bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3447: IL-6 promotes tumor metastasis by promoting anoikis resistance and stemness phenotype in cancer cells via the activation of FAK and nanog stabilization
Authors: Yadav Arti , Kumar Bhavna , Kumar Pawan 
Published: August 2018

Abstract
The process of tumor metastasis is highly complex and involves dissemination of tumor cells from the primary tumor through the vascular system. However, most of the cancer cells, particularly epithelial cancer cells, have very low survival rates in circulation and undergo rapid anoikis. Tumor cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive while travelling though the lymphatic or circulatory systems. Recently, we have shown that IL-6 promotes epithelial-mesenchymal transition (EMT) and tumor metastasis. A number of studies have shown that FAK signaling pathways play an important role in inducing anoikis resistance in tumor cells. In this study, we examined if IL-6 promoted tumor metastasis by enhancing stemness and anoikis resistance in cancer cells via the activation of FAK signaling. Our results demonstrate that IL-6 significantly enhanced stemness phenotype in cancer cells as measured by tumorsphere formation and ALDH positive cells by upregulating nanog protein levels. Nanog knockdown significantly reversed IL-6-mediated cancer stem cell (CSC) phenotype. IL-6 treatment of cancer cells induced FAK phosphorylation in a time dependent manner. Interestingly, FAK knockdown did not significantly decrease nanog mRNA levels but markedly decreased nanog protein levels. FAK depletion completely blocked IL-6-mediated nanog phosphorylation and enhanced nanog protein ubiquitination and degradation. These results suggest that FAK may be modulating nanog protein levels by stabilization nanog protein through phosphorylation. Furthermore, FAK knockdown significantly decreased IL-6-mediated tumorsphere formation, anoikis resistance and tumor metastasis. Taken together, our results show that IL-6 promotes tumor metastasis by enhancing stem cell phenotype and anoikis resistance in head and neck cancer cells via FAK activation and nanog protein stabilization.
Citation Format: Arti Yadav, Bhavna Kumar, Pawan Kumar. IL-6 promotes tumor metastasis by promoting anoikis resistance and stemness phenotype in cancer cells via the activation of FAK and nanog stabilization [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 3447.
Abstract 3498: Regulation of AR through an FGF5 driven mechanism
Authors: McLean Dalton 
Published: August 2018

Abstract
Purpose
To investigate the role of increasing FGF5 expression in the progression of prostate cancer and emergence of castration resistant prostate cancer.
Methods
Utilizing a cell line model representing different stages of prostate cancer progression, we assessed FGF5 expression and function in vitro and in vivo. We analyzed both an outcomes and progression tissue microarray (TMA) containing ~400 prostate cancer patient cores to assess FGF5 expression in a clinical setting.
Results
There was a significant increase in the both RNA and protein expression of FGF5 in tumorigenic cell lines compared to nontumorigenic. In TMAs that were analyzed, there was a significant increase of FGF5-positive cells across progression of prostate cancer from benign to metastatic, with the highest percentage occurring in cases of cancer.
When performing gain of function experiments with recombinant FGF5 (rFGF5) or overexpression plasmids, we found that FGF5 significantly increased the proliferation of AR-positive cell lines. Conversely, in AR-negative cell lines, FGF5 inhibited proliferation. Because FGF5 is associated with stem cells and differentiation events, we next asked whether the population of FGF5 cells that increases through cancer progression could lead to molecular changes in the total population. In addition to inhibiting proliferation of AR-negative nontumorigenic BPH1 cells, rFGF5 resulted in a robust AR expression. In LNCaP, C4-2, and C4-2B rFGF5 resulted in an increase in AR expression. In C4-2 and C4-2B cells an increase in AR protein coincided with an increase in nuclear YAP1, a potent transcriptional regulator.
