bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2991: Inhibition of Rac1 GTPase activity by SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10
Authors: Balhorn Rodney , van Adrichem Arjan J. , Hok Saphon , Balhorn Monique C. 
Published: July 2016

Abstract
SH7139, the first in a series of selective high affinity ligand (SHAL) therapeutics designed to treat non-Hodgkin's lymphoma, has been shown to be selectively cytotoxic to lymphoma cells over-expressing HLA-DR10. Recent efforts to elucidate the mechanisms of action of SH7139 show that the small molecule drug functions similar to both an antibody drug conjugate and a pro-drug. SH7139 is comprised of three small molecule recognition elements that, when linked together, collectively target the drug to HLA-DR10. Following its binding to HLA-DR10, SH7139 is shuttled into the interior of the lymphoma cell where the subsequent metabolism of these recognition elements releases a series of metabolites that inhibit multiple activities required for tumor cell growth and replication. Studies performed using the Burkitt's lymphoma cell line Raji have shown that SH7139 is metabolized by Raji cells, and the metabolic cleavage of two of the recognition elements (Ct and Dv) produce cytotoxic compounds that contribute to tumor cell killing. While the third recognition element, Cb, is not cleaved off the SHAL scaffold or hydrolyzed to release a cytotoxic metabolite, its structural similarity to known inhibitors of the GTPase activating protein (GAP) MgcRacGAP suggested that it might be active in this pathway. MgcRacGAP functions as a switch that stimulates by many orders of magnitude the activity of the Rac1 GTPase, which is required for cleavage furrow formation, ingression, and the completion of cytokinesis. Experiments conducted with the MgcRacGAP-Rac1 complex have shown that the intact SH7139 molecule (IC50 = 10.6±1.6μM) as well as SH7139 fragments containing the Cb recognition element is effective in inhibiting the GTPase activity of the MgcRacGAP:Rac1 complex. These results confirm that one mechanism action of SH7139 is the inhibition of the Rac1-dependent effector pathways that control the rounding of cells undergoing mitosis, confine Rho activation to the equator of the cell for proper cleavage furrow formation and other processes involved in the completion of cytokinesis. This research was supported by the National Cancer Institute Phase II SBIR award R44CA159843 to SHAL Technologies Inc. Part of this work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.
Citation Format: Rodney Balhorn, Arjan J. van Adrichem, Saphon Hok, Monique C. Balhorn. Inhibition of Rac1 GTPase activity by SH7139, a new drug candidate for non-Hodgkin's lymphoma targeting HLA-DR10. [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 2991.
Abstract 2992: Propranolol induces G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway
Authors: Zhou Chengfang , Chen Xiang , McLeod Howard L , Knepper Todd C , He Yijing 
Published: July 2016

Abstract
Both preclinical and clinical studies implied that β-adrenoceptor-blockers (β-blockers) could inhibit the growth of melanoma. However, the underline mechanism is still unclear, especially in acral melanoma. MAPK and AKT pathway is involved in tumor survival and apoptosis. Therefore, we investigated the effect of propranolol on melanoma in the A375, two primary acral melanoma cell lines and mice model. In this study, propranolol significantly reduced cell viability and induced apoptosis by activating intrinsic mitochondrial pathway and inhibiting MAPK and AKT pathway in vitro. Meanwhile, we further highlighted that low dose propranolol could slow down the growth of tumor in immunodeficient mice engrafted with human melanoma cells. Thus, our data firstly showed that propranolol may inhibit melanoma by activating intrinsic mitochondrial pathway and regulating MAPK pathway and AKT pathway.
Citation Format: Chengfang Zhou, Xiang Chen, Howard L McLeod, Todd C Knepper, Yijing He. Propranolol induces G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway. [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 2992.
Abstract 2994: Orlistat decreases endometrial cancer cell proliferation: implications for a novel treatment strategy
Authors: Wysham Weiya Z. , Roque Dario R. , Han Jianjun , Guo Hui , Zhang Lu , Gehrig Paola A. , Zhou Chunxiao , Bae-Jump Victoria L. 
Published: July 2016

