bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 132: Role of IL-17-CXCR2 axis in neutrophil recruitment facilitating breast cancer metastasis and therapy resistance
Authors: Wu Lingyun , Sharma Bhawna , Singh Rakesh K. 
Published: August 2018

Abstract
The major challenges for breast cancer includes therapy resistance and metastasis to distant organs. Chronic inflammation has been intimately linked with these processes. We have observed increased level of CXCR2 ligands, inflammatory immunosuppressive microenvironment, and increased metastasis in chemotherapy resistant cells. CXCR2 and its ligands have been shown to be the primary mechanism for neutrophils recruitment to the sites of primary tumors and metastases. However, their precise roles in therapy resistance and metastasis remains unclear. The aim of this project is to investigate the role of neutrophils in chemotherapy resistance and metastasis in breast cancer. In this report, we investigated the mechanisms and putative role of neutrophils in chemotherapy resistance and metastasis. We evaluated the expression level of the factors critical for neutrophil recruitments, such as interleukin (IL)-17 and its receptors (IL-17R), granulocyte colony stimulating factor (GCSF), CXCR2 and its ligands in primary tumors and metastases established from parents and chemotherapy resistant cells. The frequency of neutrophils and T-helper 17 (Th17) cells were analyzed using immunohistochemistry. Chemotherapy-resistant cell lines express higher levels of GCSF, IL-17, and IL-17R compared to Cl66 parent cells. We observed higher expression of IL-17R, CXCR2, and CXCR2 ligands in metastatic lesions compared to primary tumors. Furthermore, there were more recruitments of neutrophils and Th17 cells in resistant tumors than parent tumors. In addition, treatment of tumor cells with IL-17 significantly increased cellular proliferation together with CXCL1 and CXCL5 expression in a concentration-dependent manner. Moreover, we observed higher expression of TGFβ 2 and Th17 cell priming factors, IL-6 and IL-23, in neutrophils co-cultured with therapy resistant cells compared to the control suggesting a feed forward loop. In addition, we observed that IL17 treatment of tumor cells did not increase their tolerance to chemotherapy drug, indicating its role in establishing immune suppressive microenvironments. Together our data demonstrate an IL17-CXCR2 ligands axis induces protumorigenic inflammation, facilitating therapy resistance and metastasis through recruited neutrophils.
Citation Format: Lingyun Wu, Bhawna Sharma, Rakesh K. Singh. Role of IL-17-CXCR2 axis in neutrophil recruitment facilitating breast cancer metastasis and therapy resistance [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 132.
Abstract 1322: A systems-level approach identifies novel links between iron and fatty acid metabolism in high-grade serous ovarian cancer
Authors: Konstorum Anna , Lynch Miranda L. , Torti Suzy V. , Torti Frank M. , Laubenbacher Reinhard C. 
Published: August 2018

Abstract
The low survival rate for high-grade serous ovarian cancer (HGSOC) motivates novel approaches to identify causative and therapeutically targetable factors involved in HGSOC initiation and progression. Cancer cells are known to sequester iron, which can potentiate cancer progression via mechanisms that have not yet been completely elucidated. In order to uncover novel, and potentially therapeutically tractable links, between iron and HGSOC, we developed an algorithm to identify perturbed regulatory pathways containing differentially expressed iron-related genes in microarray data from clinical sources and an experimental model of HGSOC. Used in tandem with over-representation analysis for iron-related genes, the algorithm led us to uncover an iron dependence of fatty acid import and synthesis pathways, which are upregulated in HGSOC and other cancers, and to develop a network synthesizing the relationship between iron, fatty acid metabolism, and HGSOC. We use the network to derive specific hypotheses of mechanisms by which iron impacts fatty acid metabolic pathways to promote tumorigenesis. We have thus shown that a systems-level approach to identifying novel regulatory links between iron and HGSOC has yielded a previously unappreciated association between iron and fatty acid metabolism that may be exploited for therapeutic potential. This work has been supported in part by NIH grants F32CA214030 to AK, R01CA188025 to SVT, and RO1CA171101 to FMT.
Citation Format: Anna Konstorum, Miranda L. Lynch, Suzy V. Torti, Frank M. Torti, Reinhard C. Laubenbacher. A systems-level approach identifies novel links between iron and fatty acid metabolism in high-grade serous 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 1322.
Abstract 1326: Nonprotective autophagy fails to confer resistance to radiation
Authors: Xu Jingwen , Cudjoe Emmanuel Kenneth , Saleh Tareq , Patel Nipa , Alotaibi Moureq , Wu Yingliang , Lima Santiago , Gewirtz David 
Published: August 2018

