bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2835: Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition
Authors: Dey Joyoti , Casalini Joseph , Ditzler Sally , Biery Matt , Merrell Angela , Thirstrup Derek , Grenley Marc , Klinghoffer Richard 
Published: July 2016

Abstract
Triple negative breast cancer (TNBC) is a highly heterogeneous disease, notoriously challenging to treat with standard chemotherapy options, and therefore is an area of intense focus for discovery of novel effective combination therapies. Here we used a previously described technology platform called CIVO, which enables assessment of multiple drugs and drug combinations simultaneously in living tumors, to identify drug combinations that result in synergistic anti-tumor activity in the HCC1187 model of TNBC. Our study focused on agents that combine with Voruciclib, a novel clinical stage oral CDK inhibitor with potent activity (&lt;100 nM) against CDKs 1, 4, and 9. Among the drug combinations investigated, robust localized anti-tumor activity as measured by cleaved caspase 3 (CC3) positive apoptotic cells, was observed upon combined tumor exposure to Voruciclib and the proteasome inhibitor Bortezomib. In contrast, exposure to either Voruciclib or Bortezomib as single agents showed little anti-tumor activity. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies where tumor regression was induced by the Voruciclib/Bortezomib combination, but no significant impact on tumor progression was observed in xenografted subjects treated with either single agent. The ability of TNBC cells to withstand stressors such as chemotherapy may be due in part to activation of adaptive survival pathways including the unfolded protein (UPR) and endoplasmic reticulum (ER) stress responses. As observed in previous reports, exposure of HCC1187 cells to Bortezomib alone led to an increase in two markers of the cytoprotective arm of the UPR/ER stress pathway: XBP-1s and GRP-78/BIP. Consistent with the possibility that Voruciclib impedes the cytoprotective UPR/ER stress response induced by Bortezomib, exposure to the drug combination substantially reduced protein expression of both XBP-1s and GRP-78 with concomitant induction of cPARP. Voruciclib also neutralized upregulation of these same proteins by the classic ER stress inducing agent Tunicamycin. These studies provide a foundation for further investigation of breast cancer relevant anti-cancer agents that induce UPR/ER stress responses in combination with Voruciclib for treating TNBC patients.
Citation Format: Joyoti Dey, Joseph Casalini, Sally Ditzler, Matt Biery, Angela Merrell, Derek Thirstrup, Marc Grenley, Richard Klinghoffer. Voruciclib, a clinical stage oral CDK inhibitor, sensitizes triple negative breast cancer xenografts to proteasome inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2835.
Abstract 2838: The role of cyclin D1-associated kinase activity in the regulation of autophagy and senescence in gastric cancer cells
Authors: Vargas Leandro , Bravo Sindy , Valenzuela Claudio , Brown Nelson E. 
Published: July 2016

Abstract
Introduction: Cyclin D1 regulates cell cycle progression through its ability to bind and activate cyclin-dependent kinases 4 and 6 (CDK4/6). Recent work carried out in mammary epithelial cells (MECs) propagated in vitro has revealed that the functional status of cyclin D1 modulates a balance between senescence and autophagy, two processes commonly disrupted in human cancers. Thus, in contrast to the commonly held assumption that autophagy is an effector process of senescence, inhibition of autophagy was accompanied by an induction or exacerbation of senescence in MECs deficient in cyclin D1-associated kinase activity, a reflection of the pro-survival function of autophagy in these cells. Materials and methods: In the present study, we set out to confirm these findings in gastric cancer cell lines (AGS, MKN-45 and KATO III) that may differ in their ability to induce senescence. To this end, we first treated AGS (cyclin D1+; pRB+; p53+) cells with Palbociclib (a specific inhibitor of cyclin D-CDK4/6 complexes), Spautin-1 (a specific inhibitor of autophagy), or a combination of these drugs, and assessed the effect of the treatment on the ability of these cells to proliferate or undergo senescence. Results and discussion: Unlike what was previously reported, our results suggest that autophagy is not required for the implementation of the senescent phenotype in AGS cells treated with Palbociclib. Nonetheless, senescent cells in which autophagy was disrupted were larger and often displayed multiple nuclei, suggesting the existence of different senescence programs depending on autophagy function.
Citation Format: Leandro Vargas, Sindy Bravo, Claudio Valenzuela, Nelson E. Brown. The role of cyclin D1-associated kinase activity in the regulation of autophagy and senescence in gastric cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2838.
Abstract 2851: EGFR-TERT cooperation in the development of EGFR-TKI treatment induced pulmonary fibrosis
Authors: Wei Rongrong , Liu Wanqing 
Published: July 2016