Abstract
Objectives: Fatty acid synthase (FAS) is a key enzyme involved in fatty acid synthesis. It also plays an important role in tumorigenesis and is highly expressed in many cancers, including endometrial cancer. Orlistat is a weight loss medication that has been shown to be a potent inhibitor of FAS. The goal of this study was to evaluate the anti-tumorigenic potential of orlistat in endometrial cancer cell lines.
Methods: The endometrial cancer cell lines ECC-1 and KLE were treated with varying doses of orlistat (0.01-500 μM). Cell proliferation was assessed using the MTT assay. Cell cycle progression was evaluated by Cellometer and apoptosis was assessed using the Annexin V assay. Reactive oxygen species (ROS) was measured using the DCFH-DA assay. Western immunoblotting was performed to determine changes in FAS, cellular stress, cell cycle progression and the AMPK/mTOR pathways.
Results: Orlistat inhibited cell proliferation in a dose-dependent manner in both cell lines (IC50 = 81.7 μM in ECC-1; IC50 = 145.5 μM in KLE). Treatment with orlistat resulted in G1 arrest but did not affect apoptosis. Orlistat increased ROS at high doses (500 uM, p = 0.008 for ECC-1 cells and p = 0.012 for KLE cells) and induced expression of BIP and PERK. Western immunoblot analysis demonstrated that orlistat decreased expression of FAS, acetyl-CoA carboxylase (ACC), and carnitine palmitoyltransferase 1A (CPT1A), important proteins in fatty acid metabolism. Treatment with orlistat also increased expression of phosphorylated AMPK and decreased expression of the downstream S6 protein.
Conclusions: Orlistat suppressed cell growth in endometrial cancer cell lines through inhibition of fatty acid metabolism, induction of cell cycle G1 arrest, and modulation of the AMPK/mTOR pathway. Given that patients with endometrial cancer have high rates of obesity, orlistat should be further investigated as a novel strategy for endometrial cancer treatment and prevention.
Citation Format: Weiya Z. Wysham, Dario R. Roque, Jianjun Han, Hui Guo, Lu Zhang, Paola A. Gehrig, Chunxiao Zhou, Victoria L. Bae-Jump. Orlistat decreases endometrial cancer cell proliferation: implications for a novel treatment strategy. [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 2994.
Abstract 2998: Molecular and cellular effects of individual and combinatorial silencing of HSP90 paralogs
Authors: Powers Marissa V. , Te Poele Robert H. , Murphy Ravindhi L. , de Billy Emmanuel , Clarke Paul A. , Workman Paul 
Published: July 2016

Abstract
HSP90 is an ATP-dependent molecular chaperone critical for the folding, stability and function of over 350 client proteins, including many that are oncogenic. Pharmacologic inhibition of the essential ATPase domain inhibits HSP90 function and produces a well-documented molecular and cellular response comprising depletion of client proteins, induction of heat shock proteins and reduction of tumor cell proliferation. There are four paralogs within the HSP90 family, HSP90α, HSP90β, GRP94 and TRAP1, and it is not currently clear what precise role each one plays in the molecular and therapeutic response to HSP90 inhibitors. Here we use an siRNA approach to selectively reduce the expression of each HSP90 paralog, alone or in combination, in an attempt to dissect the individual roles of each chaperone in the molecular and cellular response associated with pharmacologic HSP90 inhibition. In the human cancer models used we found that by simultaneously silencing HSP90α and HSP90β we could phenocopy aspects of pharmacologic HSP90 inhibition including reduction of cell proliferation, induction of HSP72 and other HSF-1 target genes and depletion of oncogenic client proteins. Through analysing representative HSP90 client proteins we observed interesting patterns of paralog-dependence that were related to their overall sensitivity to pharmacologic HSP90 inhibition. Our results reveal the importance of HSP90 paralogs in particular aspects of the molecular and cellular response to pharmacologic HSP90 inhibition.
Citation Format: Marissa V. Powers, Robert H. Te Poele, Ravindhi L. Murphy, Emmanuel de Billy, Paul A. Clarke, Paul Workman. Molecular and cellular effects of individual and combinatorial silencing of HSP90 paralogs. [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 2998.
Abstract 3: Amino acid profiles indicate dependence on different metabolic pathways between leukemia subtypes
Authors: Sweeney Shannon R. , Sentandreu Enrique , Tiziani Stefano 
Published: July 2016

