bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A45: Targeting eIF4A dependent translation as therapeutics in pancreatic cancer
Authors: Singh Kamini , Lecomte Nicolas , Stark Stefan , Burčul Antonija , Olivera Grbovic-Huezo , Grimont Adrien , Viale Agnes , Mohan Prathibha , Jiang Man , Destanchia Elisa , Gokce Askan , Rätsch Gunnar , Leach Steve D. , Wendel Hans-Guido 
Published: May 2017

Abstract
RNA translation is activated in aggressive pancreatic cancer and at the same time is also refractory to mTOR inhibition. We have used a translation inhibitor for eIF4A, RNA helicase that is downstream of mTOR signaling and can be functionally targeted in pancreatic cancer. We establish that Silvestrol and its analog CR-31B showed potent anti-tumor activity in pancreatic cancer cell lines in vitro and in vivo. Silvestrol/CR-31B reduced pancreatic cancer cells and organoids growth derived from mouse model of pancreatic cancer and human patient samples in vitro. Further we identify the genome wide translational targets of Silvestrol in pancreatic cancer cell line that lacks response to mTOR signaling through loss of EIF4EBP1. Silvestrol down regulate translation of many key oncogenes and others cellular factors involved in oncogenic signaling specific to pancreatic cancer. Silvestrol targets were also enriched for G-quadruplex structure in their 5' UTR. With this study we establish a new mechanism of targeting pancreatic cancer cells through translation inhibition and identify newer proteins as therapeutic targets that are regulated independent of mTOR signaling.
Citation Format: Kamini Singh, Nicolas Lecomte, Stefan Stark, Antonija Burčul, Grbovic-Huezo Olivera, Adrien Grimont, Agnes Viale, Prathibha Mohan, Man Jiang, Elisa Destanchia, Askan Gokce, Gunnar Rätsch, Steve D. Leach, Hans-Guido Wendel. Targeting eIF4A dependent translation as therapeutics in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A45.
Abstract B03: A whole genome screening platform to identify genes that overcome the poor translation of KRAS
Authors: Peterson Jackson J. , Kaltenbrun Erin , Counter Christopher 
Published: May 2017

Abstract
We discovered that KRAS mRNA is highly enriched in rare codons, which limited translation of the encoded KRAS protein. Accumulating evidence suggests that there is a selective pressure during tumorigenesis to overcome the poor translation of KRAS imposed by rare codons to produce more oncogenic protein and promote more malignant phenotypes. To identify how cancer cells achieve this feat, we are screening whole genome gain- and loss-of-function libraries for genes capable of increasing the translation of a rare-codon enriched fluorescent reporter. More specifically, we have created a reporter cell line encoding a rare-codon enriched GFP and a common-codon enriched mCherry protein. Normalizing to mCherry expression, we further demonstrate that FACS can effectively isolate cells expressing a common-codon enriched GFP from those expressing the rare codon counterpart. Given this, the reporter line was stably infected with a CRISPR library targeting 19,050 genes and sorted by FACS for those expressing high levels of GFP, with these cells now being subjected to deep sequencing. A whole genome ORF library is being screened in an identical fashion. In the future, we will rescreen candidate CRISPRs or ORFs identified from these screens, and those that reproducibly increase the expression of the rare-codon enriched reporter will be analyzed further, especially with regards to the underlying mechanism and expression in cancer cells.
Citation Format: Jackson J. Peterson, Erin Kaltenbrun, Christopher Counter. A whole genome screening platform to identify genes that overcome the poor translation of KRAS. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B03.
Abstract B09: hnRNPA1 is a regulator of UNR IRES activity
Authors: Lampe Sebastian , Brauß Thilo , Kunze Michael , Scholz Anica , Winslow Sofia , Brüne Bernhard , Schmid Tobias 
Published: May 2017