Abstract
Background: Previous studies have shown that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer can lead to the development of pulmonary fibrosis (PF). In other studies, it has been shown that reduced telomerase reverse transcriptase (TERT) function increases susceptibility to PF. In this work, we hypothesize that TERT is associated with the pathogenesis of EGFR-TKI induced PF via important signaling pathways.
Methods: HCC827 cells (EGFR L858R) was treated with gefitinib and TERT expression level was detected following the treatment. To investigate the molecular changes following gefitinib treatment, we also performed a 84-TF qPCR- microarray and a qPCR microarray for 84-key secreted proteins of cytokines and chemokines. The level of interleukin-6(IL-6) was further measured with ELISA in cell medium following the gefitinib treatment. Fibrogenic markers were detected after co-culturing HCC827 with lung fibroblast IMR-90 cells.
Results: TERT gene expression was significantly decreased over 90% after gefitinib treatment. Early growth response protein 1(EGR-1) and E2F transcription factor 1(E2F1) were significantly down-regulated as major TFs that are responsive to gefitinib treatment. Both EGR-1 and E2F1 have been shown to regulate TERT expression in previous studies. In addition, TFs including JUN and most REL members involved in the NF-κB pathway, were significantly up-regulated after gefitinib treatment, which are known to lead to the activation of the senescence-associated secretory phenotype (SASP) pathway. IL-6 mRNA as well as protein secretion were both significantly up-regulated after gefitinib treatment. After co-culturing HCC827 and IMR-90 for 7 days and treating with gefitinib, the growth of IMR-90 cells were increased compare to the control group. Fibrogenic markers, e.g. COL1A1 (Collagen, Type I, Alpha 1), α-SMA (alpha smooth muscle actin), FSP-1(Fibroblast-specific protein 1), etc. were all up-regulated.
Conclusion: Our data suggest that EGFR inhibition leads to lung epithelial cell senescence via inhibiting TERT function and activating of the SASP pathway, which further activates fibroblasts and induces fribrogenesis. Continued studies are warranted to further understand the molecular signaling in this mechanism.
Citation Format: Rongrong Wei, Wanqing Liu. EGFR-TERT cooperation in the development of EGFR-TKI treatment induced pulmonary fibrosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2851.
Abstract 2856: Inhibition of glycolysis sensitizes cancer cells to metformin-induced anoikis
Authors: Yi Yong , Xiao Zhi-Xiong Jim 
Published: July 2016

Abstract
Metformin is a widely used medicine to treat type 2 diabetes. Clinical studies have shown that metformin can reduce cancer incidence, yet the molecular mechanism of which is not totally understood. The p53-related p63 plays a critical role in regulation of cell proliferation, apoptosis, differentiation and development. We and others have shown that the major isform of p63 proteins, ΔNp63α, is important in regulation of squamous carcinoma cell proliferation, survival and cancer metastasis (Bergholz et al.,Oncogene 33:212-224, 2014;Li et al.,CDDis,2013, e943; doi:10.10384). In this study, we show that metformin can induce instability of ΔNp63α protein, leading to subsequent anoikis. In addition, glucose restriction or inhibition of glycolysis significantly sensitizes cells to metformin. Furthermore, we show that integrin β1 is involved in this process. Taken together, this study reveals a novel molecular mechanism by which metformin inhibits squamous carcinoma formation in vitro and in vivo.
Citation Format: Yong Yi, Zhi-Xiong Jim Xiao. Inhibition of glycolysis sensitizes cancer cells to metformin-induced anoikis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2856.
Abstract 2859: Chloroquine and vitamin D3 modulate proliferation in early stage breast cancer models
Authors: Espina Virginia A. , Yeon Solomon , VanHouten Joshua N. , Wysolmerski John , Liotta Lance A. 
Published: July 2016

