bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A29: Targeting adenylate kinase-4 modulation of HIF-1α: Stability identifies Withaferin-A suppresses lung cancer metastasis
Authors: Hsiao Michael 
Published: May 2017

Abstract
Aberrant activation of hypoxia inducible factor (HIF-1α) often plays a crucial role in promoting metabolic reprogramming and metastatic dissemination. Here we report functional evidences of adenylate kinase 4 (AK4), one of the hypoxia-responsive genes, in enhancing HIF-1α; transcriptional activity to drive epithelial-to-mesenchymal transition (EMT). By analyzing lung adenocarcinoma microarray datasets, we identified AK4-associated metabolic gene signature and revealed HIF-1α; was transcriptionally activated and associated with poor prognosis. Immunohistochemistry analysis confirms the positive correlation between AK4 and HIF-1α; in non-small cell lung (NSCLC) cancer patients. Overexpression of AK4 induces metabolic shift towards aerobic glycolysis and increases intracellular reactive oxygen species (ROS), which exaggerates HIF-1a; protein expression under hypoxia and concurrently induces EMT in a HIF-1α-dependent manner. Furthermore, overexpression of AK4 reduces hypoxic necrosis in tumors and promotes liver metastasis in vivo. Connectivity map analysis of AK4 gene signature identifies Withaferin-A as a potential inhibitor to inverse AK4 signature and proven to be a potent anti-metastatic agent in orthotopic xenograft model of lung cancer. Our findings offer an alternative strategy to treat metastatic lung cancer via targeting AK4-HIF-1α axis.α
Citation Format: Michael Hsiao. Targeting adenylate kinase-4 modulation of HIF-1α: Stability identifies Withaferin-A suppresses lung cancer metastasis. [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 A29.
Abstract A31: eIF4F links translation to energy stress response in cancer
Authors: Hulea Laura , Cargnello Marie , Gravel Simon-Pierre , Im Young , McLaughlan Shannon , Zhao Yunhua , Ching Jenna , Cai Yutian , Larsson Ola , Ohh Michael , Ursini-Siegel Josie , St-Pierre Julie , Pollak Michael , Topisirovic Ivan 
Published: May 2017

Abstract
Protein synthesis is one of the most energy consuming process in the cell. Oncogenic kinases (e.g. EGFR/HER2, BCR/ABL and BRAF) play a central role in reprogramming translation and energy metabolism in neoplasia, whereby cancer cells must provide sufficient ATP to support increased levels of protein synthesis required for neoplastic growth. The downstream mechanisms that link translational machinery and energy homeostasis in cancer, however, remain largely unknown.
We found that widely used anti-diabetics (biguanides) abrogate adaptations to EGFR/HER2 inhibitor-induced energetic stress, which results in synergistic anti-neoplastic effects both in vitro and in vivo. In turn, breast cancer cells in which 4E-BP1/2 expression was abrogated by CRISPR were partially resistant to the combination of EGFR/HER2 inhibitors and biguanides. This was paralleled by the inability of the drugs to inhibit the eIF4F complex assembly and translation of mRNAs encoding important metabolic regulators including those involved in serine biogenesis (PHGDH, PSAT1) and one carbon metabolism (MTHFD1L).
Comparable results were observed when BRAF and BCR/ABL inhibitors were combined with biguanides, which suggests that translational regulation of metabolic genes via the mTORC1/4E-BE/eIF4E pathway plays a major role in energy stress response in cancer.
Together our findings demonstrate that the eIF4F complex is an important mediator of metabolic adaptation in response to the combination of biguanides and clinically-used kinase inhibitors and suggest that the efficiency of such anti-cancer strategies are dependent on the integrity of the translation initiation machinery.
Citation Format: Laura Hulea, Marie Cargnello, Simon-Pierre Gravel, Young Im, Shannon McLaughlan, Yunhua Zhao, Jenna Ching, Yutian Cai, Ola Larsson, Michael Ohh, Josie Ursini-Siegel, Julie St-Pierre, Michael Pollak, Ivan Topisirovic. eIF4F links translation to energy stress response in 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 A31.
Abstract A41: Crosstalk between adipocytes and breast cancer promotes epithelial-mesenchymal transition
Authors: Eun-Sol Kim , Seung Koo Ja 
Published: May 2017

