bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5386: Investigating the role of N-terminal protein methylation in colon cancer progression.
Authors: Tooley John G. , Trent John O. , Tooley Christine E. Schaner 
Published: August 2014

Abstract
We have recently identified the first mammalian N-terminal methyltransferase, NRMT. NRMT is a highly conserved, ubiquitously expressed nuclear enzyme that is predicted to methylate more than 300 target proteins, including the proven targets Retinoblastoma Protein (RB), DDB2, and the oncoprotein SET. N-terminal methylation has been shown to regulate protein-DNA interactions and has also been implicated in regulating protein stability. Multiple microarray analyses have shown that NRMT is overexpressed in human colon cancer, and our preliminary data indicate the more aggressive the cancer, the higher the NRMT expression. However, there are currently no commercially available inhibitors specific for this enzyme and very little is known about the downstream signaling consequences of NRMT misregulation. We have used in silico screening of the ZINC small molecule library to identify potential NRMT-specific inhibitors. Screening of the top 100 candidates produced 10 compounds that could inhibit NRMT methyltransferase activity in vitro. The top compound of these 10 can also inhibit NRMT methyltransferase activity in cell culture and specifically stops the growth of colon cancer cell lines that have high NRMT expression. We are currently working to optimize this small molecule inhibitor for stability and solubility, understand its downstream signaling consequences, and test its efficacy in a murine model system. We are especially interested in the potential of NRMT inhibitors as a treatment for patients with mutant kRAS. These patients are often insensitive to anti-EGFR therapy, but oncogenic RAS seems to require functional RB. Therefore, impairment of NRMT activity could also impair oncogenic RAS signaling through destabilization of RB. Data from this study will enhance our understanding of how colon cancer develops and could lead to novel treatments for the disease.
Citation Format: John G. Tooley, John O. Trent, Christine E. Schaner Tooley. Investigating the role of N-terminal protein methylation in colon cancer progression. [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 5386. doi:10.1158/1538-7445.AM2013-5386
Abstract 5424: CD44-mediated glucose metabolism affects ROS level and drug sensitivity in glycolytic cancer cells.
Authors: Tamada Mayumi , Suematsu Makoto , Saya Hideyuki 
Published: August 2014

Abstract
Low reactive oxygen species (ROS) level of cancer cells is implicated in chemo-resistance. One of the reasons why cancer cells keep their ROS level low is an increased glycolytic flux accompanied by activation of pentose phosphate pathway (PPP).
We found that CD44, a cell surface marker for cancer stem cells, interact with pyruvate kinase M2 (PKM2) which is one of the most important regulators of aerobic glycolysis (Warburg effect), and thereby promotes the glycolysis of cancer cells. CD44 ablation by RNA interference increased PKM2 enzymatic activity and then induced metabolic shift from glycolysis to mitochondrial respiration and concomitantly reduced glucose uptake and PPP flux via suppression of glucose transporter1 (Glut1) expression. Such metabolic changes by CD44 ablation depleted cellular reduced glutathione(GSH) contents and increased intracellular ROS level. Our group previously reported that CD44 variant expression promotes xCT-mediated cysteine uptake and consequent GSH synthesis. Taken together, we suggested that CD44 maintains GSH synthesis and low ROS level in glycolytic cancer cells not only through xCT-mediated cysteine uptake but also by maintenance of the PPP flux and consequent NADPH production.
Additionally, CD44 depleted cancer cells more sensitized them anticancer drugs even in more glycolytic environments, such as p53-deficient or hypoxia, in which cancer cells show more chemo-resistance. This increased sensitivity to anticancer drugs conferred by CD44 ablation was inhibited by pretreatment with a precursor of GSH that functions as an antioxidant. Therefore, these results indicated that enhanced ROS level by CD44 ablation sensitizes highly glycolytic cancer cells to conventional chemotherapy.
The possibility that CD44-targeted therapy may perturb the metabolism of cancer cells and thereby impair their capacity to defend against ROS warrants further investigation.
Citation Format: Mayumi Tamada, Makoto Suematsu, Hideyuki Saya. CD44-mediated glucose metabolism affects ROS level and drug sensitivity in glycolytic cancer cells. [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 5424. doi:10.1158/1538-7445.AM2013-5424
Abstract 5444: Role of CRD-BP in the pathogenesis of human basal cell carcinoma.
Authors: Noubissi Felicite Kamdem , Kim Tae Won , Kawahara Tisha , Longley B. Jack , Berg Eric , Athar Mohammad , Spiegelman Vladimir S. 
Published: August 2014