Abstract
Despite the growing body of evidence that the tumor microenvironment protects leukemia cells from chemotherapeutic stresses (1-3), the effect of many extracellular metabolites remains largely unknown. To explore the influence of extracellular metabolites on different leukemia subtypes, cells were treated for 24 hours in vitro with either a supplemental amino acid or amino acid derivative. From this initial screening, a subset of metabolites were chosen for metabolomics analysis. Mass spectrometry (UPLC-MS/MS) was performed on intracellular fractions to identify metabolic differences that resulted from supplementation. Metabolite profiles were also compared between leukemia cell types, namely AML, pre-B cell ALL, and T cell ALL. Of the metabolites tested, lysine and 4-hydroxyphenylpyruvate, an intermediate of tyrosine and phenylalanine metabolism, had the greatest impact on global amino acid profiles. In AML and T cell ALL cell lines, intracellular glutamate, glutamine, proline, and aspartate were increased relative to their respective controls. These amino acids can enter the tricarboxylic acid (TCA) cycle as either α-ketoglutarate or oxaloacetate, suggesting a central role of the TCA cycle in both AML and T cell ALL metabolism. Interestingly, these metabolites were not significantly increased in pre-B cell ALL, signifying the inverse it true for pre-B cells. This observation provides metabolomics evidence that is consistent with a previous study that reported downregulated expression of TCA cycle related genes in pre-B cell ALL (4). Our findings indicate that uptake and metabolism of amino acids and their derivatives is distinct for different leukemia types. Moreover, supplementation with a single metabolite can result in global changes in intracellular metabolite profiles, suggesting an influence not only as an energy substrate, but on overall metabolic pathway activity. Specifically, we conclude that the TCA cycle is more active in AML and T cell ALL and can be modulated by changing the extracellular environment, while pre-B cells are less sensitive to amino acid modulation.
(1) Meads MB, et al. Clin Cancer Res 2008;14(9):2519-2526.
(2) Ayala F, et al. Leukemia 2009;23:2233-2241.
(3) Konopleva M, et al. Drug Resist Updat 2009;12:103-113.
(4) Boag JM, et al. Leukemia 2006;20:1731-1737.
Citation Format: Shannon R. Sweeney, Enrique Sentandreu, Stefano Tiziani. Amino acid profiles indicate dependence on different metabolic pathways between leukemia subtypes. [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 3.
Abstract 30: Kras mediates amino acid metabolism during nutrient stress
Authors: Gwinn Dana , Sweet-Cordero Alejandro 
Published: July 2016

Abstract
Kras is a small GTPase that functions in the transmission of extracellular mitogenic stimuli, and is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC). Previously, Kras has been demonstrated to play a role in tumor metabolism in certain cell types and cancers, but this has yet to be analyzed in the context of NSCLC. We have analyzed how Kras changes metabolic gene expression by expressing a doxycycline-inducible hairpin against Kras in 4 NSCLC cell lines. One of the most regulated metabolism genes is asparagine synthetase (Asns), which transfers the γ-amino group of glutamine to aspartate, yielding glutamate and asparagine. We find elevated levels of Asns in Kras mutant tumors, and that expression of Asns correlates with poor patient outcome. Knockdown of Asns in the absence of exogenous asparagine in the media results in inhibition of cell growth and induction of apoptosis that is rescued by addition of asparagine. Additionally, under conditions of low glutamine levels, knockdown of Asns sensitizes cells to apoptosis, and overexpression of Asns is protective under these conditions. We also find a role for the glutaminase-activity of Asns in glutamine-mediated anapleurosis of the TCA cycle. These observations suggest Asns may be an interesting therapeutic target for NSCLC tumors with mutations in Kras.
Citation Format: Dana Gwinn, Alejandro Sweet-Cordero. Kras mediates amino acid metabolism during nutrient stress. [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 30.
Abstract 3009: Targeting G-protein coupled receptor-related pathway in mucinous tumors
Authors: Dilly Ashok K. , Lee Yong J. , Zeh Herbert J. , Bartlett David L. , Choudry. Mohammad Haroon A. 
Published: July 2016

Abstract
Introduction: Pseudomyxoma peritonei (PMP) is an indolent malignancy characterized by excessive production of Mucin 2 (MUC2; a gel-forming secreted mucin). We have previously demonstrated mucinous tumor growth inhibition in a patient-derived murine xenograft model of PMP using the cyclooxygenase-2 (COX-2) inhibitor celecoxib. We evaluated the downstream mechanism for celecoxib-mediated MUC2-inhibition.
Methods: In vitro and in vivo studies were conducted using MUC2-secreting LS174T cells, PMP explant tissue and a unique intraperitoneal patient-derived murine xenograft model of PMP (PDX model of PMP).
Results: LS174T cells treated with COX-2 inhibitor celecoxib (5-20 μM) for 24 hours demonstrated a significant reduction in MUC2 protein expression measured by flow cytometric analysis. Similarly, in the PDX model of PMP chronic oral therapy with celecoxib (20 mg/kg/d) for 28 days significantly inhibited MUC2 protein expression in harvested tumor tissue. In the LS174T cells, PGE2 (a COX-2 product) induced MUC2 mRNA (real-time PCR) and protein expression (flow cytometry) and this was inhibited by the G-protein coupled-EP4 receptor inhibitor AH23848 as well as siRNA for CREB (cAMP response element-binding protein). Using chromatin immunoprecipitation assay in LS174T cells, we found that treatment with celecoxib or protein kinase A inhibitor (fragment 6-22 amide) significantly decreased CREB-transcription factor binding to the MUC2 promoter.
Conclusions: These data suggest that celecoxib inhibits MUC2 expression via the G-protein coupled receptor/ cAMP/ Protein kinase A/ CREB pathway. Since activating G-protein (GNAS) mutations are commonly found in PMP and may be responsible for its unique mucinous phenotype, our data provide a rationale for targeting this pathway to control mucin production in this malignancy.
Citation Format: Ashok K. Dilly, Yong J. Lee, Herbert J. Zeh, David L. Bartlett, Mohammad Haroon A. Choudry. Targeting G-protein coupled receptor-related pathway in mucinous tumors. [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 3009.
Abstract 3014: ONC201 anti-cancer effects against solid tumors are mediated through eIF2α kinases HRI and PKR but are PERK-independent
Authors: Kline Christina Leah B. , El-Deiry Wafik S. 
Published: July 2016