Abstract
Alternative translation initiation via internal ribosome entry sites (IRESs) allows for sustained expression of specific proteins under conditions, such as stress, where global translation is inhibited. As cells in tumors are constantly facing stress conditions, e.g. hypoxia or nutrient deprivation, it is not surprising that mRNAs encoding for oncogenes appear to be enriched in IRESs. IRES-dependent translation in eukaryotes commonly involves certain RNA-binding proteins, the so-called IRES trans-acting factors (ITAFs), that can directly interact with the IRESs to facilitate translation initiation. Upstream of N-Ras (UNR) is such an ITAF that can regulate the IRES activity of several cellular and viral IRESs. It is known that its 5' untranslated region (5' UTR) also contains an IRES that is regulated by polypyrimidine-tract binding protein (PTB), heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2 and UNR itself. Prediction analyses indicated that hnRNPA1 might bind to the 5' UTR of UNR as well. hnRNPA1 was previously already shown to serve as an ITAF in the regulation of the IRES activities of numerous mRNAs including egr2 and sST2. The aims of this project were to determine the impact of hnRNPA1 on the IRES activity of UNR. To test, if hnRNPA1 interacts with the 5' UTR of UNR, as predicted, we employed RNA affinity chromatography. We found that hnRNPA1 indeed strongly bound to the UNR 5' UTR. To assess, if hnRNPA1 consequently affects UNR IRES activity, we overexpressed hnRNPA1. Overexpression of hnRNPA1 markedly increased UNR IRES activity. hnRNPA1 overexpression further induced total UNR protein expression, which indicates that elevated UNR IRES activity results in enhanced translation. With respect to the exact interaction sites, hnRNPA1 binding was predicted to occur at overlapping sites to the previously published PTB binding sites. Deletion of the hnRNPA1 binding sites not only decreased the UNR IRES activity, it further rendered it insensitive to elevated hnRNPA1 levels. Taken together, we found that the 5' UTR of UNR contains specific hnRNPA1 binding sites and that binding of hnRNPA1 at these sites enhances the UNR IRES activity. Our findings therefore add a new piece to the complex puzzle of UNR regulating ITAFs. Having established hnRNPA1 as a new regulator of UNR IRES activity, might further put hnRNPA1 forward as an interesting target to regulate UNR expression.
Citation Format: Sebastian Lampe, Thilo Brauß, Michael Kunze, Anica Scholz, Sofia Winslow, Bernhard Brüne, Tobias Schmid. hnRNPA1 is a regulator of UNR IRES activity. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B09.
Abstract B11: Oncogenic KRAS regulates 4E-BP1, a repressor of cap-dependent translation, independently of growth factor activity
Authors: Silva Jillian M. , Bagni Rachel K. , Ruggero Davide , McCormick Frank 
Published: May 2017

Abstract
Oncogenic mutations in K-Ras often occur at high frequencies in human cancer resulting in the sustained activation of the ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathway. However, the unique dependencies on upstream or downstream oncogenic signaling amongst the mutant K-Ras proteins remains elusive and often masked by the remaining wild-type allele, other Ras isoforms, or additional secondary genetic alterations. Thus, we employed an isogenic mouse embryonic fibroblast (MEFs) system devoid of H-, N-, and K-Ras alleles and reconstituted with a single Ras isoform to examine the dependencies of growth factors on K-Ras mediated control of translational regulation. Although oncogenic K-Ras G12D and G12V mutant MEF lines proliferated at twice the rate of K-Ras4b wild-type MEF cells, growth factor deprivation led to a cytostatic effect on the proliferation of all MEF lines. Analysis of signaling downstream of K-Ras revealed that phosphorylation of 4E-BP1, eIF4E, and ERK1/2 occurred in a growth factor-independent manner, which stood in contrast to the substantive effects of growth factor inhibition on AKT, p70S6K, and ribosomal protein S6 phosphorylation. Moreover, growth factor deprivation resulted in a marginal decrease of global protein synthesis with negligible effects on cap-dependent translation initiation in all K-Ras MEF cell lines. Taken together, these data suggest that oncogenic K-Ras signaling regulates 4E-BP1 phosphorylation independently of growth factor and mTORC1/2 effects.
Citation Format: Jillian M. Silva, Rachel K. Bagni, Davide Ruggero, Frank McCormick. Oncogenic KRAS regulates 4E-BP1, a repressor of cap-dependent translation, independently of growth factor activity. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B11.
Abstract B13: EGF/Ras/Erk signaling controls growth and proliferation through regulation of tRNA synthesis
Authors: Sriskanthadevan-Pirahas Shrivani , Grewal Savraj S. 
Published: May 2017