Abstract
Although the number of new cases of Basal Cell Carcinoma (BCC) has increased rapidly each year in the last few decades, the molecular basis of its pathogenesis is not completely understood. Activation of Hedgehog (Hh) signaling pathway was shown to be a key factor driving the development of BCC. The Wnt/β-catenin signaling pathway was also shown to be activated in BCCs and to perhaps modulate the activity of Hh pathway. We previously identified a novel mechanism by which Wnt signaling regulates the transcriptional outcome of Hh signaling pathway. We demonstrated that CRD-BP, a direct target of the Wnt/β-catenin signaling, induces the expression and transcriptional activity of the Hh transcriptional activator GLI1. We hypothesized that Wnt-induced and CRD-BP-dependent regulation of GLI1 expression and activities is important to the development of BCC. In this study, the role of CRD-BP in the development of human BCC will be discussed.
Citation Format: Felicite Kamdem Noubissi, Tae Won Kim, Tisha Kawahara, B. Jack Longley, Eric Berg, Mohammad Athar, Vladimir S. Spiegelman. Role of CRD-BP in the pathogenesis of human basal cell carcinoma. [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 5444. doi:10.1158/1538-7445.AM2013-5444
Abstract 5445: Differential roles of E2F1 in melanoma.
Authors: Meng Peng , Ghosh Rita 
Published: August 2014

Abstract
Melanoma, the malignant tumor of melanocytes, accounts for 4% of all skin cancer incidence but approximately 78% of skin cancer related deaths. No current treatment significantly enhances disease-free survival once distant metastases have established. The 5 year survival rate drops dramatically from 99.9% to 9% when melanoma progresses. To facilitate the development of effective treatment strategies, it is imperative that we obtain a better understanding of the biology of melanoma cells as they progress through the various stages of disease. Previous studies have shown that E2F1, a transcription factor, is over-expressed in melanoma cells. Interaction between E2Fs and tumor suppressor, Rb is essential for regulation of cell cycle progression. E2F1 is known to be involved in many other important biological processes, including DNA damage, DNA repair, differentiation, development, autophagy and apoptosis. Involvement of E2F1 in so many diverse functions underscores the importance of this protein under normal and pathologic conditions including melanoma. Previously we have found that primary melanoma cells have high level of E2F1 message and protein, and that the acetylation of E2F1 (active form) is higher in late stage melanoma cells. This led us to propose that E2F1 may function differentially in various stages of melanoma progression. Therefore we generated stable E2F1 knockdown cells in early stage primary and advanced metastatic melanoma cells. Our results show that E2F1 reduction works more effectively to inhibit cell growth in primary melanoma cells. Further, we also found differential effects on apoptosis and invasion in early and late stage melanoma cells. There is increased spontaneous cell death in primary melanoma cells after E2F1 knockdown, while there is increased apoptosis resistance in response to UV or valinomycin. These results taken together suggest that E2F1 has pleotropic effects in melanoma. It can switch between oncogenic or tumor suppressive functions during melanoma progression. A better understanding of the mechanism involved in this switch may allow combining gene therapies with other therapies for improved therapeutics for malignant melanoma. Supported by R21 CA125719 (RG).
Citation Format: Peng Meng, Rita Ghosh. Differential roles of E2F1 in melanoma. [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 5445. doi:10.1158/1538-7445.AM2013-5445
Abstract 5452: High-fat diet induces inflammation by increasing estrogen levels through Stat3, estrogen receptor alpha and aromatase in the mouse prostate.
Authors: Bhaskaran Natarajan , Shukla Sanjeev , Thakur Vijay S. , Babcook Melissa A. , MacLennan Gregory T. , Liu Guiming , Daneshgari Firouz , Gupta Sanjay 
Published: August 2014