Abstract
Radiation remains a predominant treatment option for advanced, inoperable lung cancer, however, resistance represents a major barrier against effective therapy. The exact mechanisms through which cancer cells exhibit resistance to radiotherapy still remains unresolved. Traditionally, radiation-induced autophagy is considered as a mechanism of resistance which attenuates the antitumor effects of radiotherapy i.e., autophagy plays a cytoprotective role on cell survival. To examine this concept further, we employed H460 non-small cell lung cancer (NSCLC) cells that were either p53 wild-type (p53 +/+) or p53 null (p53 -/-) to study the contribution of autophagy to radiation sensitivity. While autophagy was markedly higher in p53 +/+ cells (determined by p62 degradation, LC3B conversion, and acidic vesicle formation) the p53 +/+ cells were actually more radiosensitive than their counterpart H460 p53 -/- cells, which showed lower levels of radiation-induced autophagy. Despite modest radiosensitization by chloroquine, alternative pharmacological (3-methly adenine) and genetic (ATG5 silencing) inhibition of autophagy failed to radiosensitize either p53 +/+ or p53 -/- cells, indicating that radiation induced autophagy is not cytoprotective in function in these experimental models. Furthermore, secretome analysis (nLC-MS/MS) of p53 +/+ H460 cells showed no significant association with radioresistance-related proteins in comparison with p53 -/- H460 cells. The rate and extent of apoptosis was quite low and similar in the two cells lines, essentially ruling out apoptotic cell death as the basis for differential radiation sensitivity. Finally, Senescence was more pronounced in the p53 +/+ cells compared to the p53 -/- cells, which may contribute to the greater radiation sensitivity in the p53 +/+ cells. However, the most relevant finding in this work was that when autophagy is the nonprotective form, it does not confer inherent radiation resistance in tumor cells.
Citation Format: Jingwen Xu, Emmanuel Kenneth Cudjoe, Tareq Saleh, Nipa Patel, Moureq Alotaibi, Yingliang Wu, Santiago Lima, David Gewirtz. Nonprotective autophagy fails to confer resistance to radiation [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 1326.
Abstract 133: Synergistic effect between natural killer cells and anysomycin against hepatocellular carcinoma cells
Authors: Lee Chang Hoon , Kim Miok , Lee Kyung Won 
Published: August 2018

Abstract
Although advances in the clinical management of hepatocellular carcinoma (HCC) have been made, HCC is the second leading cause of cancer-related death worldwide. Currently, there are limited treatment options for advanced HCC. Therefore, novel treatment strategies for HCC are required. Here, we described a promising anti-tumor effect of anisomycin, which not only had direct killing effects but also enhanced a natural killer cell-mediated immunotherapeutic effect in HCC. To better elucidate the anti-tumor mechanisms of anisomycin, we performed a genome-scale analysis of gene expression profiles. We found that anisomycin treatment of HCC differentially regulated a broad range of immune regulation-associated genes; among them, we found that CD58, which was significantly increased on anisomycin treated HCC cells was one of the critical components for natural killer cell-mediated immunotherapeutic effect enhanced by anisomycin. Notably, this is the first report for synergistic effect of anisomycin in combination with NK cell therapy as a potential therapeutic option for HCC.
Citation Format: Chang Hoon Lee, Miok Kim, Kyung Won Lee. Synergistic effect between natural killer cells and anysomycin against hepatocellular 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 133.
Abstract 1330: Role of epigenetic remodeling in sensitizing triple-negative breast cancer cells to treatment through enhanced chemotherapy-induced autophagy
Authors: Tyutyunyk Liliya , Landry Joseph , Gewirtz David , Dao Nga 
Published: August 2018

