bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3454: HIV-1 envelope protein gp120 promotes glioma tumor growth through the Akt and MAP kinase pathways
Authors: Valentin-Guillama Gabriel , Kucheryavykh Yuriy , Kucheryavykh Lilia 
Published: August 2018

Abstract
The median survival of glioblastoma (GBM) patients with HIV is significantly shorter compared to HIV-negative GBM patients, despite the fact that they receive the same treatments. This indicates that HIV infection is associated with more aggressive tumor behavior. Earlier we shown that gp120, a glycoprotein found in the HIV shell, stimulates up-regulation of glycolysis in glioma cells. The purpose of this study was to evaluate the underlying signaling mechanisms of gp120 dependent up-regulation of glycolysis in glioma cells.
Using antibody array and western blot we have identified that U87 glioma cells treated with gp120 (200 ng/ml) for 5 consequent days showed increased activation of MAP kinase and Akt/mTOR pathways. Increase of pAkt(pS473), pGSK3b(pS9), pMKK3(S189), pmTOR(S2448), p38(T180/Y182), pJNK(T183) has been identified. This data coincides with previously obtained results showing that glioma cells treated with gp120 exhibit higher proliferation rates and increased cell survival compared to un-treated glioma cells.
In summary, we conclude that gp120 triggers activation of regulatory kinases Akt and MAPK involved in cell growth, cell proliferation, cell survival, protein synthesis, transcription, glycolysis, and cell migration.
Citation Format: Gabriel Valentin-Guillama, Yuriy Kucheryavykh, Lilia Kucheryavykh. HIV-1 envelope protein gp120 promotes glioma tumor growth through the Akt and MAP kinase pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3454.
Abstract 3456: Molecular mechanisms of RSK2-ELK3 signaling axis in neoplastic cell transformation
Authors: Cho Seon-Yeon , Lee Cheol-Jung , Yoo Sun-Mi , Kim Seung-Min , Park Juhee , Cho Yong-Yeon 
Published: August 2018

Abstract
Constitutive active Ras mutation (RasG12V) plays a key role in cell proliferation and transformation in many solid human cancers. RSK2, a member of p90RSK superfamily, controlled by ERKs is an intermediate signaling molecule transducing Ras activation signal to downstream substrates including transcription factors, epigenetic factors and some kinases. Since RSK2 shows wide range of substrate spectrum, identification of RSK2's novel substrates is important to understand the role of RSK2 in cancer. We found that ELKs including ELK1, ELK3 and ELK4 are novel interaction partners of RSK2 by mammalian two-hybrid assay. In vitro kinase assay and immunoprecipitation assay indicated that ELK3 is a major binding partner of RSK2. Luciferase reporter assay demonstrated that ELK3 transactivation activity was increased by RSK2, resulted in the increase of c-fos promoter activity. Importantly, constitutive active (CA)-RasG12V-mediated foci formation in NIH3T3 cells were more increased by ectopic co-expression of CA-RasG12V and RSK2. Additionally, signaling blockage of the CA-RasG12V/ELK3 by RSK2 knockdown suppressed foci formation. These results demonstrated that RSK2-ELK3 signaling axis plays an important role in RasG12V-mediated neoplastic cell transformation.
Key words : MAPK, RSK2, ELKs, cell proliferation, cell transformation
Citation Format: Seon-Yeon Cho, Cheol-Jung Lee, Sun-Mi Yoo, Seung-Min Kim, Juhee Park, Yong-Yeon Cho. Molecular mechanisms of RSK2-ELK3 signaling axis in neoplastic cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3456.
Abstract 3463: Crosstalk between PKCalpha and TGF-beta signaling suppresses inhibitor of DNA binding 1 (Id1) expression in intestinal epithelial cells
Authors: Li Xinyue , Lum Michelle , Black Adrian , Black Jennifer 
Published: August 2018