Abstract
Ras signaling promotes growth and proliferation in many tissues throughout animal development. An important challenge is to identify how the Ras-Erk pathway alters cellular metabolism to drive growth. Here we report on the control of tRNA synthesis as growth effector of EGF/Ras/Erk signaling in Drosophila. I find that overexpression of oncogenic Ras (RasV12) leads to increased mRNA translation and protein content in Drosophila S2 cells, suggesting that Ras may promote growth through enhanced protein synthesis. The conventional view is that the Ras pathway functions by controlling translation initiation factor activity. However I have identified an alternate mechanism involving control of tRNA synthesis. My data suggest that overexpression of RasV12 or the activated versions of EGFR and the Raf1 in wing imaginal discs increases tRNA synthesis. Similarly, expression of RasV12 in S2 cells increases tRNA levels, while blocking Ras/Erk signaling using the MEK inhibitor, U0126 or RNAi reduces tRNA synthesis. We previously identified the RNA polymerase III (Pol III) factor, Brf, as regulator of cell and tissue growth in Drosophila. Here we show that knockdown of either Brf blocks the effects of Ras signaling on growth and proliferation in larval wing imaginal discs, adult midgut progenitor cells and adult intestinal stem cells. Several transcription factors have been shown to link Ras signaling to changes in mRNA expression and growth. I have identified Myc is required but not sufficient for Ras-induced cell proliferation and growth through tRNA synthesis. Previously we have shown that TOR signaling regulates protein synthesis through RNA Pol III repressor, Maf1. I found that Maf1 RNAi increases tRNA synthesis in S2 cells. In addition, the decrease in tRNA synthesis induced by the MEK inhibitor is blocked in the presence of Maf1 RNAi suggesting Maf1 is downstream of Ras signaling pathway. My data point to control of tRNA synthesis possibly through Myc and/or Maf1 as a new mechanisms by which Ras signaling enhances protein synthesis to promote cell and tissue growth.
Citation Format: Shrivani Sriskanthadevan-Pirahas, Savraj S. Grewal. EGF/Ras/Erk signaling controls growth and proliferation through regulation of tRNA synthesis. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B13.
Abstract B22: Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors together with AR antagonists in advanced prostate cancer
Authors: D'Abronzo Leandro S. , Crapuchettes Michael , Beggs Ryan , Vinall Ruth , Tepper Clifford , Siddiqui Salma , Mudryj Maria , Melgoza Frank , Durbin-Johnson Blythe , White Ralph deVere , Ghosh Paramita 
Published: May 2017

Abstract
The anti-androgen bicalutamide is widely used in the treatment of advanced prostate cancer (CaP) in many countries, but its effect on castration resistant CaP (CRPC) is limited. We previously showed that resistance to bicalutamide results from increased activation of the mechanistic target of rapamycin (mTOR); indicating a role for mTOR inhibitors in CaP treatment. Interestingly, a clinical trial testing combinations of the mTOR inhibitor RAD001 with bicalutamide were initially effective (PSA decline&gt;50%) in 62.5% CRPC patients, but many initial responders later developed resistance. Here we investigate causes for their difference in response. Evaluation of various CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E phosphorylation at S209 is associated with resistance to the combination. To recognize potential causes of resistance, we demonstrated using a human tumor xenograft mouse model, that bicalutamide use is associated with an increase in eIF4E(S209) phosphorylation. Investigations revealed that AR suppressed eIF4E phosphorylation, while the use of anti-androgens relieved this suppression, thereby triggering its increase. Additional investigation on the consequences of increased eIF4E phosphorylation in human prostatectomy samples revealed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67, indicating a role for eIF4E in tumor growth. Inhibition of eIF4E phosphorylation by siRNA suppression or treatment with CGP57380 (an inhibitor of MAPK interacting serine-threonine kinases Mnk1/2, the eIF4E upstream kinase,) sensitized CRPC cells to RAD001+bicalutamide, while eIF4E overexpression induced resistance. Our results demonstrate that bicalutamide treatment induced an increase in eIF4E phosphorylation by inhibition of AR which otherwise suppressed this phosphorylation. Increased eIF4E phosphorylation then induced resistance to the combination of anti-androgens with mTOR inhibitors by increasing proliferation. These results also indicate that resistance to RAD001+bicalutamide can be prevented by the concurrent use of a Mnk1/2 inhibitor.
Citation Format: Leandro S. D'Abronzo, Michael Crapuchettes, Ryan Beggs, Ruth Vinall, Clifford Tepper, Salma Siddiqui, Maria Mudryj, Frank Melgoza, Blythe Durbin-Johnson, Ralph deVere White, Paramita Ghosh. Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors together with AR antagonists in advanced prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B22.
Abstract B33: Translational control pathways form a molecular hub that regulates tamoxifen resistance in ER+ breast cancer
Authors: Geter Phillip A. , Schneider Robert J. 
Published: May 2017