Abstract
Dysregulation of the epigenome is implicated in initiation and progression of variety of cancers and their acquired resistance to chemotherapy. As such targeting epigenetic regulators has the potential to modulate cancer cell biology and their sensitivity to chemotherapy and/or radiation. Our studies demonstrates that silencing of the epigenetic regulator Nucleosome Remodeling Factor (NURF) sensitizes breast tumor cells to chemotherapy and enhances the anti-tumor immune response. A screen of a variety of chemotherapeutic agents shows that NURF KD cells are selectively sensitized to Topo II inhibitors, which includes doxorubicin. NURF KD increases DNA damage (gamma H2AX staining) and autophagy (acridine orange staining) in breast tumor cells exposed to doxorubicin (Dox) and enhances growth inhibition as well as suppressing the ability of the cells to recover proliferative capacity. Increased autophagy as well as breast tumor sensitization to doxorubicin were observed using a small molecule inhibitor of NURF, suggesting that NURF can also be targeted pharmacologically. Our studies suggest that enhanced autophagy may be a primary contributor to chemo sensitivity in NURF KD cells. Studies are currently underway to confirm the role of autophagy in chemosensitization in- vitro and enhanced immune response in-vivo using autophagy deficient cells (through ATG silencing). Doxorubicin produces profound DNA damage and promotes immunogenic cell death enhanced by NURF KD. Increased cell autonomous antitumor effects by doxorubicin in concert with increased cell non-autonomous antigenicity could help to achieve tumor regression, reduce metastasis, and possibly promote long term remission in breast cancer.
Citation Format: Liliya Tyutyunyk, Joseph Landry, David Gewirtz, Nga Dao. Role of epigenetic remodeling in sensitizing triple-negative breast cancer cells to treatment through enhanced chemotherapy-induced 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 1330.
Abstract 1332: Autophagic clearance of protein aggregates is impaired in cancer cells with dysfunctional mitochondria
Authors: Biel Thomas , Rao Ashutosh 
Published: August 2018

Abstract
Mitophagy and aggrephagy are selective types of autophagy that degrade damaged mitochondria and protein aggregates, respectively. Dysfunctional mitochondria are known to undergo mitophagy and cause protein aggregation. How a cell can simultaneously coordinate the removal of dysfunctional mitochondria and protein aggregates via autophagy is unknown. Here, two agents, Mitoquinone (MitoQ) and MitoApocynin (MitoApo), known to induce mitochondrial dysfunction and mitophagy in MDA-MB-231 cells were used to investigate the accumulation of protein aggregates and the mechanisms that contribute to selective autophagy. Using a protein aggregate dye and a poly-ubiquitinated antibody, carbonyl cyanide m-chlorophenyl hydrazine (CCCP), MitoQ, and MitoApo were identified as agents that caused an accumulation of poly-ubiquitinated protein aggregates in cancer cells by FACS analysis and confocal imaging. Microflow imaging of the cellular lysates confirmed a relative accumulation of large protein (&gt;460 kDa) complexes. To establish the presence of aggrephagy, the aggregates were colocalized with LC3. Wild type and ATG7 knockout MEF cells were used to test whether protein aggregates accumulated in an autophagy-dependent manner. Our data currently demonstrates the kinetics of autophagic clearance of drug-induced protein aggregation and dysfunctional mitochondria.
Citation Format: Thomas Biel, Ashutosh Rao. Autophagic clearance of protein aggregates is impaired in cancer cells with dysfunctional mitochondria [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 1332.
Abstract 1339: Development of a novel autophagy-inducing multikinase inhibitor for the treatment of castration-resistant prostate cancer
Authors: Qiao Yuanyuan 
Published: August 2018