We hypothesized that androgens could be regulating FGF5 expression in the prostate. When androgen dependent LNCaP cells are subjected to an androgen-depleted environment, FGF5 protein and RNA significantly increased within 24hrs. Additionally, when AR is stimulated using dihyrotestosterone, FGF5 protein and RNA levels significantly decreased. These effects are not observed in cell lines that do not express AR.
Conclusions
These results suggest that FGF5 is increased in prostate cancer progression cell lines as well as patient samples, with highest expression in aggressive cancer cores. Data also suggests that AR plays a role in the regulation of FGF5 and vice versa. These data suggest that FGF5 driven AR expression could be driven by YAP1 nuclear localization. This mechanism will be further interrogated.
Citation Format: Dalton McLean. Regulation of AR through an FGF5 driven mechanism [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 3498.
Abstract 3505: Tumor radiosensitization by suppression of hexosamine biosynthetic pathway
Authors: Efimova Elena V. , Appelbe Oliver K. , Lee Steve Seung-Young , Ricco Natalia , Ramamarthy Aishwarya , Rymut Nicolas , Collins Tamica , Wolfgeher Donald J. , Warrington Sara , Kron Stephen J. 
Published: August 2018

Abstract
The elevation of glucose and glutamine metabolism characteristic of cancer has been ascribed to increased demand for metabolic intermediates that provide building blocks for rapid cell growth. However, recent discoveries have highlighted complementary effects mediated by metabolites serving as cofactors for chromatin modifying enzymes and providing metabolic intermediates for proteins posttranslational modification. Along with epigenetic regulation of gene expression, multiple chromatin modifiers modulate DNA damage repair, raising the question of whether metabolic reprogramming may thereby promote genomic instability and cell immortality. In our prior work, we uncovered a role for the glycolysis hexosamine biosynthetic pathway (HBP) in DNA repair, ionizing radiation induced foci (IRIF) resolution, and prevention of radiation induced cancer cell senescence. Here we report that the targeting of key enzymes in the HBP pathway, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) or O-GlcNAcase (OGA/ MGEA5), have contrary effects on the DNA damage response in tumors. shRNA knockdown of OGA resulted in increased GlcNAc protein modification, protection of cancer cells from irradiation through improved double strand break (DSB) repair and IRIF resolution in tumor cells, increased proliferation, and prevented radiation-induced senescence. In turn, silencing of OGT diminished O-GlcNAc modification, prevented DSB repair, increased IRIF persistence, reduced proliferation, and promoted radiation-induced senescence in tumor xenografts. These findings reveal an important relationship between cancer cell metabolism, DSB repair, and senescence and provide a rationale for
targeting metabolic reprogramming, specifically O-GlcNAc modification, to block cancer cell immortality and overcome resistance to genotoxic stress.
Citation Format: Elena V. Efimova, Oliver K. Appelbe, Steve Seung-Young Lee, Natalia Ricco, Aishwarya Ramamarthy, Nicolas Rymut, Tamica Collins, Donald J. Wolfgeher, Sara Warrington, Stephen J. Kron. Tumor radiosensitization by suppression of hexosamine biosynthetic pathway [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 3505.