Abstract
Inhibitor of DNA binding (Id) proteins (Id1-Id4) are dominant negative antagonists of basic helix-loop-helix (bHLH) transcription factors with recognized functions in development, stem cell self-renewal, and cell fate determination. Recent studies have identified Id proteins as master regulators of cancer-initiating cells and tumor aggressiveness, with critical roles in regulation of central hallmarks of cancer, including cell proliferation, survival, senescence, angiogenesis, migration, metastasis, and chemoresistance. In colorectal cancer (CRC), Id1 overexpression is associated with aggressive clinical behavior and poor prognosis, while decreasing sensitivity to chemotherapeutic agents. Protein kinase C α (PKCα) is a serine/threonine kinase that functions as a tumor suppressor in CRC. PKCα signaling induces cell cycle arrest in nontransformed IEC-18 intestinal epithelial cells via an ERK-dependent mechanism. A major target of PKCα negative control in these cells is Id1. To further characterize mechanisms underlying the tumor-suppressive effects of PKCα, we modulated PKCα expression and activation in CRC cells and nontransformed IEC-18 cells and performed RNA-seq analysis to identify changes in gene expression. This analysis identified transforming growth factor beta receptor 1 (TGFβR1) as an mRNA upregulated by PKCα signaling. Subsequent RT-PCR and Western blot analysis confirmed that PKCα upregulates TGFβR1 at both the mRNA and protein levels. The MEK inhibitors U0126 and PD98059 blocked PKCα upregulation of TGFβR1, pointing to an ERK-dependent mechanism. Notably, inhibition of TGFβR1 with GW788388 prevented PKCα-mediated Id1 downregulation, linking TGF-β signaling to the tumor-suppressive effects of PKCα. Further studies indicated that TGFβR1 activates a p38-mediated noncanonical pathway to downregulate Id1 in response to PKCα activity. Collectively, these findings identify a PKCα→Erk→TGFβR1→p38→Id1 signaling axis in intestinal epithelial cells. Both PKCα and TGF-β function as tumor suppressors in the intestinal epithelium and both pathways are inactivated during intestinal tumor progression. By providing a direct link between two tumor-suppressive signaling pathways with established effects on intestinal tumorigenesis, our findings broaden our understanding of CRC and open avenues for potential novel therapeutic approaches to this disease. (Supported by NIH grants DK60632, CA54807, CA036727 and CA191894.)
Citation Format: Xinyue Li, Michelle Lum, Adrian Black, Jennifer Black. Crosstalk between PKCalpha and TGF-beta signaling suppresses inhibitor of DNA binding 1 (Id1) expression in intestinal epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3463.
Abstract 3465: Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand
Authors: Ali Remah , Brown Wells , Davisson Jo , Wendt Michael 
Published: August 2018

Abstract
Inhibition of EGFR signaling by small molecule kinase inhibitors and monocloncal antibodies has proven effective in the treatment of multiple metastatic cancers. In contrast, metastatic breast cancer (BC) derived from EGFR-driven mammary tumors is inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here we show that in contrast to primary tumors, ligand-mediated activation of EGFR is dominated by signaling transducer and activator of transcriptional 1 (STAT1) signaling in metastatic BC. This change in downstream signaling leads to apoptosis and growth inhibition in response to EGF in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal EGFR signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death without affecting EGFR:MAPK signaling. Pharmacologic blockade of MAPK signaling through the use of the MEK1/2 inhibitor trametinib led to a dramatic increase in EGF-mediated STAT1 phosphorylation and enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, use of a trametinib:EGF combination also facilitated the apoptotic switch in EGFR function in primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental switch in EGFR in metastatic BC. Furthermore, they demonstrate that pharmacological biasing EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway.
Citation Format: Remah Ali, Wells Brown, Jo Davisson, Michael Wendt. Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3465.
Abstract 3470: Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models
Authors: Ghoshal Kalpana , Lin Cho-hao , Elkholy Khadija , Wani Nissar A. , Li Ding , Barajas Juan M. , Hu Peng , Zhang Xiaoli , Yu Lianbo , Motiwala Tasneem 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is the second major cause of cancer-related death worldwide with limit therapeutic options. Thus, there is an urgent need to develop novel alternative therapies for HCC. In this study, we report that ibrutinib, recently approved for the treatment of B cell malignancies, and a covalent inhibitor of TEC (BTK, ITK etc.) and ERBB (EGFR, Her2 etc.) family of tyrosine kinases, inhibits tumorigenic functions of human HCC cells in vitro and in xenografts. More importantly, co-treatment with ibrutinib and sorafenib, an approved targeted therapy for advanced HCCs that marginally improve patients' survival, synergistically inhibited proliferation and clonogenic survival of HCC cells including those with acquired sorafenib resistance. Mechanistically, ibrutinib inhibits Akt and ERK signaling pathways through inactivating EGFR, its irreversible substrate in HCC cells. Besides, tumor sphere formation and expression of cancer stem cell markers were suppressed by ibrutinib and sorafenib co-treatment in HCC cells. Ectopic expression of the constitutively active Akt mutant abrogated the synergism of these two kinase inhibitors on HCC cell survival. Ibrutinib and sorafenib combination therapy significantly suppressed tumor growth of highly aggressive HCCLM3 subcutaneous xenografts in NSG mice. Collectively, these results demonstrate that ibrutinib could be a re-purposed anti-HCC drug, and our data provides the evidence for the therapeutic potential of ibrutinib and sorafenib combination as an effective and attractive strategy for treating HCCs including those with sorafenib resistance.
Citation Format: Kalpana Ghoshal, Cho-hao Lin, Khadija Elkholy, Nissar A. Wani, Ding Li, Juan M. Barajas, Peng Hu, Xiaoli Zhang, Lianbo Yu, Tasneem Motiwala. Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3470.
Abstract 3473: Investigating RAS and RTK signaling in MPNST progression and drug resistance
Authors: King Candace N. , Graveel Carrie , Steensma Matthew 
Published: August 2018

