bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5552: Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death.
Authors: Evans Myron , Tovmasyan Artak , Batinic-Haberle Ines , Devi Gayathri 
Published: August 2014

Abstract
Resistance to therapy-mediated apoptosis in inflammatory breast cancer (IBC), an aggressive and distinct subtype of breast cancer was recently attributed to increased antioxidant expression (superoxide dismutase [SOD]; reduced glutathione) and decreased accumulation of reactive oxygen species (ROS) resulting in redox adaptation and increased cell survival. Mn porphyrins (MnPs) are amongst the most potent synthetic mimics of the antioxidant, superoxide dismutase (SOD). In the present study, we demonstrate the unique ability of two Mn porphyrin (MnP)-based SOD mimics (MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+) to act as pro-oxidants when combined with ascorbate (vitamin C) and enhance ROS-mediated cell death. We identified that the ethyl species, MnTE-2-PyP5+, was less stable than its butoxyethyl analog, MnTnBuOE-2-PyP5+, resulting in greater potency in inducing cytotoxicity via radical-driven oxidative degradation in cellular models of IBC isolated from patient tumors and an isogenic derivative with acquired resistance to therapeutic apoptosis. The combination of MnP and ascorbate induced accumulation of mitochondrial superoxide and H2O2-derived radicals in both therapy-sensitive and therapy-resistant cell lines. High intracellular ROS resulted in decreases in both pro-survival signaling (pNF-κB, pERK1/2) and expression of X-linked inhibitor of apoptosis protein (XIAP), the most potent caspase inhibitor. Although markers of classical apoptosis were observed, including PARP cleavage and Annexin V staining, administration of a pan-caspase inhibitor (QVD-OPh) did not reverse the observed cytotoxicity. Nuclear translocation of apoptosis inducing factor (AIF) was observed, suggesting a caspase-independent cell death following mitochondrial outer membrane permeabilization after treatment with this combination. In conclusion, this study provides the molecular basis of a novel MnP-based anti-cancer strategy and suggests the feasibility of using MnPs to sensitize cancer cells to many chemotherapies and radiotherapy that are dependent on potent induction of the oxidative stress response.
Citation Format: Myron Evans, Artak Tovmasyan, Ines Batinic-Haberle, Gayathri Devi. Manganese porphyrins in combination with ascorbate act as pro-oxidants and mediate caspase-independent cancer cell death. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5552. doi:10.1158/1538-7445.AM2013-5552
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 556: Cot/Tpl2 is required for neoplastic cell transformation induced by interleukin-22: a possible mechanism in breast carcinogenesis.
Authors: Kim Karam , Choi Hong Seok 
Published: August 2014

Abstract
Interleukin 22 (IL-22), a member of the IL-10 family of cytokines, is secreted T helper 17 (Th17) cells. Although IL-22 was recently reported to be a novel inflammation mediator through STAT3 signaling activation, the precise mechanisms of IL-22 in neoplastic cellular transformation and breast carcinogenesis are not well explored yet. Here, we report that IL-22 induced neoplastic transformation of JB6 Cl41 cells through activation of Cot/Tpl2. IL-22 dose- and time-dependently increased Cot/Tpl2 phosphorylation in JB6 Cl41 cells through IL-22 receptor. IL-22 phosphorylated MEK1/2, JNK1/2 and STAT3, which were inhibited by a specific inhibitor of Cot/Tpl2 kinase. When small interfering RNA (siRNA) of IL-22 and IL-22 receptor (IL-22R) were transfected into JB6 Cl41 cells, IL-22-induced Cot/Tpl2 phosphorylation was markedly decreased, followed by inhibition of MEK-ERK, JNK-c-Jun and STAT3 signaling pathway. Also, IL-22 activated c-fos and c-jun promoter activity, leading to increased activator protein-1 (AP-1) activity, which was suppressed by Cot/Tpl2 inhibitor. The in vivo chorioallantoic membrane (CAM) assay also showed that IL-22 increased tumor growth of JB6 Cl41 cells, whereas Cot/Tpl2 inhibitor suppressed the tumorigenesis induced by IL-22. In addition, knockdown of IL-22 and/or inhibition of Cot/Tpl2 diminished tumorigenecity of human breast cancer SKBR3 cells. Consistent with these observations, immunohistochemical staining showed that both expressions of IL-22 and Cot/Tpl2 proteins were highly upregulated in human breast cancers. Thus, this suggests that Cot/Tpl2 plays a pivotal role in IL-22-induced neoplastic cell transformation, and that Cot/Tpl2 may be the therapeutic target of breast cancer promoted by IL-22.
