bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1135: Loss of HSulf-1 promotes defective autophagy and increased lipid droplet biogenesis in ovarian cancer
Authors: Roy Debarshi , Mondal Susmita , Khurana Ashwani , He Xiaoping , Hammond Edward , Dredge Keith , Shridhar Viji 
Published: August 2015

Abstract
Dysregulation of autophagy and altered metabolic pathways are frequently observed in cancer. Due to these alterations, pharmacological targeting of these two pathways simultaneously could provide a viable therapeutic option. Although the association between these two pathways is well characterized in metabolic disorders, it is not well defined in ovarian cancer (OVCA). In this regard, we found that loss of endosulfatase HSulf-1, a known putative tumor suppressor, suppresses LC3-GFP foci formation and promotes increased lipid droplet (LD) biogenesis suggesting that absence of HSulf-1 in OVCA affects both autophagy and lipid metabolism. While isogenic cells with genetic ablation of HSulf-1 (OV202Sh1/2 and TOV2223Sh1 cells) displayed LDs, the nontargeted control transduced (NTC) OV202 and TOV2223 cells had significantly less LDs. In contrast, Transmission Electron Micrographs (TEMs) showed that OV202 and TOV2223 NTC cells had significantly more autophagic vacuoles (AVs) compared to their isogenic ShRNA targeted cells. Conversely, ectopic expression of HSulf-1 in SKOV3 cells decreased the number of LDs and increased the number of AVs compared to vector transfected controls. Here we report that OV202Sh1 cells and HSulf-1 deficient OV2008 cells have increased p-cPLA2α(ser505) levels that are associated with biogenesis of large number of LDs with reduced AVs. Interestingly, pharmacological inhibition of cPLA2α with AACOCF3 in OV202Sh1 cells resulted in reduced LD biogenesis, inhibited colony formation and reduced tumorigenesis in vivo. More importantly, treatment of HSulf-1 deficient cells with HS mimetic PG545 which can compensate for loss of HSulf-1, reduced LD biogenesis, promoted autophagy and inhibited tumor growth in vivo. Collectively, these results show a critical role of HSulf-1 in regulating both autophagy and LD biogenesis in ovarian cancer.
Citation Format: Debarshi Roy, Susmita Mondal, Ashwani Khurana, Xiaoping He, Edward Hammond, Keith Dredge, Viji Shridhar. Loss of HSulf-1 promotes defective autophagy and increased lipid droplet biogenesis in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1135. doi:10.1158/1538-7445.AM2015-1135
Abstract 1137: Mitochondrial targeting of EGFR-VIII in temozolomide resistant glioblastoma models
Authors: Velpula Kiran Kumar , Asuthkar Swapna , Martin Sarah E. , Lathia Justin D. , Tsung Andrew J. 
Published: August 2015