Abstract
Currently, ER+ breast cancer is treated with adjuvant antiestrogen therapies (i.e. tamoxifen and raloxifene). Despite maintaining expression of the estrogen receptor, many women treated with adjuvant therapy develop resistance several years after curative care. In fact, resistance to tamoxifen therapy is responsible for a vast majority of deaths resulting from metastatic disease. Our lab and others have shown that upregulation of the abundance and/or activity of translation initiation factors eIF4E and eIF4G1 occurs widely in advanced breast cancer, selectively upregulating translation of certain mRNAs required for survival, proliferation, and metastasis. Therefore, we hypothesized that tamoxifen resistance in ER+ breast cancer involves selective mRNA translation mediated by hyperactivation of the mTORC1 translational control pathway via regulating the availability and activity of eIF4E. Tamoxifen resistant (R) and sensitive (S) ER+ cell lines have been developed by several labs by long-term cultivation in tamoxifen and are used in my work. We define here, using the aforementioned cell lines, a molecular hub consisting of the two translational control pathways, PI3K/Akt/mTOR and MAPK/ERK/MNK which converge on translation initiation factor 4E (eIF4E) increasing its availability and activity. We show that blocking eIF4E-mediated translation was able to resensitize drug resistant cells to tamoxifen; conversely, overexpression of eIF4E, without concurrent mTORC1 hyperactivity, was not sufficient to generate resistance. Furthermore, knockdown of two genes identified from our genome-wide translation state analysis, TEX14 and RUNX2, significantly impacted drug resistance and serve as a major regulators in disease progression. Our findings demonstrate that eIF4E is a key player regulating tamoxifen resistance in ER+ disease.
Citation Format: Phillip A. Geter, Robert J. Schneider. Translational control pathways form a molecular hub that regulates tamoxifen resistance in ER+ breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B33.
Abstract B42: Combination of liquid chromatography-surface enhanced Raman spectroscopy and liquid chromatography-mass spectrometry to identify SUMOylated proteins due to nutrient restriction in colorectal cancer
Authors: Schroll Monica M. , Schultz Zachary D. , Hummon Amanda B. 
Published: May 2017