Citation Format: Karam Kim, Hong Seok Choi. Cot/Tpl2 is required for neoplastic cell transformation induced by interleukin-22: a possible mechanism in breast carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 556. doi:10.1158/1538-7445.AM2013-556
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5596: Linkage between the lipogenic pathway and the progression of breast carcinomas.
Authors: Gonzalez-Guerrico Anatilde M. , Park-Hong Cheol , Kleer Celina , Espinoza Ingrid , Lupu Ruth 
Published: August 2014

Abstract
Fatty acid synthase (FASN) is a lipogenic enzyme responsible for the novo synthesis of fatty acids (FAs) from acetyl-CoA and malonyl-CoA in a NADPH dependent manner in cells. FAs are essential constituents of all biological membranes lipids and are important substrates for energy metabolism. While normal cells (except liver and adiposities) express low levels of FASN and have low to undetectable levels of FASN enzymatic activity, FASN expression and activity is observed in a vast majority of human cancers. Whether the increase in FASN is merely a consequence of disease progression or it is a “metabolic oncogene” that drives disease progression remains unclear. Here, we undoubtedly demonstrated that knockdown FASN results in inhibition of tumor formation and angiogenesis in athymic nude mice. Moreover, the histopathological features of the FASN knockdown remaining tissue in vivo appear globular, well differentiated with low nuclear grade compared to the control tumors, which appear invasive, undifferentiated, and of high nuclear grade. When tissues where stained for Ki-67, Vimentin and E-Cadherin the classical mesenchymal to epithelial transition (MET) was observed in the tissue derived from FASN knockdown tumors. Our studies establish a possible role for FASN as a “metabolic oncogene” in breast cancer. Given the data presented here, we propose that FASN is a perfect marker to develop personalized targeted therapy.
Citation Format: Anatilde M. Gonzalez-Guerrico, Cheol Park-Hong, Celina Kleer, Ingrid Espinoza, Ruth Lupu. Linkage between the lipogenic pathway and the progression of breast carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5596. doi:10.1158/1538-7445.AM2013-5596
Abstract 5633: Co-targeting the IGF1R pathway and compensatory signaling enhances cytotoxicity in head and neck cancer.
Authors: Axelrod Mark J. , Gioeli Daniel , Sharlow Elizabeth R. , Conaway Mark C. , Mendez Rolando E. , Khalil Ashraf , Taniguchi Linnea , Petricoin Emmanual F. , Leimgruber Stephanie , Weber Michael J. , Jameson Mark J. 
Published: August 2014

Abstract
The 5-year survival rate for patients with cancer of the Head and Neck (HNC) has not significantly improved over the past decade. Clearly, new therapeutic targets and strategies for employing existing targeted and cytotoxic therapies are needed. Studies have shown both expression and phosphorylation of the insulin-like growth factor 1 receptor (IGF1R) in both head and neck cancer cell lines and patient tumor samples. We found that small molecule inhibitors targeting IGF1R, when used as a single agent, caused varying degrees of cytotoxicity in HNC cell lines. In order to determine whether the variable biological response to IGF1R inhibition was caused by differences in the effects of the IGF1R inhibitors on the cell signaling networks of the HNC cell lines, we performed reverse phase proteomic array analysis on a panel of HNC cell lines treated with IGF1R inhibitors. Preliminary results suggest that treatment with IGF1R inhibitors caused increased expression and/or phosphorylation of a number of proteins in the array. We hypothesize that these alterations represent compensatory signaling pathways that provide resistance to cytotoxicity upon treatment with IGF1R inhibitors. In order to identify possible mechanisms of compensation for the loss of IGF1R pathway signaling, we screened a panel of small molecule inhibitors of the IGF1R/PI3K/AKT signaling pathway against a panel of inhibitors of proteins important in HNC cell signaling Preliminary results indicate that the inhibition of epigenetic modifying proteins as well as members of canonical cell signaling pathways in combination with inhibition of IGF1R signaling leads to a synergistic increase in cytotoxicity. This suggests that compensatory mechanisms exist in HNC that serve to blunt the cytotoxic effect of inhibition of IGF1R. Co-targeting IGF1R and members of these compensatory pathways may be a viable therapeutic strategy.