Abstract
Introduction: Adipocytes are known to be involved in epithelial-mesenchymal transition (EMT) associated with tumor cell invasion and metastasis in several cancers. However, the role of adipocytes in the EMT of breast cancer cells is poorly understood. The purpose of this study was to investigate the involvement of adipocytes in the EMT in breast cancer.
Methods: We investigated that co-culture with adipocytes induces morphological changes, proliferation activity, EMT markers expression, status of migration and invasion in MCF-7, MDA-MB-453, MDA-MB-435S, MDA-MB-231, and MDA-MB-468 cell lines. By tissue microarray (TMA) of 296 cases of human breast cancer, immunochemical staining for estrogen receptor (ER), progesterone (PR), HER2, Ki-67, N-cadherin, Twist1, HMGA2, TGFb, and S100A4 was conducted. We classified into fibrous stroma and adipose stroma (when adipose tissue is at least 50% of the entire tumor stroma) based on standard histological classification.
Results: After co-culture with adipocytes, MCF-7, MDA-MB-435S, and MDA-MB-231 cells exhibited elongated spindle-like morphology and increased proliferation; MDA-MB-435S and MDA-MB-231 cells also showed increased dispersion. In all tested breast cancer cells, adipocytes induced migration and invasion. The EMT-like phenotypic changes and increased cell migration and invasion were accompanied by the upregulation of matrix metallopeptidase 9 and TWIST1. Consistently, breast cancer tumors with the adipose stroma showed higher TWIST1 expression than those with the adipose stroma; however, no difference was observed in the levels of other EMT-related proteins.
Conclusion: Adipocytes enable breast cancer cells to acquire aggressive tumor biology by inducing EMT features, and breast cancer with adipose stroma expresses EMT markers as breast cancer with fibrous stroma.
Citation Format: Lee YuKyung, Kim Eun-Sol, Koo Ja Seung. Crosstalk between adipocytes and breast cancer promotes epithelial-mesenchymal transition. [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 A41.
Abstract A46: Wnt5a signals through DVL1 to repress ribosomal DNA transcription by RNA polymerase I
Authors: Dass Randall , Sarshad Aishe , Carson Brittany , Feenstra Jennifer , Kaur Amanpreet , Obrdlik Ales , Parks Matthew , Prakash Varsha , Love Damon , Pietras Kristian , Serra Rosa , Blanchard Scott , Percipalle Piergiorgio , Brown Anthony , Vincent Clara Theresa 
Published: May 2017

Abstract
Ribosome biogenesis is essential for cell growth and proliferation and is commonly elevated in cancer. Accordingly, numerous oncogene and tumor suppressor signaling pathways target rRNA synthesis. In breast cancer, non-canonical Wnt signaling by Wnt5a has been reported to antagonize tumor growth. Here, we show that Wnt5a rapidly represses rDNA gene transcription in breast cancer cells and generates a chromatin state with reduced transcription of rDNA by RNA polymerase I (Pol I). These effects were specifically dependent on Dishevelled1 (DVL1), which accumulates in nucleolar organizer regions (NORs) and binds to rDNA regions of the chromosome. Upon DVL1 binding, the Pol I transcription activator and deacetylase Sirtuin 7 (SIRT7) releases from rDNA loci, concomitant with disassembly of Pol I transcription machinery at the rDNA promoter. These findings reveal that Wnt5a signals through DVL1 to suppress rRNA transcription. This provides a novel mechanism for how Wnt5a exerts tumor suppressive effects and why disruption of Wnt5a signaling enhances mammary tumor growth in vivo.
Note: This abstract was not presented at the conference.
Citation Format: Randall Dass, Aishe Sarshad, Brittany Carson, Jennifer Feenstra, Amanpreet Kaur, Ales Obrdlik, Matthew Parks, Varsha Prakash, Damon Love, Kristian Pietras, Rosa Serra, Scott Blanchard, Piergiorgio Percipalle, Anthony Brown, Clara Theresa Vincent. Wnt5a signals through DVL1 to repress ribosomal DNA transcription by RNA polymerase I. [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 A46.
Abstract B02: A regulatory role for codon bias in KRAS-driven tumor progression and therapeutic resistance
Authors: Kaltenbrun Erin , Ali Moiez , Stephens Sarah Jo , Counter Christopher , Wood Kris 
Published: May 2017