Abstract
Inhibition of the androgen axis has revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC continues to be a leading cause of cancer-related deaths in men. Here, we characterized a phase I-cleared multikinase inhibitor, ESK981, in prostate cancer preclinical models. ESK981 was markedly more potent in vitro than other kinase inhibitors, including cabozantinib and crizotinib, that have been evaluated clinically in prostate cancer. Surprisingly, we observed that ESK981 was a potent inducer of cellular vacuolization that was associated with an autophagic response. ESK981-induced autophagy could be blocked by either the depletion of the autophagy vesicle formation gene, atg5, or by autophagy inhibitors such as bafilomycin. ESK981 was further shown to induce autophagy in yeast, which is an evolutionarily conserved core cellular pathway. Moreover, ESK981 triggered prostate cancer cells to release chemokines such as CXCL10 into the cell secretome, thus suggesting that ESK981 may stimulate immune surveillance while exerting its tumor inhibitory effect. Together, ESK981 is a novel and potent autophagy-inducing multikinase inhibitor that effectively inhibits CRPC growth through the activation of the autophagic cascade.
Citation Format: Yuanyuan Qiao. Development of a novel autophagy-inducing multikinase inhibitor for the treatment of castration-resistant prostate 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 1339.
Abstract 1354: TonEBP mediates PCNA polyubiquitination on DNA damage sites via interaction with SHPRH and USP1
Authors: Kang Hyunje , Park Hyun , Yoo Eun Jin , Lee Jun Ho , Choi Soo Youn , Lee-Kwon Whaseon , Lee Kyoo-young , Hur Jin-Hoe , Seo Jeong Kon , Myung Kyungjae , Kwon Hyug Moo 
Published: August 2018

Abstract
PCNA ubiquitination is important for DNA damage tolerance in eukaryotic replication. While PCNA monoubiquitination activates a mutagenic translesion synthesis pathway, polyubiquitination activates an error-free template switching for DNA damage bypass. Even though PCNA polyubiquitination is critical for the maintenance of genomic integrity, underlying mechanisms are poorly understood. Here, we report that TonEBP (tonicity-responsive enhancer binding protein) is involved the PCNA polyubiquitination in response to DNA damage. TonEBP sequentially recruited an E3 ubiquitin ligase SHPRH followed by a deubiquitinase USP1 into DNA damaged sites, which showed direct correlation with dynamics of PCNA polyubiquitination. The Rel-homology domain (RHD) of TonEBP, which encircles DNA, was required for the interaction with SHRPH and USP1. Consistent with its importance for DNA damage bypass, knockdown or deletion of RHD in TonEBP increased sensitivity to methyl methanesulfonate. Collectively, TonEBP is a key player in the post-replication DNA repair.
Citation Format: Hyunje Kang, Hyun Park, Eun Jin Yoo, Jun Ho Lee, Soo Youn Choi, Whaseon Lee-Kwon, Kyoo-young Lee, Jin-Hoe Hur, Jeong Kon Seo, Kyungjae Myung, Hyug Moo Kwon. TonEBP mediates PCNA polyubiquitination on DNA damage sites via interaction with SHPRH and USP1 [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 1354.
Abstract 1356: NSMCE2 enables rescue of collapsed replication forks to prevent mitotic DNA damage
Authors: Pond Kelvin W. , DeRenty Christelle , Yagle Mary K. , Ellis Nathan 
Published: August 2018