Abstract
Epidermal growth factor receptor (EGFR) over-expression is the most frequent genetic alteration associated with glioblastoma and has emerged as a highly attractive therapeutic target based on its high frequency of gene amplification and mutation as well as its deregulated cell signaling cascades that drive GBM pathophysiology. The genetic aberration of wtEGFR is often accompanied by the overexpression of a mutant EGFR known as EGFR variant III (EGFRvIII), which is expressed in 30% of GBM tumors. Despite recent innovations, may it be neurosurgical techniques, chemotherapeutics or molecular targeted therapies only few treatments showed promise. Temozolomide (TMZ) is one such and has shown improved survival in GBM when administered with concomitant radiotherapy. However, acquired TMZ chemoresistance occurs in more than 90% of recurrent GBMs. To delineate the mechanisms in the context of TMZ resistance, we generated an aggressive TMZ resistant model by continual exposure of U373 cells constitutively expressing EGFRvIII (U373vIII) to 150uM TMZ for 6 months (U373vIIIR). Our preliminary data showed that dichloroacetic acid (DCA) induced apoptosis and demonstrated reduced cell survival in the context of TMZ resistance. DCA treatment also demonstrated reduced EGFRvIII mitochondrial translocation in U373vIIIR cells. Micro array studies conducted on U373vIII or U373vIIR and their subsequent treatment with DCA revealed that PDK1 is the sole target in TMZ resistant tumors expressing EGFRvIII. Since EGFRvIII expression displays an aggressive phenotype yet remains tumor specific, we propose studying DCA alone or in combination with dasatinib, an inhibitor of EGFR subcellular translocation, in U373vIII and U373vIII-TMZ-R cell lines. By more accurately depicting the status of GBM at the time of recurrence after standard of care chemotherapy treatment, the investigation of DCA will augment and possibly redefine our current understanding of resistance mechanisms and establish novel methods of circumventing this pervasive phenomena.
Note: This abstract was not presented at the meeting.
Citation Format: Kiran Kumar Velpula, Swapna Asuthkar, Sarah E. Martin, Justin D. Lathia, Andrew J. Tsung. Mitochondrial targeting of EGFR-VIII in temozolomide resistant glioblastoma models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1137. doi:10.1158/1538-7445.AM2015-1137
Abstract 1143: EGF induces epithelial to mesenchymal transition and cancer stem-like cell properties in human head and neck cancer cells via promoting Warburg Effect
Authors: Xu Qilin , Zhang Qunzhou , Le Ahn D. 
Published: August 2015

Abstract
Head and neck cancer is one of the 10 most common cancers worldwide. Over-expression of EGFR has been demonstrated in approximately 90% of head and neck cancers, which is associated with progressive tumor growth, metastasis, recurrence, and resistance to chemo- and radiation therapies. Recurrent tumors are often therapy-resistant and may have their origin in resistant cancer stem cells (CSCs) and/or in tumor cells with an epithelial-mesenchymal transition (EMT) phenotype. Recently it is increasingly accepted that metabolic changes in cancer cells can drive tumor formation and progression.
In our study, we used 20ng/ml EGF to treat human tongue cancer cell line, SCC-1 cells. Our results demonstrated that EGF induces EMT in oral SCC cells as characterized by a downregulation of E-cadherin (an epithelial marker), an upregulation of vimentin (a mesenchymal marker), increased invasive and metastatic capacities, and acquisition of stem-like properties such as the increased expression of ALDH1 and enrichment of CD44+/CD24− proportion of cancer cells. We also found that EGF treatment concomitantly enhanced L-lactate production and blocking glycolysis by 2-DG robustly reversed EGF-induced EMT and CSC-like phenotypes of OSCC cells. Then we further demonstrated that EGF regulates glycolysis/EMT/CSCs axis through downstream EGFR/PI3K signaling pathways in an EGFR/PI3K-dependent but AKT-independent manner. Importantly, we showed that in vivo treatment with 2-DG remarkably reduced the expression of ALDH1 and vimentin at both the in situ tumors and regional lymph nodes.
Taken together, these findings have demonstrated that EGF drives tumor growth and metastasis through induction of EMT and CSC generation, which is orchestrated by an enhanced glycolytic metabolic program in OSCC cells. This work was supported by National Institute of Health Research Grant, R01DE 019932, Oral and Maxillofacial Surgery Foundation (OMSF) Research Grant, and the Schoenleber funding support
Citation Format: Qilin Xu, Qunzhou Zhang, Ahn D. Le. EGF induces epithelial to mesenchymal transition and cancer stem-like cell properties in human head and neck cancer cells via promoting Warburg Effect. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1143. doi:10.1158/1538-7445.AM2015-1143
Abstract 1147: Differential expression of enzymes associated with glycine metabolism in ovarian cancer stem like cell
Authors: Shin So-Jin , Chung Hye-Won , Lee Hyun-Gyo , Choi Eun Som , Cho Chi-Heum 
Published: August 2015