Abstract
The RAS genes HRAS, NRAS, and KRAS are mutated in a quarter of all human cancers to drive the initiation and maintenance of cancer. While all three genes encode nearly identical proteins, KRAS is highly enriched, compared to the other isoforms, in rare codons. These rare codons impede translation and subsequent protein expression. Despite this, increased KRAS expression and signaling is associated with malignancy and cancer progression, and KRAS mutations have been implicated as drivers of resistance to diverse targeted therapies. Using a pathway-activating genetic screen in a panel of human cancer cell lines, we find that mutant HRAS actually has greater resistance conferring potential than mutant KRAS. This differential resistance is governed by codon bias, suggesting that KRAS-driven resistance is limited by inefficient protein expression. We hypothesized that KRAS-driven cancer progression and primary resistance to a targeted therapeutic, such as an EGFR inhibitor, is dependent upon both the presence of a KRAS mutation as well as the ability of cancer cells to overcome this translational barrier. Indeed, we find that KRAS-mutant cancer cells globally upregulate translation, which results in enhanced expression of mutant KRAS and the formation of a translationally primed state that can be therapeutically exploited using inhibitors of protein translation. Collectively, these findings reveal a critical regulatory role for codon bias in mediating KRAS-driven therapeutic resistance and cancer progression. Ongoing work seeks to more precisely define the mechanisms governing KRAS translation in the setting of cancer and therapeutic resistance to obtain more specific approaches to target these tumors.
Citation Format: Erin Kaltenbrun, Moiez Ali, Sarah Jo Stephens, Christopher Counter, Kris Wood. A regulatory role for codon bias in KRAS-driven tumor progression and therapeutic resistance. [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 B02.
Abstract B07: Loss of APC induces a dependence on elevated eIF2B5 function in colorectal cancer
Authors: Peter Stefanie , Uthe Friedrich-Wilhelm , Eilers Martin , Germer Christoph-Thomas , Wiegering Armin 
Published: May 2017

Abstract
Colorectal cancer (CRC) is the most common gastrointestinal malignancy and one of the leading causes of cancer death worldwide. Truncating mutations of the tumor suppressor APC that lead to deregulated WNT signaling are driver mutations in CRC. APC and its downstream effector, β-catenin, are regarded as non-druggable, prompting the search for novel interactions essential for survival of cells that have lost APC function. Here, we have restored doxycycline-inducible expression of full-length APC (APC wt) in SW480 cells, which carry truncated APC (APC mut). To identify genes that are essential for viability of APC mut cells, we conducted an shRNA screen targeting 5,000 genes with 25,000 shRNAs. The best scoring differential hits were multiple shRNAs that target the translation initiation factor eIF2B5, a subunit of the guanidine exchange factor (GEF) for eIF2. Validation experiments demonstrate a strong synthetic lethal effect of eIF2B5 knockdown with APC truncation in SW480 cells that can be rescued by APC induction. There is a clear survival window, which we can visualize using several shRNA sequences with different knockdown efficiencies.
We confirm previous observations that loss of APC function results in an increase of global protein synthesis. Loss of APC also strongly induces expression of eIF2B5 and other subunits of eIF2B. Knockdown of eIF2B5 reduces overall protein translation. Although eIF2 function and overall ribosomal assembly are compromised upon depletion of eIF2B5, MYC protein levels are strongly upregulated, arguing that MYC can be translated in an eIF2-independent manner. Apoptosis upon eIF2B5 knockdown strictly depends on MYC upregulation. APC mut cells also display higher basal levels of the unfolded protein response (UPR) markers CHOP and ATF4, which are both further enhanced by eIF2B5 depletion. The UPR branch reflected by CHOP induction may contribute to cell death in our system.
In conclusion, our data demonstrate a dual regulatory mechanism in which loss of APC induces expression of both MYC and eIF2B5. Full eIF2 activity is required to restrict the pro-apoptotic activity of MYC in APC mut cells. Thus, interfering with eIF2B5 function as GEF or GDF may be a promising treatment strategy for cells with truncated APC.
Citation Format: Stefanie Peter, Friedrich-Wilhelm Uthe, Martin Eilers, Christoph-Thomas Germer, Armin Wiegering. Loss of APC induces a dependence on elevated eIF2B5 function 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 B07.
Abstract B14: Evidence that Tma20 and Tma22 do not promote translation re-initiation in yeast
Authors: Torrance Victoria , Lydall David 
Published: May 2017