Abstract
High-fat diet (HFD), an unfortunate lifestyle choice common in the Western world, is associated with inflammation and thereby is regarded as a risk factor for various diseases including obesity, diabetes, and cancer. The molecular mechanism(s) responsible for HFD-induced inflammation in the prostate gland are not well understood. Estrogen receptor alpha (ER-α), signal transducer and activator of transcription (Stat)-3 and aromatase are important signaling molecules constitutively activated during inflammation and have been shown to be upregulated in prostate cancer. We have previously reported that HFD activates a pro-inflammatory response in the prostate through elevated expression of Stat-3 (Prostate 72:233-43, 2012). In the current study, we sought to investigate a possible link between intraprostatic inflammation, HFD feeding, signaling molecules involved in inflammation viz. ER-α, Stat-3, p-Stat3 (Ser727) and aromatase. C57BL/6 mice were fed either a regular diet (RD) or a HFD for 4, 8 and 12 weeks. Serum, visceral fat and prostate tissues were obtained for analysis. HFD intake caused an increase in fat and serum testosterone levels. No significant changes were observed in the testosterone levels in the prostate. A marked increase in estrogen levels was noted in the prostate and visceral fat at 8 weeks of HFD intake. HFD feeding resulted in a significant increase in the expression of aromatase, ER-α, Stat-3 and p-Stat3 (Ser727) at the message and protein levels. Immunoprecipitation and ChIP analysis demonstrated an increased association between aromatase, p-Stat-3 and ER-α in the HFD group. IHC analysis revealed higher expression of Stat-3, ER-α and aromatase in the prostate, accompanied by the morphologic evidence of increased intraprostatic inflammation in the HFD group. Taken together, our findings suggest that HFD increases estrogen levels by increased binding of ER-α and p-Stat-3 to the promoter of aromatase and their interaction is associated with increased intraprostatic inflammation which might contribute to the initiation and development of prostate cancer.
Citation Format: Natarajan Bhaskaran, Sanjeev Shukla, Vijay S. Thakur, Melissa A. Babcook, Gregory T. MacLennan, Guiming Liu, Firouz Daneshgari, Sanjay Gupta. High-fat diet induces inflammation by increasing estrogen levels through Stat3, estrogen receptor alpha and aromatase in the mouse prostate. [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 5452. doi:10.1158/1538-7445.AM2013-5452
Abstract 5454: Androgen-independent regulation of cellular signaling, transcriptional activity, and mRNA stability in a cell model of prostate cancer.
Authors: Smith Suzanne M. , Opperman Kay K. , Kaboord Barbara J. , Bell Peter A. 
Published: August 2014

Abstract
Prostate cancer progression relies on the interplay between androgen dependent and independent processes. Depending on the cell type and stimulus, the independent pathway may result in proliferation, progression, or inhibition. It recently has become evident that the molecular mechanisms that drive the differentiation of normal prostate cells towards abnormal proliferation involve multiple signal transduction cascades that often overlap and interact. Through a combination of multiple techniques, including chromatin immunoprecipitation (chIP) and RNA pull-down, we are able to correlate cellular signaling events to androgen receptor transcriptional activity, and how it relates to cancer progression by using growth factors and hormones. In growth factor stimulated LNcap prostate cancer cells, we observed activation of Stat3 and PI3K pathways and reduced transcriptional activity of typical androgen receptor DNA targets, such as prostate-specific antigen (PSA) and cyclin-dependent kinase inhibitor (CDKN1A or p21). However, in estradiol stimulated cells we detected an increase transcriptional activity of the above targets as well as activation of proliferation pathways. Because the androgen receptor and its targets are also regulated by mRNA stability through the UTR, we assessed RNA stability using RNA pull-down assays and RT-PCR. Our results, and those already published, indicate that multiple overlapping signal transduction pathways are involved in the abnormal differentiation of prostate cells; therefore, our use of a combination of tools is advantageous in further defining the model of cancer progression and potential therapies.
Citation Format: Suzanne M. Smith, Kay K. Opperman, Barbara J. Kaboord, Peter A. Bell. Androgen-independent regulation of cellular signaling, transcriptional activity, and mRNA stability in a cell model of prostate 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 5454. doi:10.1158/1538-7445.AM2013-5454
Abstract 5457: FOXO3a transcriptionally regulates pro-apoptotic function of Par-4 and induces apoptosis in prostate cancer cells.
Authors: Das Trinath P. , Damodaran Chendil 
Published: August 2014