Abstract
Background: Replication forks that are persistently blocked cannot restart, even after DNA damage is repaired. These forks are termed collapsed forks. In order to fully duplicate the genome, collapsed forks must be rescued by activation of nearby dormant origins of replication. Homologous recombination (HR) is essential in collapsed-fork rescue. Cells deficient in the SUMO E3 ligase NSMCE2 exhibit mitotic defects, are sensitive to DNA damaging agents, and have defects in HR. Thus, NSMCE2 regulates HR during replication stress, but the molecular mechanisms are poorly understood. In yeasts, hypomorphic NSMCE2 (MMS21) alleles accumulate HR intermediates during replication stress. We therefore hypothesized that NSMCE2 regulates RAD51 function during collapsed fork rescue.
Results: It was previously shown that sumoylation of the BLM helicase results in recruitment of RAD51 to stalled forks. Consistent with data in yeast, we found that BLM sumolyation is dependent on NSMCE2. However, contrary to our expectation, we found that the amount of RAD51 protein that accumulated at collapsed forks was over two times greater in NSMCE2-deficient cells than in normal cells. In contrast, the levels of BLM, RPA, single-stranded DNA, and γH2AX at stalled forks is reduced by half. Consistent with the low levels of γH2AX, the double-strand breaks and sister chromatid exchanges that accumulate during collapsed fork rescue were also greatly diminished in NSMCE2-deficient cells. Thus, despite the over-accumulation of RAD51 to sites of collapsed replication forks, cells are unable to perform HR efficiently, indicating that RAD51 is unable to complete its function there. In NSMCE2-deficient cells, the hyper-accumulated RAD51 at collapsed forks persists into mitosis where excess under-replicated DNA causes mitotic DNA damage.
Conclusions: The hyper-accumulation of RAD51 at stalled forks we observed in NSMCE2-deficient cells suggests that NSMCE2 is required for the remodeling of collapsed forks that normally leads to the rescue of collapsed forks, namely, the unloading of RAD51, DNA breakage, repair by HR, and completion of DNA synthesis. We suggest that the excess accumulation of RAD51 that is observed in a substantial number of cancers is not sufficient to demonstrate that the cells are HR proficient. The identification of NSMCE2 as a controller of HR-mediated fork rescue also highlights NSMCE2's potential as a new therapeutic target for combinatorial therapy of HR-dependent cancers.
Citation Format: Kelvin W. Pond, Christelle DeRenty, Mary K. Yagle, Nathan Ellis. NSMCE2 enables rescue of collapsed replication forks to prevent mitotic DNA damage [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 1356.
Abstract 1358: Translational regulation of DNA repair: The mechanism under cap-independent translational regulation of RPA2
Authors: Cui Jia-Jia , Wang Lei-Yun , Guo Ao-Xiang , Yin Ji-Ye 
Published: August 2018

Abstract
Purpose: Maintenance of genome integrity is critical for any living cells. A variety of endogenous and exogenous factors can cause DNA damage. RPA2 (Replication protein A2) is a kind of single-stranded DNA binding protein complexes and play an important role in the DNA repair. Internal ribosome entry site (IRES) element is a RNA sequence with a complex structure, the activation of RPA2 IRES element can cause its abnormal expression and finally effects DNA repair pathway. IRES is regulated by eukaryotic translation initiation factors (eIFs) and IRES trans-acting factors (ITAFs). UNR (upstream of N-ras), as one of the important IRES trans-acting factors, and eIF3a (Eukaryotic initiation factor 3a) as one of the important eIFs play important roles in the regulation of RPA2 protein expression via IRES elements. We want to explore the role and potential mechanism of translational regulation of UNR and eIF3a in DNA repair. Methods: In the current study, biotin pull down assay was taken to investigate the interaction between RPA2 IRES and UNR. Western blot and qPCR were used to detect protein and mRNA level respectively. CO-IP assay were conducted for interaction of eIF3a with UNR. Immunofluorescence assay was taken to investigate the intracellular localization of UNR and eIF3a, as well as the regulation of UNR on DNA double strand break repair pathway. GST pull down assay was carried out to further identify the interaction between two proteins. Electrophoretic mobility shift assay was carried out to explore the domains of UNR and eIF3a that bind to RPA2 IRES element. Dual-luciferase reporter assay, comet assay and immunofluorescence assay were used to investigate the DNA repair pathway activity. Results: UNR and eIF3a translationally regulate RPA2 by combining with RPA2 IRES. It was found that the expression of RPA2 was down-regulated by UNR with no change on mRNA level. We further found that UNR combined with RPA2 IRES via CSD1 domain. And no domains of eIF3a bind to RPA2 IRES RNA.Meanwhile, the location of UNR and eIF3a was consistent. A series of assays indicate that CSD1 domain of UNR bind to PCI domain of. RPA2 play an important role in the DNA repair. We found that UNR down-regulated double-strand break repair (DSB) activity and nucleotide excision repair (NER) activity. Conclusion: UNR and eIF3a can regulate the expression of RPA2 on translational level, and further regulate the activity of DNA repair, which may reveal the potential mechanism of translational regulation and DNA repair.
Citation Format: Jia-Jia Cui, Lei-Yun Wang, Ao-Xiang Guo, Ji-Ye Yin. Translational regulation of DNA repair: The mechanism under cap-independent translational regulation of RPA2 [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 1358.