Abstract
Neurofibromatosis, type 1 (NF1) is a tumor predisposition syndrome affecting about 1 in 2,500 live births in the United States. The protein product of the NF1 gene, neurofibromin, loses its function as a negative regulator of the RAS protein, leading to the development of painful and disfiguring benign tumors known as a neurofibromas. Eight to thirteen percent of these neurofibromas will transform into malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive soft tissue sarcomas that do not respond to the standard sarcoma treatment of chemotherapy and surgical resection. There is a critical need for efficacious targeted therapy to increase the average life span of these patients. Current targeted therapy efforts have shown modest efficacy clinically due to the establishment of compensatory feedback mechanisms that propagate tumor progression and recurrence. These feedback mechanisms are not completely understood in MPNSTs. In lung cancer, inhibition of MEK in the RAS pathway has been shown to activate upstream receptor tyrosine kinases (RTK). Genomic studies of MPNST samples have shown that 30% of tumors have amplification of the RTKs MET and EGFR. Furthermore, in a study of the genomic progression of a NF1 patient pre- and post-treatment, we found amplification of MET and EGFR that increased following treatment. In a study on triple-negative breast cancer cells, it has been shown that MET and EGFR crosstalk may be responsible for the reactivation of the inhibited cancer pathways and drug resistance. Therefore, we hypothesize that coordinated deregulated RAS signaling and MEK inhibition leads to MET and EGFR amplification, expression, activation, and crosstalk, which drives MPNST progression, drug resistance, and tumor recurrence. To test our hypothesis, we will use both in vitro and in vivo experimental methods to pursue the following specific aims: (1) determine the effect of MEK inhibition on establishing compensatory feedback loops that increase RTK activation and downstream signaling, (2) determine the role of MET-EGFR crosstalk signaling in MPNST tumor progression and resistance to kinase inhibition, and (3) determine the efficacy of combination RTK and MEK inhibition in vivo.
Citation Format: Candace N. King, Carrie Graveel, Matthew Steensma. Investigating RAS and RTK signaling in MPNST progression and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3473.
Abstract 3488: Elucidation of Warburg effect and cell cycle regulations through analysis of cancer tissue omics data and kinetic modeling
Authors: Sheng Tao 
Published: August 2018

Abstract
Cancer cells tend to depend more on anerobic glycolysis to generate adenosine 5'- triphosphate (ATP), which is an inefficient energy producing process termed as “The Warburg effect”. The causes or functions of Warburg effect have been extensively studied, however, the growth advantage it confers to cancer cells still remains unclear. In this study, we propose that the metabolic shift in cancer cells would facilitate the accumulation of nutrients and biomass (e.g., nucleotides, amino acids and lipids), which would promote the cell cycle initiation and progression as unicellular organisms do. Specifically, by comprehensively analyze the gene expression and mutational profile in 16 cancer types, we identified (1) the gene expression profile of cancer cells is evolutionarily more unicellular like when compared to normal; and (2) certain cell cycle associated mutations are associated with the metabolic alternations in cancer cells, such as nucleotide synthesis pathways and lipids metabolism. Moreover, we developed a system of kinetic equations to capture the metabolic relations between nutrient metabolism and cell cycle initiation and progression. The kinetic model shows that the rapid nucleotide synthesis as well as high influx of glutamate would affect the activities of cell cycle signaling and CDKs genes. Our study provides a novel mechanistic view in linking the Warburg effect and cancer cell cycle initiation and progression.
Citation Format: Tao Sheng. Elucidation of Warburg effect and cell cycle regulations through analysis of cancer tissue omics data and kinetic modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3488.
Abstract 35: Triple-negative breast cancer cells alter the pulmonary landscape to favor metastasis via exosome-mediated release of NM23
Authors: Duan Suzann , Nordmeier Senny , Byrnes Aidan E. , Brown Miles A. , Buxton Iain L. 
Published: August 2018