Abstract
Deletion and mutation of tumor suppressor genes (PTEN and p53) may play an important role in the carcinogenesis of prostate cancer (CaP). Constitutive activation of Akt promotes cell proliferation and survival by regulating a number of transcription factors/genes in many cancer cells including CaP. Activation of AKT negatively regulates the pro-apoptotic functions of Fork head transcription factor (FOXO3a) and prostate apoptosis response-4 (Par-4) in CaP cells. In our studies, we found a molecular interplay between FOXO3a and Par-4 in CaP cells and more precisely, how, FOXO3a regulates Par-4 function in CaP cells. Knockin and knockout assays in CaP cells suggest that FOXO3a is upstream of Par-4 and FOXO3a may responsible for the transactivation of Par-4 and its pro-apoptotic function in CaP cells. Further, Immunofluorescence assays suggest during apoptotic stimuli, Par-4 and FOXO3A colocalization in nucleus, which in turn initiates pro-apoptotic signaling and induction of apoptosis. These results were further confirmed by pull down assays, which supports the physical interaction of these two proteins. These findings encouraged us to explore the FOXO3a binding sites in the promoter region of Par-4. We identified four FOXO3a binding sites at -2075 to -2069, -1810 to -1804, -1561 to -1555, and -1340 to -1334 in the promoter region of Par-4 gene. Luciferase reporter constructs of Par-4 promoter (2.1 kb) spanning the FOXO3a binding sites and sequentially deleted constructs were utilized to identify the crucial FOXO3a binding site for the regulation of Par-4. Sequential deletion of FOXO3a binding sites in Par-4 promoter resulted in inhibition of Par-4 function and induction of apoptosis in CaP cells. Further, confirm the role of FOXO3a, we specifically activated Par-4 function by small molecules and simultaneously co-transfect with dominant-negative FOXO3a constructs. As expected dominant negative FOXO3a abrogates Par-4 function in CaP cells, confirming FOXO3a is an upstream of Par-4 signaling and it is required for Par-4 induced apoptosis in CaP cells. We believe, these results decipher the mechanisms associated with FOXO3a induced Par-4 gene activation and apoptosis in CaP cells and activating of FOXO3a may result Par-4 mediated apoptosis in CaP cells.
Citation Format: Trinath P. Das, Chendil Damodaran. FOXO3a transcriptionally regulates pro-apoptotic function of Par-4 and induces apoptosis in prostate cancer cells. [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 5457. doi:10.1158/1538-7445.AM2013-5457
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 546: GDC-0032 PI3K inhibitor enhances the efficacy of endocrine therapies in breast cancer cells by differentially regulating the expression of ER-targeted genes and increasing apoptosis.
Authors: Wallin Jeffrey J. , Guan Jane , Hong Rebecca , O'Brien Carol , Wilson Timothy , Nannini Michelle , Sampath Deepak , Belvin Marcia , Friedman Lori S. 
Published: August 2014