Abstract 3509: The glutaminase inhibitor CB-839 synergizes with CDK4/6 and PARP inhibitors in pre-clinical tumor models
Authors: Emberley Ethan D. , Bennett Mark , Chen Jason , Gross Matthew , Huang Tony , Makkouk Amani , Marguier Gisele , Pan Alison , Spurlock Sandra M. , Steggerda Susanne , Parlati Francesco 
Published: August 2018

Abstract
Many tumor cells utilize the amino acid glutamine to meet the elevated bioenergetic and biosynthetic demands of rapid cell growth. The enzyme glutaminase converts glutamine to glutamate, which is used to fuel the TCA cycle, synthesize amino acids and nucleotides, and balance cellular oxidative stress. We developed CB-839, a potent and orally bioavailable small molecule inhibitor of glutaminase, that blocks production of glutamate and generation of downstream metabolites glutathione, malate and aspartate. Mice treated with CB-839 had decreased levels of nucleotides in their tumors, likely due to glutamine-derived aspartate being required for nucleotide biosynthesis. Consistent with our finding that CB-839 decreases nucleotide pools, CB-839 treatment delayed cancer cells from either entry into S-phase or progression through S-phase. Based on this observation, the ability of CB-839 to synergize with therapies that block cell cycle progression was tested. CB-839 synergized with the CDK4/6 inhibitor palbociclib in colorectal carcinoma (CRC), triple negative breast cancer (TNBC) and ER+ breast cancer cell lines resulting in anti-proliferative activity. The combination of CB-839 with palbociclib also led to decreased cell cycle progression through S-phase and caused an accumulation of cells in G1 as measured by an EdU DNA incorporation assay. In vivo, the combination of CB-839 with palbociclib resulted in enhanced anti-tumor activity in both an ER+ breast cancer and CRC xenograft tumor model. We next investigated whether CB-839 treatment would enhance the anti-tumor effects of DNA repair inhibitors, given the ability of CB-839 treatment to decrease nucleotide pools. CB-839 treatment in combination with the PARP inhibitors niraparib and talazoparib led to synergistic anti-proliferative activity in TNBC, CRC, non-small cell lung carcinoma, ovarian and prostate cancer cells. In vivo, the combination of CB-839 with PARP inhibitors showed enhanced anti-tumor activity compared to single agent treatment in a CRC tumor xenograft model. CB-839 is currently undergoing evaluation for efficacy in the treatment of cancer in several phase I/II clinical trials. These encouraging pre-clinical results support the testing of CB-839 with CDK4/6 or PARP inhibitors in cancer patients.
Citation Format: Ethan D. Emberley, Mark Bennett, Jason Chen, Matthew Gross, Tony Huang, Amani Makkouk, Gisele Marguier, Alison Pan, Sandra M. Spurlock, Susanne Steggerda, Francesco Parlati. The glutaminase inhibitor CB-839 synergizes with CDK4/6 and PARP inhibitors in pre-clinical tumor 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 3509.
Abstract 3511: The mechanism of antitumor effect of metformin forgemcitabine-resistant pancreatic adenocarcinoma
Authors: Suzuki Keiichi , Takeuchi Osamu , Suzuki Yukio 
Published: August 2018

Abstract
Metformin (MET) is the first-line treatment for type 2 diabetes mellitus. Several epidemiological studies have reported anti-cancer effects of MET, including against pancreatic ductal adenocarcinoma (PDAC), which mainly acts through induction of AMP activated protein kinase (AMPK). Gemcitabine (GEM) has become the standard chemotherapy for PDAC but tolerance to GEM has become a burdensome issue. We evaluated the anti-tumor effects of MET for GEM-resistant PDAC in a xenograft mouse model. For this in vivo study, BxG30 (the cell line for GEM-resistant PDCA) was implanted into both flanks of female BALB/c nude mice. Mice were divided into four groups: (i) control (no treatment); (ii) the GEM-treated group (100 mg/kg); (iii) the MET-treated group (600 mg/kg); and (iv) the combined treatment group (G+M). Mice were fed for 4 weeks. Estimated tumor volumes and body weights were measured each week. Treatments were initiated 2 weeks after implantation. MET was administrated orally once per day. GEM was given by intraperitoneal injection once per week. Compared with the control, the final tumor volumes were decreased significantly only in the G+M group. [SCW1] The treated control ratio (T/C%) was calculated: GEM, 80.2%; MET, 54.0%; G+M, 47.2%. The anti-tumor effect of GEM for BxG30 was clearly limited[SCW2] . MET group showed satisfactory anti-tumor effects, but T/C% was &lt;50% only in the G+M group. This result revealed that combination therapy had excellent anti-tumor effects even for GEM-resistant PDAC. The phosphorylation of ribosomal proteins S6 and 4E-BP, important targets of the mammalian target of rapamycin (mTOR) signaling pathway, was surveyed by western blot analysis. Western blot analysis showed inhibition of S6 and 4E-BP phosphorylation by co-incubation with MET, but not with GEM. Hypoxia-inducible factor 1 (HIF-1) is the one of the most important target of mTOR signaling pathway influencing tumor cell to progress, thus the expression level of HIF-1 was evaluated by western blot analysis as well. The results showed significant inhibition of HIF-1 expression by MET treatment, but not by GEM incubated under hypoxia (95%N2, 5%O2). Then the production of VEGF was evaluated by ELISA under hypoxia. The result showed suppression of VEGF production by MET treatment, but not by GEM. Our data showed that MET develops a different anti-tumor effect from GEM by suppression of mTOR-HIF-1 signaling. These results are of great clinical interest and reveal the potential of another anti-tumor agent for treatment of PDAC.