Abstract
Nutrient restriction, also known as caloric restriction, has been extensively examined for its positive impact on lifespan, immune system boost, and aging. Nutrient restriction, defined as providing essential nutrients but restricting total caloric intake, has shown to decrease disease rate in humans. In addition, nutrient restriction is implicated in decreasing cancer initiation and progression. We have previously established three dimensional cell culture models, known as spheroids, in the HCT 116 colorectal cancer cell line as a high throughput model for studying the proteomic changes associated with nutrient restriction. We found that SUMOylated proteins are up regulated in colorectal cancer 3D cell cultures when subjected to metabolic stress. The attachment of the SUMO protein leads to changes in subcellular location, DNA repair, transcriptional regulation, and mitosis. We will explore SUMOylated in response to nutrient restriction via a novel technique to detect biomolecules using LC-SERS. This method allows the can detection of chemical differences associated with biomolecule structure. We first will enhance this system to detect and quantify metabolites in a more complex matrix, such as a cell lysate. Once the methodology has been optimized we use LC-SERS to identify and quantitate SUMOylated proteins in response to NR. When compared to available MS methods to identified SUMOylated proteins, we hypothesize our novel LC-SERS methodology will be able to surpass the limitations found with MS methods. Nutrient restriction has overwhelming effects on cancer and this study will provides further evidence that SUMOlyation, in response to metabolic stress, has a role in cancer progression.
Citation Format: Monica M. Schroll, Zachary D. Schultz, Amanda B. Hummon. Combination of liquid chromatography-surface enhanced Raman spectroscopy and liquid chromatography-mass spectrometry to identify SUMOylated proteins due to nutrient restriction in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B42.
Abstract IA02: Regulation of growth by the mTOR pathway
Authors: Sabatini David M. 
Published: May 2017

Abstract
mTOR is the target of the immunosuppressive and anti-cancer drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth and proliferation. We now appreciate that this pathway becomes deregulated in many human cancers and has key roles in the control of metabolism, cell and organ size, and aging. We have identified two distinct mTOR-containing proteins complexes, one of which regulates growth through S6K and another that regulates cell survival and metabolism through Akt. These complexes, called mTORC1 and mTORC2, define both rapamycin-sensitive and insensitive branches of the mTOR pathway. Over the last few years we have focused on how nutrients, particularly amino acids, regulate mTORC1. We have identified a complex signaling pathway that relays amino acid availability to mTORC1 through the heterodimeric Rag GTPases. We recently discovered several of the amino acid sensors for the pathway. I will discuss new results from our lab on the regulation and functions of mTORC1.
Citation Format: David M. Sabatini. Regulation of growth by the mTOR pathway. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA02.
Abstract IA04: Control of cell senescence by cancer-associated protein HuR and target noncoding RNAs
Authors: Abdelmohsen Kotb , Panda Amaresh C. , Grammatikakis Ioannis , Noh Ji Heon , Gorospe Myriam 
Published: May 2017

Abstract
Senescent cells accumulate in aging tissues, and their metabolic and gene expression profiles are linked to cancer and other age-associated pathologies. Our recent studies have focused on the cancer-associated RNA-binding protein HuR [1], a suppressor of senescence, and its interaction with different classes of noncoding RNAs—long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs). I discuss the ribonucleoprotein (RNP) complexes that HuR forms with several noncoding RNAs that influence protein abundance and modulate the senescent phenotype. HuR association with lncRNAs such as LINCP21 suppresses the translation of select mRNAs [2], its interaction with lncRNA HOTAIR promotes the ubiquitin-mediated proteolysis of select proteins [3], and its association with RMRP enhances mitochondrial homeostasis [4], while its competition with 7SL modulates TP53 mRNA translation [5]. Likewise, HuR can bind microRNAs like let-7, which can function as tumor suppressors [6], modulating their availability to repress mRNAs bearing let-7 sites. Finally, our ongoing studies show that HuR can also bind circRNAs, an interaction that reduces the expression of select proliferative proteins and reduces cell division. In summary, HuR is well known for regulating target mRNAs encoding proteins that modulate cancer traits [1], but growing evidence indicates that HuR also regulates many target noncoding RNAs that govern protein expression patterns affecting growth arrest and cell senescence.
References:
[1] Abdelmohsen and Gorospe, WIRES RNA 2010
[2] Yoon et al., Mol Cell, 2012
[3] Yoon et al., Nat Commun, 2013
[4] Noh et al., Genes Dev, 2016
[5] Abdelmohsen et al., Nucleic Acids Res, 2014
[6] Yoon et al., Genes Dev 2015
Citation Format: Kotb Abdelmohsen, Amaresh C. Panda, Ioannis Grammatikakis, Ji Heon Noh, Myriam Gorospe. Control of cell senescence by cancer-associated protein HuR and target noncoding RNAs. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA04.