Citation Format: Mark J. Axelrod, Daniel Gioeli, Elizabeth R. Sharlow, Mark C. Conaway, Rolando E. Mendez, Ashraf Khalil, Linnea Taniguchi, Emmanual F. Petricoin, Stephanie Leimgruber, Michael J. Weber, Mark J. Jameson. Co-targeting the IGF1R pathway and compensatory signaling enhances cytotoxicity in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5633. doi:10.1158/1538-7445.AM2013-5633
Abstract 693: Inhibitory effect of the CDK4/6 inhibitor, PD 0332991, is enhanced by mTOR inhibition in Non-Small Cell Lung Cancer (NSCLC).
Authors: Gopalan Priya K. , Gordillo-Villegas Andres , Zajac-Kaye Maria , Kaye Frederic J. 
Published: August 2014

Abstract
The p16 protein plays a critical role in the regulation of the retinoblastoma (RB) pathway, which inhibits cell growth through cell cycle regulation. The p16 gene, CDKN2a, is inactivated in 70% of NSCLC tumors, resulting in unregulated activation of CDK 4/6, and consequently increased cell cycling. The drug PD 0332991 (PD) is a highly specific inhibitor of CDK4/6. Western blots of p16-deficient NSCLC cell lines have confirmed a decrease in phosphorylated RB with PD-treated cells compared to untreated cells. We have observed a 34% decrease in viability by an MTS assay, and a 30% increase in cell senescence by a β-galactosidase assay in PD-treated p16-deficient cell lines compared to untreated cells. Based on these data, we are currently conducting a single-arm phase II clinical trial of single-agent PD 0332991 in patients with advanced NSCLC who have failed at least one prior chemotherapy regimen. We hypothesized that a combination of PD with other targeted therapies, acting on the same and intersecting pathways, would result in increased tumor cell death. Using MTS viability assays, we tested PD with and without other inhibitors in p16-deficient NSCLC cell lines. These inhibitors were: 1) the demethylating agent, decitabine, since the p16 gene, CDKN2a, is most often inactivated by hypermethylation (PD 66.1%, decitabine 49.7%, combination 80.2% viability); 2) the MEK inhibitor, AZD 6244, based on a report of a potential synthetic lethal interaction between K-Ras and CDK4 (PD 66.1%, AZD 6244 90.1%, combination 72.0% viability); 3) the CDK1/2/9 inhibitor, AZD 5438, since CDK 1 and 2 are thought to play a role in resistance to CDK 4/6 inhibition (PD 66.1%, AZD 5438 76.3%, combination 96.6% viability), and 4) the mTOR inhibitor, everolimus, since the mTOR pathway can upregulate cyclin D1, which complexes with CDK4/6 in the RB pathway (PD 67.3%, everolimus 65.1%, combination 46.4% viability, p&lt;0.02 for PD compared to combination). Based on our studies, we saw that the combination of PD and everolimus significantly decreased cell viability. Western blots of p16-deficient NSCLC cell lines showed a further decrease in phosphorylated RB with the combination compared with PD alone. These data are promising, and we will be further determining the mechanism of inhibition of this combination. This study provides the groundwork for a future clinical trial of everolimus and PD 0332991 in combination in NSCLC patients with p16-deficient tumors.