Abstract
The defining feature of premalignant mammary lesions is proliferation of cells within the intraductal niche. Survival in this stressful duct microenvironment requires sophisticated mechanisms to avoid apoptosis caused by hypoxia, nutrient deprivation, metabolic acidosis, and intracellular calcium overload. Two major survival mechanisms of breast ductal carcinoma cells (DCIS) are 1) the upregulation of autophagy and 2) the enhanced export of calcium via plasma membrane calcium-ATPase isoform 2 (PMCA2) efflux pumps. We hypothesize that calcium efflux, through PMCA2, and activation of autophagic catabolism are critical interdependent mechanisms for the survival of pre-invasive human breast neoplastic cells.
To assess the proteomic response to autophagy inhibition and/or elevated intracellular calcium, 41 signal transduction proteins/post-translationally modified proteins related to proliferation, autophagy, and calcium pathways were quantified by reverse phase protein microarrays (RPPA) in time course studies of T-47D metastatic ductal breast cancer cell line, and MCF-10A non-tumorigenic breast cell line, both of which express low basal levels of PMCA2, and in human primary DCIS organoid cultures. Cell lines were treated with chloroquine (50μM), or 1,25 dihydroxyvitamin D3 (Calcitriol) (50nM or 100nM), or chloroquine + Calcitriol, and harvested at periodic intervals over 197 hours. Stoichiometric time course studies (24 hours) were evaluated for Calcitriol as a single agent in both T-47D and MCF-10A cell lines. Cell morphology, adhesion, proliferation and autophagic flux in the DCIS organoids were assessed by Immunohistochemistry and RPPA.
Calcitriol alone did not increase proliferation based on PCNA expression within DCIS ducts. Chloroquine markedly increased Cleaved PARP (Chi Sq p = 0.004) and CAMKinase II (p = 0.0068). Chloroquine (50μM) plus Calcitriol (100nM) increased E-Cadherin (p = 0.0379) and phosphoPAK1/2 (p = 0.0163), while PMCA2 levels were not significantly different between treatment groups.
Autophagy inhibition and calcium efflux may be exploited therapeutically by co-administration of chloroquine and Calcitrol, to inhibit lysosomal catabolism and increase intracellular calcium levels, respectively, switching them from autophagic survival into apoptotic death.
Citation Format: Virginia A. Espina, Solomon Yeon, Joshua N. VanHouten, John Wysolmerski, Lance A. Liotta. Chloroquine and vitamin D3 modulate proliferation in early stage breast cancer models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2859.
Abstract 286: Preclinical study: HDAC inhibition combined with gemcitabine for the treatment of leiomyosarcoma
Authors: Lopez Gonzalo , Choy Edwin , Patel Shreyaskumar , Bid Hemant , Braggio Danielle , Lev Dina , Pollock Raphael 
Published: July 2016