Abstract
ONC201 is a first-in-class small molecule inducer of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway. We recently reported that ONC201-mediated induction of the TRAIL pathway is largely promoted by a preceding early activation of the integrated stress response pathway (ISR) (Kline et al., Sci. Sig., in press, 2015). ONC201 engages the ISR to exert its broad-spectrum anti-cancer effects through pro-apoptotic and anti-proliferative activities. ONC201 upregulates ATF4, the key indicator of ISR activation, in a manner that is dependent on two eIF2α kinases: heme-regulated inhibitor (HRI) and double-stranded RNA activated protein kinase (PKR). Of note, the activation of ATF4 and downstream cell death signaling by ONC201 is PERK-independent. We now further elucidate how the novel dual engagement of HRI and PKR by ONC201 contributes to the anti-cancer effects of ONC201. ONC201 treatment results in early phosphorylation of eIF2α in a manner that is dependent on HRI. On the other hand, we have shown that ONC201-induced downregulation of cyclin D1 is dependent, at least in part, on PKR, but not on eIF2 α phosphorylation per se. This occurs potentially via PKR-mediated ubiquitination and subsequent proteasome degradation of cyclin D1. Treating cells with ONC201 and the proteasome inhibitor MG132 prevents ONC201-induced decrease of cyclin D1. Despite distinctions in their regulatory protein domains, HRI and PKR have both been shown to respond to oxidative stress. Treating cells with ONC201 in the presence of the antioxidant N-acetylcysteine abrogated ATF4 induction. Our findings document a unique activity of ONC201 on protein translation, via activation of HRI and PKR, as well as effects on protein stability through the proteasome leading to anti-cancer effects.
Citation Format: Christina Leah B. Kline, Wafik S. El-Deiry. ONC201 anti-cancer effects against solid tumors are mediated through eIF2α kinases HRI and PKR but are PERK-independent. [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 3014.
Abstract 303: Compensatory up-regulation of NEK9 contributes to resistance to PLK1 inhibition in triple-negative breast cancer cells
Authors: Wong Nelson K. Y. , Mitchell Devon , Khan Mohamed K. 
Published: July 2016

Abstract
Patients with triple-negative breast cancers (TNBCs) have very poor prognosis in terms of relapse and overall survival. There is currently no targeted therapy for this heterogeneous group of patients and it presents a pressing unmet medical need. Recent data suggest that Polo-like kinase 1 (PLK1) is a plausible target for treating TNBCs, and many small-molecule inhibitors are currently under development for targeting this kinase. Since clinical data have shown that single-agent treatment often leads to resistance and relapse of the cancer, it is essential to identify potential resistance mechanisms of TNBCs to PLK1 inhibition such that combination therapy can be rationally designed to increase treatment efficacy.
We have selected ten individual cell clones from a TNBC cell line, MDA-MB-231, through long-term incubation of the cells with increasing concentrations of a PLK1 inhibitor BI 2536. We hypothesized that increased expression and/or activities of other kinases can compensate for the PLK1 inhibition. To identify these kinases, we screened the expression levels of &gt;500 human kinases in the resistant clones in comparison to the parental cells, using the Nanostring platform, and generated a list of candidate kinases. Among the candidates, NEK9, a downstream effector of PLK1, was confirmed to be over-expressed in all resistant cell clones through Western blotting. MDA-MB-231 parental cells were then infected with a lentiviral over-expression vector that contains NEK9 and GFP. When a mixed population of NEK9-over-expressing cells (GFP+) and parental cells (GFP-) were incubated in the presence of BI 2536, increased proportion of GFP+ cells and increased mean GFP fluorescence intensity was observed over time through flow cytometry. Increase of NEK9 expression was also confirmed with Western blotting in the mixed cell culture experiment, indicating the selection of the NEK9-over-expressing cells in the presence of BI 2536.
In conclusion, we have constructed a list of over-expressed kinase candidates that may contribute to the resistance to PLK1 inhibition. We further identify that over-expression of NEK9 contributes to the resistance phenotype. Our data prompt the need to further study the biology around NEK9 and suggest the possibility of combination therapy through inhibition of PLK1 and NEK9 in treating TNBCs.
Citation Format: Nelson K. Y. Wong, Devon Mitchell, Mohamed K. Khan. Compensatory up-regulation of NEK9 contributes to resistance to PLK1 inhibition in triple-negative 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 303.