Citation Format: Keiichi Suzuki, Osamu Takeuchi, Yukio Suzuki. The mechanism of antitumor effect of metformin forgemcitabine-resistant pancreatic adenocarcinoma [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 3511.
Abstract 3513: Curcumin induces a fatal energetic impairment by inhibiting ATP-synthase activity and decreasing ATP generation and oxygen consumption in in vitro and in vivo tumor models
Authors: Pfeffer Ulrich , Bianchi Giovanna , Ravera Silvia , Traverso Chiara , Amaro Adriana , Piaggio Francesca , Emionite Laura , Bacchetti Tiziana , Raffaghello Lizzia 
Published: August 2018

Abstract
Curcumin has been reported to inhibit inflammation, tumor growth, angiogenesis and metastasis by decreasing cell growth and by inducing apoptosis mainly through the inhibition of nuclear factor kappa-B (NFkB), a master regulator of inflammation. Recent reports also indicate potential metabolic effects of the polyphenol and we therefore analyzed whether and how it affects the energy metabolism of tumor cells. We show that curcumin inhibits the activity of ATP-synthase in isolated mitochondrial membranes leading to a dramatic drop of ATP and a reduction of oxygen consumption in in vitro in several murine tumor cell lines (CT26 colon cancer, B16 melanoma, L1210 lymphocytic leukemia, 4T1 breast cancer) and in vivo in syngeneic tumor models. The effects of curcumin on ATP-synthase are independent of the inhibition of nuclear factor kB (NFkB) since the IkB Kinase inhibitor, SC-514, inhibits the expression of the NFkB target gene, BCL2, but does not affect the activity of the ATP-synthase. The activities of the glucose metabolism enzymes hexokinase, phosphofructokinase, pyruvate kinase and lactate dehydrogenase are only slightly affected in a cell type specific manner. The energy impairment translates into decreased tumor cell viability. Apoptosis is induced by promoting the generation of reactive oxygen species and malondialdehyde (MDA), a marker of lipid oxidation. Tumor autophagy is induced by curcumin at least in part due to the activation of the AMP-activated protein kinase (AMPK). These activities translate into a significant delay of in vivo tumor growth likely due to a reduction of tumor angiogenesis since we observe reduced number and size of tumor vessels in vivo. These results establish the ATP-synthase, a central enzyme of the cellular energy metabolism, as a target of the anti-tumoral polyphenol leading to inhibition of cancer cell growth and a general reprogramming of tumor metabolism.
Citation Format: Ulrich Pfeffer, Giovanna Bianchi, Silvia Ravera, Chiara Traverso, Adriana Amaro, Francesca Piaggio, Laura Emionite, Tiziana Bacchetti, Lizzia Raffaghello. Curcumin induces a fatal energetic impairment by inhibiting ATP-synthase activity and decreasing ATP generation and oxygen consumption in in vitro and in vivo tumor 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 3513.