Abstract
Translation Machinery Association 20 (Tma20) and Tma22 are two conserved proteins which form a complex involved in translation initiation. The human homolog of TMA20 is an oncogene, originally identified in a T-cell lymphoma and has been shown to induce cell proliferation. Tma20 and Tma22 homologs in Drosophila have been shown to promote translation of mRNAs which contain uORFs by promoting translation re-initiation. uORFs serve as major regulators of gene expression, repressing translation. In yeast Tma20 and Tma22 have recently been shown to have a role in telomere biology by decreasing fitness of cells with uncapped telomeres. To understand how Tma20 and Tma22 affect growth of cells with uncapped telomeres we have investigated translation re-initiation in yeast using new luciferase reporter constructs. Using transcript leader sequences from 22 genes we showed that, as expected, the majority of uORFs repressed expression but found no evidence to suggest that Tma20 or Tma22 promote translation re-initiation in 21 of these genes. However our data suggests that Tma20 and Tma22 inhibit translation re-initiation of the remaining gene, BRE4. Our data suggests that the function of Tma20 and Tma22 is not conserved from Drosophila to yeast. Our finding that Tma20 and Tma22 inhibit translation re-initiation on BRE4 is in agreement with studies in mammalian cells which have shown that Tma20 and Tma22 promote the dissociation of 40S ribosomal subunit from mRNA following translation termination. Our data suggests that perhaps the human homologs of Tma20 and Tma22 may not promote translation re-initiation as has previously been assumed.
Citation Format: Victoria Torrance, David Lydall. Evidence that Tma20 and Tma22 do not promote translation re-initiation in yeast. [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 B14.
Abstract B25: Discovery of molecular probes inhibiting La:RNA interactions in cancer cells
Authors: Sommer Gunhild , Fedarovich Alena , Kota Venkatesh , Peterson Yuri K. , Heise Tilman 
Published: May 2017

Abstract
The RNA-binding protein La is overexpressed in a number of tumor tissues and is proposed to support tumorigenesis via binding to mRNAs encoding tumor-promoting and anti-apoptotic factors to facilitate their translation. Our data suggest that those mRNAs might need La to be translated mainly in a cap-independent mechanism in cancer cells. Hence, small molecules able to block the binding of La to specific RNAs could represent a novel therapeutic strategy for cancer treatment.
In an attempt toward this approach we developed a high-throughput fluorescence polarization assay to screen small compound libraries for molecules inhibiting the binding of La to an RNA element derived from cyclin D1 mRNA. Herein we describe a robust fluorescence polarization assay and the validation of primary hits by electrophoretic mobility shift assays. Using isothermal titration calorimetry we show that a compound binds to La and molecular modeling suggests an interaction between the compound and the RNA recognition motif of La.
We have shown recently that La protects cells against cisplatin treatment by stimulating the protein synthesis of the anti-apoptotic factor Bcl2. Here we show by RNA immunoprecipitation experiments that one small compound specifically impairs the association of La with Bcl2 mRNA, reduces Bcl2 protein expression and sensitizes cells for cisplatin-induced cell death.
Taken together, herein we report the development of a high-throughput fluorescence polarization assay to identify small compounds able to impair the binding of cancer-associated La to RNAs encoding tumor-promoting and anti-apoptotic factors in vitro and cancer cells.
Citation Format: Gunhild Sommer, Alena Fedarovich, Venkatesh Kota, Yuri K. Peterson, Tilman Heise. Discovery of molecular probes inhibiting La:RNA interactions in cancer cells. [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 B25.
Abstract B27: Morphological changes, cadherin switching, and growth suppression in pancreatic cancer by GALNT6 knockdown
Authors: Tarhan Yunus Emre , Taigo Kato , Jang Miran , Nakamura Yusuke , Park Jae-Hyun 
Published: May 2017