Abstract
Objective
Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastasic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of pan-HDACi alone and in combination with gemcitabine in LMS.
Methods
Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies. Compounds tested included a pan-HDAC inhibitor (HDACi) and nucleoside analog, gemcitabine (Gem). MTS and clonogenic assays were used to evaluate the effect of HDACi on LMS cell growth. Cell cycle FACS and annexin V PI/FACS analysis were used to determine the effects of HDACi on cell cycle and apoptosis, respectively. Compusyn software was used to determine in vitro synergy studies for the combination of HDACi + Gem. A LMS xenograft model in SCID mice was used to test the impact of HDACi alone, Gem alone and the combination of HDACi + Gemcitabine.
Results
Pan-HDAC inhibition abrogated LMS cell growth and clonogenic potential. HDACi induced G2/M cell cycle growth arrest and enhanced apoptosis in LMS cell lines. The combination of HDACi + Gem exhibited a synergistic effect in LMS cells in vitro. Similarly, HDACi combined with Gem resulted in superior anti-LMS effects in vivo.
Conclusion
LMS are aggressive, metastatic tumors with poor prognosis where effective therapeutic interventions are wanting. Our studies demonstrate the potential utility of pan-HDAC inhibition combined with gemcitabine for the treatment of LMS.
Citation Format: Gonzalo Lopez, Edwin Choy, Shreyaskumar Patel, Hemant Bid, Danielle Braggio, Dina Lev, Raphael Pollock. Preclinical study: HDAC inhibition combined with gemcitabine for the treatment of leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 286.
Abstract 2863: Mechanisms underlying estrogen-induced inflammation in estrogen-deprived breast cancer cells
Authors: Fan Ping , Agboke Fadeke A. , Kumar Tyagi Amit , Jordan V. Craig 
Published: July 2016

Abstract
Inflammation is critical for estrogen (E2) to undertake apoptosis in E2-deprived breast cancer cells. However, it remains unclear how E2 induces inflammation. Here, we demonstrate that E2 increases lipid metabolism and accumulates unfolded proteins in the endoplasmic reticulum in E2-deprived breast cancer cells. These two major alterations result in different inflammatory responses. E2 rapidly increases lipid metabolism related genes such as fatty acid desaturase 1 (FADS1) and CCAAT/enhancer binding protein beta (CEBPB) to modulate adipose inflammation related factors, e.g. IL6/IL6R after two hours treatment, which regulate the cellular proliferation or differentiation. Simultaneously, accumulation of the unfolded protein activates unfolded protein response (UPR) sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring protein 1 alpha (IRE1α) within few hours after exposure to E2. Importantly, inhibition of PERK, rather than IRE1α, is able to completely prevent E2 from induction of late event inflammatory genes associated with apoptosis, such as tumor necrosis factor (TNF) superfamily members, BCL2L11 (Bim), and HMOX1,which are activated by E2 after 48 hours. Consistently, nuclear factor-kappa B (NF-κB) is activated when TNFα is maximal after E2 treatment. Further examination revealed that an anti-inflammatory agent, dexamethasone (Dex), activates glucocorticoid receptor (GR) transcriptional activity and blocks E2-induced apoptosis. These effects can be reversed by the knockdown of GR. A notable mechanistic change is that Dex effectively blocks the phosphorylation of PERK and produces equivalent inhibitory effects on the apoptosis-associated inflammatory genes as the PERK inhibitor. However, Dex has an additional potential to activate lipid metabolism and are additive with E2 to elevate FADS1 and adipokine IL6/IL6R. All of these data, for the first time, describe the mechanisms underlying E2-induced inflammation in E2-deprived breast cancer. It provides important information to restrict the clinical use of glucocorticoids, which will undermine the beneficial effects of E2-induced apoptosis in estrogen deprived breast cancer patients.
Citation Format: Ping Fan, Fadeke A. Agboke, Amit Kumar Tyagi, V. Craig Jordan. Mechanisms underlying estrogen-induced inflammation in estrogen-deprived breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2863.
Abstract 2871: Dual role of EpCAM cleavage in adhesion attenuation and transcription enhancement for cell migration
Authors: Hsu Ya-Ting , Osmulski Pawel A. , Wang Yao , Huang Yi-Wen , Liu Lu , Ruan Jianhua , Jin Victor X. , Kirma Nameer B. , Gaczynska Maria E. , Huang Tim H.M. 
Published: July 2016