Abstract
Endocrine therapies such as letrozole or fulvestrant are commonly used treatment options for metastatic Hormone Receptor positive (HR+) breast cancer but patients ultimately relapse. Phosphatidylinositol 3-kinases (PI3K) regulate breast tumor cell growth, migration and survival. The alpha isoform of PI3K is frequently mutated and activated in HR+ breast cancer and has been implicated in resistance to endocrine therapies. PI3K inhibitors are therefore attractive for combination with endocrine therapies. GDC 0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30 fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has increased activity against PI3K alpha isoform (PIK3CA) mutant and HER2-amplified cancer cell lines. Single agent and combination studies were carried out to determine if GDC-0032 enhances the anti-tumor activity of endocrine therapies in human breast cancer models. MCF7 cells (Estrogen Receptor positive (ER+), PI3K alpha E545K mutant) were transfected with the aromatase gene and stable clones (MCF7-ARO) were selected that are capable of converting androstenedione to estrogen in culture. When grown in the presence of androstenedione, MCF7-ARO cells were more reliant on estrogen for growth. Under these conditions the cells were treated with GDC-0032 in combination with endocrine therapies and assayed for cellular viability, modulation of PI3K pathway and ER pathway markers and apoptosis induction. The combination of GDC-0032 and endocrine therapies decreased the cellular viability of MCF7-ARO cells and increased apoptosis relative to either single agent. We observed cross-talk between the PI3K and ER pathways that suggests a mechanism of action for the combination. The data provide rationale for evaluating GDC-0032 in combination with endocrine therapies for HR+ breast cancer treatment in the clinic.
Citation Format: Jeffrey J. Wallin, Jane Guan, Rebecca Hong, Carol O'Brien, Timothy Wilson, Michelle Nannini, Deepak Sampath, Marcia Belvin, Lori S. Friedman. GDC-0032 PI3K inhibitor enhances the efficacy of endocrine therapies in breast cancer cells by differentially regulating the expression of ER-targeted genes and increasing apoptosis. [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 546. doi:10.1158/1538-7445.AM2013-546
Abstract 5538: Direct inhibition of ERK1/2 by VTX-11e leads to increased induction of apoptosis in a subset of pancreatic cancer cell lines as compared to MEK1/2 inhibition by selumetinib (AZD6244).
Authors: Miermont Anne M. , Pflicke Holger , Guan Hannah , Chinnasamy Harshini , Thomas Craig , Rudloff Udo 
Published: August 2014

Abstract
Background: Intense efforts to improve current molecular therapy in pancreatic ductal adenocarcinoma (PDAC) have focused on suppression of the MAPK/ERK1/2 pathway. Inhibitors of MEK1/2, downstream target of the frequently mutated RAS oncogene, are currently in development. Recently, results of a phase II clinical trial revealed that selumetinib, a second-generation MEK1/2 inhibitor, has not yielded its promising preclinical efficacy in PDAC patients. A novel Extracellular Signal Regulated Kinase 1/2 (ERK1/2) inhibitor, VTX-11e, has been recently developed as a potent and selective inhibitor of ERK1/2. In this study, we evaluated the effects of VTX-11e on cell growth and apoptosis in pancreatic cancer cell lines and compared VTX-11e to selumetinib.
Methods: Fifty percent Growth Inhibition (GI50) and Lethal Dose (LD) were determined at 72 hours in 65 PDAC cell lines with increasing concentrations of VTX-11e or selumetinib. Apoptosis was quantified by Annexin V/PI following VTX-11e or selumetinib treatment at increasing concentrations at 24 and 72 hours and 7 days. Elk1 phosphorylation levels were determined by Western Blotting as a well-established readout for downstream MAPK pathway output.
Results: More than a third of VTX-11e-treated PDAC lines showed GI50 concentrations of ≤2μM. LD drug response curves of cell lines treated with VTX-11e showed cell death induction at lower concentrations than selumetinib in close to half the cell lines tested. This finding was confirmed by assessment of apoptosis by the AnnexinV/PI assay. We demonstrated that VTX-11e induced significant increased apoptosis in a subset of the PDAC lines compared to selumetinib, leading to as much as 50% apoptotic cells. Furthermore, VTX-11e and selumetinib suppressed phosphorylation of downstream target Elk1 equally.
Conclusion: Our results show that the novel ERK1/2 inhibitor VTX-11e leads to a significant increase in apoptosis as compared to the MEK1/2 inhibitor selumetinib in a subset of pancreatic cancer cell lines. This finding suggests that targeting ERK1/2 directly may be a more effective therapeutic strategy than targeting upstream MEK1/2 in some PDAC. Current studies are ongoing to determine the differential mechanism of action between VTX-11e and selumetinib.
Citation Format: Anne M. Miermont, Holger Pflicke, Hannah Guan, Harshini Chinnasamy, Craig Thomas, Udo Rudloff. Direct inhibition of ERK1/2 by VTX-11e leads to increased induction of apoptosis in a subset of pancreatic cancer cell lines as compared to MEK1/2 inhibition by selumetinib (AZD6244). [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 5538. doi:10.1158/1538-7445.AM2013-5538