenous H2S on the responses of colon cancer cells to 5-FU and Oxaliplatin was further analyzed. The results suggested that inhibition of the enzymatic activity of cystathionine-β-synthase (CBS), a major producer of H2S in colon cancer cells, significantly decreased the IC50s of both 5-FU and Oxaliplatin. Inhibition of CBS leads to decreased PI3K-Akt signaling and consequently decreased expression of thymidylate synthetase (TYMS), which is the target of 5-FU. Inhibition of CBS utilizing aminooxyacetic acid (AOAA) leads to increased production of reactive oxygen species (ROS) and exaggerated mitochondrial damages in colon cancer cells. Analysis performed on CompuSyn confirmed the synergetic effect of AOAA with both 5-FU and Oxaliplatin. In vivo imaging of tumorigenesis in nude mice further confirmed the effect of inhibition of CBS on the therapeutic effect of both 5-FU and Oxaliplatin. Together, these results suggested that inhibition of production of endogenous H2S might be a promising target for chemoresistance in colon cancer.
Citation Format: Shanwen Chen, Shuai Zuo. Increased production of endogenous hydrogen sulfide (H2S) induced resistance to 5-FU and Oxaliplatin in colon 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 3824.
Abstract 3828: Differential transcriptional response of MYC to bromodomain inhibition in HPV positive head and neck squamous cell carcinoma
Authors: Rengifo Hassler , Wang Albert R. , Titi Mohammad , Nickel Kwang , Kimple Randy , Iyer Gopal 
Published: August 2019

Abstract
Differential transcriptional response of MYC to bromodomain inhibition in HPV positive head and neck squamous cell carcinoma
Targeting of bromodomain (BRD) and extra-terminal domain (BET) family protein activity has the potential to reduce proliferation in many cancers. We hypothesize that targeting BRDs using its inhibitors will lead to reduced proliferation in human papilloma virus (HPV) infected head and neck cancer squamous cell carcinoma (HNSCC). HPV infected HNSCC is predicted to surpass the incidence of cervical cancer by 2020. Amongst various HPV serotypes, HPV16 is classified as oncogenic for a various number of cancer sites including head and neck squamous cell carcinoma (HNSCC). Integration of HPV into host genomes is not part of its life cycle; however, the exception is HNSCC wherein E6 and E7 viral proteins predominantly drive its tumor progression. HPV integrated HNSCC cells will be utilized to unravel the fundamental question of epigenetic regulation of viral-host interaction using the HPV-positive HNSCC model. Results from our lab indicate that despite high nanomolar IC50 in cell proliferation assays, downregulation of MYC expression was not observed using BRD inhibitor in all MYC expressing HNSCC cell lines. Further interrogation revealed differential phosphorylation of tumor suppressors - p53 and pRb might influence the sensitivity to BRD inhibition, which in turn could explain the contrasting regulation of MYC RNA levels. Intriguingly, combining radiation with bromodomain inhibitors led to increased radio-sensitization suggesting that BRDs have a role to play in DNA damage repair pathway and altered cell cycle regulation. Taken together, we will present MYC dependent and independent mechanism following BRD inhibition in HPV positive HNSCC.
Note: This abstract was not presented at the meeting.
Citation Format: Hassler Rengifo, Albert R. Wang, Mohammad Titi, Kwang Nickel, Randy Kimple, Gopal Iyer. Differential transcriptional response of MYC to bromodomain inhibition in HPV positive head and neck squamous cell carcinoma [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 3828.
Abstract 3830: Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models
Authors: Xiong Rui , Li Yangfeng , Zhao Jiong , Tonetti Debra , Thatcher Gregory 
Published: August 2019

Abstract
Approximately 70% of breast cancer patients have estrogen receptor positive (ER+) tumors. Fulvestrant (FUL), a selective estrogen receptor degrader (SERD) able to ablate ER, was first introduced to clinical practice in 2002 as the second and third line treatment for ER+ metastatic breast cancer. In August 2017, FUL was added to first-line therapy in postmenopausal women by demonstrating superiority compared to first-line AI therapy, anastrozole, with improved progression-free-survival (PFS) and a 20% reduction in the risk of disease progression or death. However, acquisition of FUL-resistance in both first-line setting or as combination therapy with CDK4/6 inhibitor has been observed clinically, leaving patients and oncologists with chemotherapy as the only backup therapy. Little is known about resistance mechanisms to FUL alone or in combination with CDK4/6 inhibitors. Here, we showed that targeting epigenetic vulnerabilities in breast cancer using novel bromodomain and extra-terminal (BET) inhibitors can effectively inhibit growth of tamoxifen-, FUL- and CDK4/6- resistant breast cancer cells. We designed and developed a novel series of pyridinone-based BET inhibitors, optimized by growth inhibition in tamoxifen- and FUL- resistant breast cancer cell lines (MCF7:CFR) in both 2D and 3D cultures. Optimized compounds showed superior in vitro activity to BET inhibitors in clinical trials. Selected compounds were further evaluated for pharmacokinetics and shown efficacy in endocrine-resistant xenograft models.
Citation Format: Rui Xiong, Yangfeng Li, Jiong Zhao, Debra Tonetti, Gregory Thatcher. Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models [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 3830.