Abstract
OBJECTIVES: The recent advances in understanding the relation between cancer and metabolism have highlighted the relevance of serine/glycine biosynthesis and one-carbon metabolism. The aim of this study was to evaluate the expression of enzymes associated with serine/glycine metabolism in ovarian cancer stem like cells (CSCs) and discuss their potential clinical implications.
METHODS: We established primary ovarian cancer cell cultures from dissected fresh tumor tissue. To isolate CD117(+) and CD44(+) CSCs from primary ovarian cancer cultures, we have modified and optimized the Magnetic-Activated Cell Sorting (MACS) procedure from Miltenyi resulting in high sorting purity. In the present study, we used Western blotting and immunohistochemistry to examine three serine-/glycine-metabolism-associated proteins (PHGDH, SHMT, and GLDC) in CSCs and ovarian cancer cases using tissue microarray (TMA). The expression of stemness gene (Nanog, Oct3/4, Sox2 and ABCG2) mRNA was determined by RT-PCR and protein expression was detected by Western blot analysis.
RESULTS: GLDC, PHGDH and SHMT, associated with serine/ glycine metabolism, showed lower expression in the CSCs. TMA showed that the different expressions of GLDC, PHGDH and SHMT in platinum-sensitive and platinum-resistant ovarian cancer cases (p&lt;0.004). GLDC mRNA was most frequently expressed in primary ovarian cancer culture cells. By Cox multivariate analysis, tumor SHMT1 negativity (HR: 2.132, 95% CI: 1.229-3.664, p = 0.007) was associated with short overall survival.
CONCLUSIONS: Based on our findings, we concluded that the expression of serine-metabolism-associated proteins was related with resistance of ovarian cancer cells and patient's survival.
Citation Format: So-Jin Shin, Hye-Won Chung, Hyun-Gyo Lee, Eun Som Choi, Chi-Heum Cho. Differential expression of enzymes associated with glycine metabolism in ovarian cancer stem like cell. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1147. doi:10.1158/1538-7445.AM2015-1147
Abstract 1148: Ang-(1-7) decreases HIF-1α and migration of oral squamous cell carcinoma
Authors: Guimaraes Andre Luiz Sena , Fraga Carlos Alberto de Carvalho , Farias Lucyana Conceição , Guimarães Talita Antunes , De Paula Alfredo Maurício Batista , Mota Amanda , Santiago Lais , Gomez Ricardo Santiago , Santos Sergio Henrique Sousa , Santos Robson Augusto Souza dos , Bader Michael 
Published: August 2015

Abstract
induced by cobaltous chloride and the underlying mechanism.
Methods and Results
We first confirmed that Ang-(1-7) decreases HIF-1α signaling in a newly developed hydroxypropyl-β-cyclodextrin (HPBCD)-based Ang-(1-7) nano-formulation in a novel transgenic rat model of inducible insulin resistance and DM2. The chronic administration of this compound prevented the marked elevation of HIF-1α in diabetic rat kidney. Next, mouse embryonic fibroblasts (MEFs) and SCC-9 cells were incubated in a well humidified incubator with 5% CO2 and 95% air at 37 °C (normoxic condictions). For hypoxic cultures, cells were incubated 150 μM CoCl2 for 24 hours and maintained in a 5% CO2 atmosphere at 37°C. Then, we divided cells into 4 groups including control, CoCl2, Ang-(1-7) and CoCl2 + Ang-(1-7). HIF-1α protein expression and AKT phosphorylation were decreased in hypoxic cells after treatment with Ang-(1-7). Besides, Ang-(1-7) decreased SCC-9 cell migration in hypoxic condition.
Conclusions
In conclusion, our current findings suggest that Ang-(1-7) attenuates HIF-1 α protein stabilization via AKT and Mas receptor-dependent mechanism. In addition, we found that the Ang-(1-7)/Mas receptor inhibit oral cancer cell migration.
Note: This abstract was not presented at the meeting.
Citation Format: Andre Luiz Sena Guimaraes, Carlos Alberto de Carvalho Fraga, Lucyana Conceição Farias, Talita Antunes Guimarães, Alfredo Maurício Batista De Paula, Amanda Mota, Lais Santiago, Ricardo Santiago Gomez, Sergio Henrique Sousa Santos, Robson Augusto Souza dos Santos, Michael Bader. Ang-(1-7) decreases HIF-1α and migration of oral squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1148. doi:10.1158/1538-7445.AM2015-1148
Abstract 1150: mTORC2 enhances flux through the hexosamine biosynthetic pathway by regulation of GFAT1 expression
Authors: Jacinto Estela , Moloughney Joseph , Lynch Thomas , Wu Chang-Chih , Ibironke Olufunmilola , Navia Aixa , Chou Po-Chien , Zhang Sisi , Rabinowitz Joshua , Werlen Guy 
Published: August 2015