Abstract 3534: Protein acylation mediates encapsulation of Src kinase into exosomes
Authors: Wen Ru , Li Qianjin , Kim Sungjin , Ma Yongjie , Xie Jin , Cai Houjian 
Published: August 2018

Abstract
Exosomes are nanosized vesicles (30-150 nm) secreted from almost all cell types (1). Exosomes play important roles in cell-cell communication through the transfer of exosomal proteins, mRNA, and microRNAs, mediating immune escape and promoting tumor progression (2,3). However, it remains unclear how oncogenic proteins are selectively disseminated through exosomes. Myristoylation is lipid modification of protein involved in the attachment of N-terminal glycine of proteins with a myristoyl group. It is critical for various biologic functions including cell signaling, protein localization, and cell-cell communication (4). In this study, we evaluated the role of protein acylation for the encapsulation of Src family kinases in exosomes. Myristoylation promotes the enrichment of Src kinase in exosomes whereas palmitoylation inhibits the encapsulation process. Additionally, phosphorylated Src protein was more favored to be capsulated in exosomes. Mechanistically, knockdown of TSG101 decreased expression levels of Src kinase in exosomes, indicating that Src encapsulation into exosomes is associated with endosomal sorting complexes required for transport (ESCRT). Finally, Src kinase can be translocated to normal cells via exosomes cargo to induce pathologic signaling. These results provide new insights of Src kinase encapsulation mechanism into exosomes, and therapeutic approaches for inhibiting the transfer of oncogenic proteins through targeting protein myristoylation process.
References:
1. Simons M, Raposo G. Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol 2009;21(4):575-81.
2. Skog J et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biol 2008;10(12):1470-6.
3. Abusamra AJ et al. Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis 2005;35(2):169-73.
4. Casey PJ. Protein lipidation in cell signaling. Science 1995;268(5208):221.
Citation Format: Ru Wen, Qianjin Li, Sungjin Kim, Yongjie Ma, Jin Xie, Houjian Cai. Protein acylation mediates encapsulation of Src kinase into exosomes [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 3534.
Abstract 3537: FBXW7-mediated extracellular signal-regulated kinase 3 stability in cancer development
Authors: Kim Seung-Min , Lee Cheol-Jung , Yoo Sun-Mi , Cho Seon-Yeon , Park Juhee , Cho Yong-Yeon 
Published: August 2018

Abstract
Extracellular signal-regulated kinase (ERK) is an atypical member of the mitogen-activated protein kinase (MAPK) family. Initial studies have demonstrated that ERK3 was highly expressed in the central nervous system, skeletal muscle, lung, thymus, and testis. Interestingly, unlikely with classical MAPKs including ERK1/2, JNKs and p38s, ERK3 is known to have narrow substrate specificity. Although the function of ERK3 has studied for last three decades, some information for the role of ERK3 is currently available. Recent studies indicate that ERK3 is upregulated in diverse cancer tissues including lung cancer and colon cancer and ERK2 promotes cancer cell migration and invasion in triple-negative breast cancer. Interestingly, ERK3 showed short protein half-life about 30-60 min and ubiquitin-specific protease 20, a deubiquitinase, induced the ERK3 protein level. Thus, identification of E3 ubiquitin ligase is important to understand ERK3 function in cell transformation and cancer development. In this study, we identified that FBXW7, a member of F-box protein complex, bind with ERK3. Moreover, we found that ectopic expression of FBXW7 decreased ERK3 protein level in a dose dependent manner. By proteome analysis, we found that ERK3 contained FBXW7 specific degron motif in C-terminal variable region. Importantly, FBXW7 depletion in HCT-116 restored ERK3 protein level. Taken together, we concluded that FBXW7 is a specific binding partner of ERK3 and may regulate ERK3 protein stability.
Key words: MAPK, ERK3, FBXW7, ubiquitination, protein stability
Citation Format: Seung-Min Kim, Cheol-Jung Lee, Sun-Mi Yoo, Seon-Yeon Cho, Juhee Park, Yong-Yeon Cho. FBXW7-mediated extracellular signal-regulated kinase 3 stability in cancer development [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 3537.