Citation Format: Priya K. Gopalan, Andres Gordillo-Villegas, Maria Zajac-Kaye, Frederic J. Kaye. Inhibitory effect of the CDK4/6 inhibitor, PD 0332991, is enhanced by mTOR inhibition in Non-Small Cell Lung Cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 693. doi:10.1158/1538-7445.AM2013-693
Abstract 709: Mitosis interference of cancer cells by NovoTTF-100A causes decreased cellular viability.
Authors: Lee Sze Xian , Wong Eric T. , Swanson Kenneth D. 
Published: August 2014

Abstract
Cancer cell death from traditional cytotoxic chemotherapy and radiation is a result of triggering cell cycle checkpoint with p53 playing a prominent role in orchestrating this effect. Unlike these traditional approaches, the NovoTTF-100A device, which has been approved for the treatment of recurrent glioblastomas, kills tumor cells by a novel mechanism that interferes with the proper progression through mitosis. As is the case with earlier therapeutic interventions, only a subset of patients shows significant response to TTFields treatment. Our research reveals that the tumor-treating fields (TTFields) affects processes proximal to the metaphase-to-anaphase transition, leading to cell cycle arrest in anaphase and eventual cell death. Tissue culture cells exposed to the TTFields during mitosis exhibit a variety of outcomes, including cell arrest in anaphase, cytokinesis with cytokinetic furrow regression, and slippage out of mitosis without division. Time-lapse movies of cells stained with the DNA stain DRAQ5 and exposed to the TTFields revealed membrane blebbing and oscillation, as well as failed segregation of sister chromatids from the metaphase plate, both of which were initiated near the time of metaphase-to-anaphase transition. Immunoflourescence of cells after short-term treatment with TTFields during mitosis showed disordered separation of chromosomes from metaphase plates accompanied by lagging chromosomes, dispersion of chromosomes from the metaphase plate, chromosomes de-condensation in the absence of cytokinesis, and daughter cells with asymmetric chromosomal segregation. Flow cytometry also revealed the presence of cells with abnormal DNA content in cultures treated with TTFields. In contrast to the p53 mutant cell lines, MDA-MB-231 and HCT 116, U87 cells with wild-type p53 exhibit increased Annexin V binding, Caspase activation and increased markers of endoplasmic reticulum (ER) stress after brief exposure during mitosis. This suggests the TTFields induced cellular damage is able to trigger p53-dependent cell death in cells that escape killing during M-phase. These data show that the effects of TTFields on cellular damage during M-phase and provide evidence for the notion that the differential responses to treatment seen in patients may be rooted in the underlying genetic alterations in their tumors.
Citation Format: Sze Xian Lee, Eric T. Wong, Kenneth D. Swanson. Mitosis interference of cancer cells by NovoTTF-100A causes decreased cellular viability. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 709. doi:10.1158/1538-7445.AM2013-709
Abstract 749: Characterization of p54nrb/NonO promoter in NSCLC.
Authors: Lin Sheng-Yi , Lai Yi-Hua , Chen Hsuan-Yu , Chen Huei-Wen , Yu Sung-Liang , Hong Tse-Ming , Chang Gee-Chen , Chen Jeremy J.W. 
Published: August 2014

Abstract
p54nrb/NonO is a multiple function nuclear protein. It has been implicated in numerous processes within the nucleus including transcriptional regulation, DNA unwinding, nuclear RNA processing, DNA double-strand break repair and tumorigenesis. In vivo, p54nrb usually forms a heterodimer with its partner PSF as a RNA splicing factor, but its roles in tumor progress is unknown. In recent years, p54nrb has been report in bladder cancer and prostate cancer that different expression of p54nrb between normal tissue and tumor tissue. p54nrb is upregulated in bladder cancer and prostate cancer. However, the mechanism about transcriptional regulation of p54nrb is still unknown. In this study, we characterize p54nrb function in non-small cell lung cancer cell (NSCLC) line and the transcriptional regulation of p54nrb promoter. First we find p54nrb transcription start site and use PCR technology to clone -1671/+1261 (2952 bp) p54nrb promoter. Then we analyzed p54nrb promoter region by deletion of p54nrb promoter 5’ end and luciferase report assay. The results of luciferase assay demonstrated that there is an important regulation region in p54nrb promoter +311/+414 fragment. And deletion of p54nrb promoter +109/+203 region can cause a part of luciferase activity decreasing. Furthermore, we used programe to predict what kind of transcription factor binding site on these two p54nrb promoter region. And we found three CCAAT box and AP-1, AP2α, Sp1, PEA3, NF-1, YY1 binding site. To investigate which transcription factors involve in transcriptional regulation of p54nrb. We observed the change of p54nrb after overexpressed AP-1, AP2α and Sp1 in CL1-0, CL1-5 and A549 cell line, and the protein level and mRNA level of p54nrb didn't change after overexpressed AP-1, AP2α and Sp1.