Abstract
There is strong evidence implicating exosomes, cell-derived nanoscale vesicles, and their protein cargo in facilitating dialogue between primary tumor cells and the premetastatic niche. Identified by our lab as one such protein, secreted nucleoside diphosphate kinase (NM23/NDPK) has been shown to activate endothelial remodeling in support of proangiogenic and prometastatic events. We have previously demonstrated that triple-negative breast cancer (MDA-MB-231) cells elaborate exosomes enriched with NDPK transphosphorylase activity and target the lung as a future site of metastasis. Using in vitro and in vivo approaches, we interrogate the functional role of NDPK in exosome-mediated lung remodeling. In cell-based assays, we demonstrate that MDA-MB-231 exosomes stimulate migration of pulmonary vascular endothelial cells and enhance monolayer permeability. These effects are reversed following treatment with an inhibitor of NDPK activity or an antagonist to the purinergic P2Y1 receptor. Further, we show that immune-compromised mice receiving intravenous injections of MDA-MB-231 exosomes exhibit enhanced pulmonary vascular leakage, whereas treatment with an inhibitor of NDPK attenuates this effect. Using tandem mass tag labeling and mass spectrometry, we profiled proteomic changes to the lung and identified the purinergic signaling pathway as among those significantly affected by exosome treatment. These results elucidate the functional role of exosomal NDPK in compromising vascular integrity and transforming the pulmonary landscape to support colonization by circulating breast cancer cells.
Citation Format: Suzann Duan, Senny Nordmeier, Aidan E. Byrnes, Miles A. Brown, Iain L. Buxton. Triple-negative breast cancer cells alter the pulmonary landscape to favor metastasis via exosome-mediated release of NM23 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 35.
Abstract 3500: A pipeline to identify driver mutations
Authors: Chakroborty Deepankar , Kurppa Kari , Paatero Ilkka , Elo Laura , Elenius Klaus 
Published: August 2018

Abstract
Introduction: Cancer tissues harbor thousands of mutations while the current list of clinically validated actionable variants contains only about a dozen genetic markers. Most of the somatic mutations in cancer are expected to be inconsequential passenger mutations that reflect the general instability of the tumors. The discovery of most of the currently known driver mutations has been facilitated by their accumulation in mutation hot-spots within their respective genes. However, a great majority of mutations in cancer tissues are rare and no information is currently available about their functional significance. Several lines of in vitro and in vivo clinical evidence also indicate that there is a significant number of, as yet unidentified, activating driver mutations that could serve as predictive markers for oncology.
Method: To identify functional driver mutations, we have established a functional genetics screen based on expression of random gene variants and the ability of driver mutations to promote a growth-advantage in vitro, as compared to passenger mutations. The screen was set up using a randomly mutated expression library encoding thousands of variants of epidermal growth factor receptor (EGFR), a well-known oncogene, as a model. The library was retrovirally introduced into murine lymphoid Ba/F3 cells, that normally require interleukin-3 (IL-3) for survival but can exploit ectopic expression of activated variants of oncogenic kinases to compensate for the deficiency of exogenous IL-3. While expression of wild-type EGFR did not promote IL3-independent survival of the Ba/F3 cells, as expected, transduction of the mutant EGFR library did, indicating that the surviving Ba/F3 pool included EGFR mutations with ligand-independent activity. To identify and quantify the frequency of these mutations, targeted next-generation sequencing of the EGFR inserts was carried out.
Results: Using the method we were able to identify approximately 20 candidate activating mutations out of the 7000 random EGFR mutations in the original library. The 20 candidates included the well-known activating EGFR mutation, L858R, validating the pipeline. A previously unidentified activating mutation was also found, and the growth promoted by the mutant was susceptible to inhibition by clinically available EGFR inhibitors.
Citation Format: Deepankar Chakroborty, Kari Kurppa, Ilkka Paatero, Laura Elo, Klaus Elenius. A pipeline to identify driver mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3500.