Abstract
Epithelial cell adhesion molecule (EpCAM), a membrane protein known to modulate cell-cell adhesion, is also a regulatory molecule internalized into the nucleus for transcriptional control of gene expression. Here we demonstrate that activated EGF/EGFR is a signaling factor to drive the cleavage of the extracellular fragment EpEX culminating in removal of cell-surface EpCAM as monitored with recognition atomic force microscopy (AFM). As a result, internalization of the cytoplasmic domain EpICD leads to formation of transcription factor complexes with LEF1 that regulate gene transcription for enhancing mobility functions of cancer cells. Comprehensive probing with AFM further reveals increased elasticity and decreased adhesiveness of these cells, implicating acquisition of an epithelial-mesenchymal transition phenotype. While EpCAM cleavage contributes to the loss of cell-surface adhesiveness, its internalized EpICD additionally regulates targets for promoting cell migration. Thus, this EGF/EGFR-modulated action on structural EpCAM and regulatory EpICD can enhance invasion potential of transformed cells.
Citation Format: Ya-Ting Hsu, Pawel A. Osmulski, Yao Wang, Yi-Wen Huang, Lu Liu, Jianhua Ruan, Victor X. Jin, Nameer B. Kirma, Maria E. Gaczynska, Tim H.M. Huang. Dual role of EpCAM cleavage in adhesion attenuation and transcription enhancement for cell migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2871.
Abstract 2878: The tumor-permissive role of KHSRP in colorectal cancer: Mechanistic insights from a gene expression study
Authors: Caiazza Francesco , Power Robert , Killick Kate , Higgins Des , Kolch Walter , Breen Laura , Aherne Sinead , Das Sudipto , O’Connor Darran , Tosetto Miriam , Nolan Blathnaid , Fennelly David , Sheahan Kieran , Doherty Glen , Ryan Elizabeth J. 
Published: July 2016

Abstract
Inflammation plays a key role in the development of Colorectal Cancer (CRC), but the underlying regulatory mechanisms are yet to be fully elucidated. The K-homology splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein which regulates translation of transcripts containing ARE sequences in their 3’-UTR, affecting RNA fate at different levels. KHSRP has been implicated in different functions associated with cancer cell biology, such as inflammation and cell-fate determination. Importantly, KHSRP regulates expression of pro-tumorigenic and anti-inflammatory cytokines, potentially impacting on the tumor microenvironment. We have previously shown that knockdown of KHSRP expression in CRC cell lines regulates cell proliferation and clonogenic survival. KHSRP is also required for the secretion of the pro-angiogenic cytokines, IL-8 and VEGF, impacting on endothelial tube formation. To understand the global impact of KHSRP in regulation of CRC cell function we used Affimetrix Human Transcriptome array to investigate gene expression upon KHSRP silencing in SW480 CRC cells. A total of 210 genes were differentially expressed, 155 of which were up-regulated (100 coding and 55 non-coding genes) and 55 were down-regulated (34 coding and 21 non-coding genes). Among these were genes involved in RNA biology, inflammation, immunity, cell signaling and tumor-stroma interaction, shedding light on the potential mechanisms of action of KHSRP in epithelial cells. Representative targets have been selected for validation and further mechanistic studies. These data builds upon our previous findings suggesting a role for KHSRP in creating a tumor-permissive microenvironment in CRC.
Citation Format: Francesco Caiazza, Robert Power, Kate Killick, Des Higgins, Walter Kolch, Laura Breen, Sinead Aherne, Sudipto Das, Darran O’Connor, Miriam Tosetto, Blathnaid Nolan, David Fennelly, Kieran Sheahan, Glen Doherty, Elizabeth J. Ryan. The tumor-permissive role of KHSRP in colorectal cancer: Mechanistic insights from a gene expression study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2878.