Citation Format: Sheng-Yi Lin, Yi-Hua Lai, Hsuan-Yu Chen, Huei-Wen Chen, Sung-Liang Yu, Tse-Ming Hong, Gee-Chen Chang, Jeremy J.W. Chen. Characterization of p54nrb/NonO promoter in NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 749. doi:10.1158/1538-7445.AM2013-749
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 896: miR-198 silencing is a mechanism of gemcitabine resistance in human pancreatic adenocarcinoma.
Authors: Ogunwobi Olorunseun O. , Li Jian , Zhao Xiangxuan , Trevino Jose , George Thomas , Liu Chen 
Published: August 2014

Abstract
Pancreatic adenocarcinoma (PAC) is a very aggressive disease with extremely high mortality rate. Chemotherapy with gemcitabine (G) is a standard of care for advanced disease, but chemotherapy resistance is commonly noted. Human PAC is characterized by overexpression of the proto-oncogene c-met. Increased activation of c-met has been reported in G-resistant PAC cells. Also, aberrant expression of microRNAs (miRNAs) has been linked to cancer progression. Furthermore, a recent study showed that miR-198 regulates c-met expression by binding to the 3′-untranslated region of c-met mRNA. However, the role of miR-198 in chemotherapy resistance in PAC has not previously been studied. Consequently, in this study we used the G-sensitive and G-resistant subclones of the L3.6pl human PAC cell line to examine the role of miR-198 in G-resistant PAC. We observed that the G-resistant subclone had increased expression of c-met (using qPCR and western blotting) and phosphorylated c-met (using western blotting), but not hepatocyte growth factor (HGF). Furthermore, using qPCR we observed significant silencing of miR-198 expression in the G-resistant subclone in comparison to the G-sensitive subclone (P &lt; 0.01). To determine the functional significance of miR-198 silencing in G resistance, we silenced miR-198 expression in the G-sensitive subclone by transfection of a specific oligonucleotide inhibitor of miR-198. We observed that miR-198 silencing resulted in increased expression of c-met and phosphorylated c-met. Further, miR-198 silencing on its own increased total RNA concentration significantly by 146% (P &lt; 0.05) and cell viability by 14.3% (P &lt; 0.05; using MTT assay), both suggestive of a proliferative effect. However, significant effects on apoptosis were undetectable (using Hoechst nuclear staining). Furthermore, miR-198 silencing significantly abrogated G-induced apoptosis (P &lt; 0.05) and G-induced reduction of cell viability (P &lt; 0.05). We conclude that G-resistant human PAC cells have silencing of miR-198. Moreover, miR-198 silencing in PAC cells induces increased expression and phosphorylation of c-met, increased cell proliferation and abrogation of G-induced apoptosis and induction of proliferation. Therefore, miR-198 silencing is a mechanism of G-resistance in PAC. Furthermore, therapeutic strategies to enhance miR-198 expression may be beneficial in PAC.
Citation Format: Olorunseun O. Ogunwobi, Jian Li, Xiangxuan Zhao, Jose Trevino, Thomas George, Chen Liu. miR-198 silencing is a mechanism of gemcitabine resistance in human pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 896. doi:10.1158/1538-7445.AM2013-896