Abstract
Pancreatic Cancer has one of the lowest rates of survival among other cancers. Although molecular targeted therapy has been widely applied for many types of cancer, no effective treatment has been developed for the patients of pancreatic cancer. We previously suggested that GALNT6 (polypeptide N-acetylgalactosaminyltransferase 6) is a promising molecular target in breast cancer by O-type glycosylation of Mucin1. Interestingly, GALNT6 is also up-regulated in pancreatic cancer where Mucin proteins are intensively O-glycosylated, indicating a critical role of GALNT6 in pancreatic cancer. In this study we found that knockdown of GALNT6 using siRNAs decreased Muc4 protein as well as transcription level in pancreatic cancer cells. The knockdown of GALNT6 also decreased HER2 and ERK, interacting proteins of Mucin 4, accompanied by drastic reduction of pancreatic cancer cell viability. Further analysis revealed that knockdown of GALNT6 led to cell morphologic changes like the mesenchymal to epithelial transition, which was in concordant with the cadherin switching mechanism—increase of E-cadherin meanwhile decrease of P-cadherin level. Taking into considerations of important roles of Mucin 4 in growth, invasion and resistance to gemcitabine, our findings imply that targeting GALNT6 is a very promising therapeutic strategy for the treatment of pancreatic cancer patients who still have very limited treatment modalities
Citation Format: Yunus Emre Tarhan, Kato Taigo, Miran Jang, Yusuke Nakamura, Jae-Hyun Park. Morphological changes, cadherin switching, and growth suppression in pancreatic cancer by GALNT6 knockdown. [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 B27.
Abstract B30: The RNA-binding protein LARP1 is a cancer therapeutic target
Authors: Ghazaly Essam A. , Quesne John Le , Jiang Dahai , Mangala Selanere L. , Chettle James , Rodriguez-Aguayo Cristian , Lopez-Berestein Gabriel , Gnanaranjan Chathunissa , Mura Manuela , Stavraka Chara , Sood Anil K. , Blagden Sarah P. 
Published: May 2017

Abstract
Ovarian cancer is the most lethal of gynecological cancers killing 60% of women diagnosed with the disease within 5 years. The major contributor to this high mortality is the emergence of chemotherapy resistance; the tumor is initially sensitive to chemotherapy (especially cisplatin, the mainstay of treatment) but recurs with increasingly resistant disease. Effective methods of overcoming treatment resistance are a major unmet medical need and would prolong survival and improve quality of life for women with this disease. We have shown previously that the RNA binding protein La-related protein 1 (LARP1) binds and post-transcriptionally regulates the stability of mRNAs encoding cell survival and stress response proteins including mTOR, BCL2 and BIK. In ovarian cancer tissue, elevated levels of LARP1 protein correlate with adverse survival outcome and chemotherapy resistance. In vivo inhibition of LARP1 using therapeutic RNA interference (packaged in DOPC nanoliposomes) restores cisplatin sensitivity in resistant ovarian cancer xenograft models. In concurrent studies, using a novel ultra-high performance liquid chromatography tandem mass spectrometry method, we have quantified LARP1 in the circulation of ovarian cancer patients and found that high levels correspond with poor prognosis. Circulating LARP1 has prognostic significance and may act as a companion biomarker to a LARP1 inhibitor. We conclude that LARP1, through its regulation of multiple mRNAs within critical pathophysiological pathways, is an important cancer therapeutic target and that RNA-based drugs designed to target LARP1 restore chemotherapy sensitivity in xenograft models.
Citation Format: Essam A. Ghazaly, John Le Quesne, Dahai Jiang, Selanere L. Mangala, James Chettle, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Chathunissa Gnanaranjan, Manuela Mura, Chara Stavraka, Anil K. Sood, Sarah P. Blagden. The RNA-binding protein LARP1 is a cancer therapeutic target. [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 B30.