Abstract
Metabolic and biosynthetic pathways drive cell growth and proliferation in response to nutrients and growth factors. Highly proliferating cells utilize glucose and glutamine to fuel biosynthetic processes. These two nutrients serve as substrates for the glutamine:fructose-6-phosphate amidotransferase (GFAT1), the rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), which ultimately produces UDP-GlcNAc that is necessary for protein glycosylation. Despite a role for the HBP in insulin resistance and lifespan extension, the mechanisms underlying GFAT1 regulation in vivo has remained elusive. We found mTOR complex 2 (mTORC2) controls flux through the HBP via regulation of GFAT1 expression levels in response to glucose. In the absence of mTORC2, GFAT1 expression is reduced and highly sensitive to glucose starvation. Furthermore, UDP-GlcNAc is highly diminished and glycosylation of specific transmembrane proteins such as CD147 is defective upon mTORC2 disruption. However, mTORC2 is also required for glycolysis and other biosynthetic pathways whose metabolites feed into the HBP. Thus, although exogenous UDP-GlcNAc can partially rescue glycosylation defects, it does not rescue the metabolic deficiencies in the absence of mTORC2. Like GFAT1, key enzymes of biosynthetic pathways have decreased expression in mTORC2-disrupted cells. Thus, by regulating levels of metabolic enzymes, mTORC2 coordinates flux through biosynthetic pathways in response to glucose availability. Our findings have implications for therapeutic targeting of mTORC2 in insulin resistance and cancer metabolism.
Citation Format: Estela Jacinto, Joseph Moloughney, Thomas Lynch, Chang-Chih Wu, Olufunmilola Ibironke, Aixa Navia, Po-Chien Chou, Sisi Zhang, Joshua Rabinowitz, Guy Werlen. mTORC2 enhances flux through the hexosamine biosynthetic pathway by regulation of GFAT1 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1150. doi:10.1158/1538-7445.AM2015-1150
Abstract 1155: Regulation of glutamine metabolism: Allosteric activation and inhibition of mitochondrial glutaminase
Authors: Stalnecker Clint , Ulrich Scott , Erickson Jon , Ramachandran Sekar , DeBerardinis Ralph , Cerione Rick 
Published: August 2015

Abstract
The hydrolysis of glutamine to glutamate plus ammonia, catalyzed in the mitochondria by the enzyme glutaminase (Gls), plays a crucial role in the metabolism of glutamine by cancer cells. Recently, we discovered a novel class of allosteric inhibitors of a splice variant of Gls, known as glutaminase C (GAC), which inhibits the growth of Rho-GTPase transformed cells without affecting their normal cellular counterparts, with the lead compound being the bromo-benzophenanthridinone 968. Here, we took advantage of mouse embryonic fibroblasts (MEFs) transformed by the induced expression of an oncogenic guanine nucleotide exchange factor (GEF) named Dbl, which hyper-activates the Rho GTPases Rac, Rho, and CDC42, together with 13C-labeled glutamine and stable-isotope tracing methods, to establish that 968 selectively blocks the enhancement in glutaminolysis. We then determined how 968 inhibits the catalytic activity of GAC using biophysical approaches on purified GAC enzyme. First, we developed a FRET assay to examine the effects of 968 on the ability of GAC to undergo the dimer-to-tetramer transition necessary for enzyme activation. We next demonstrated how the fluorescence of a reporter group attached to GAC provides a direct read-out of the binding of 968 and related compounds to the enzyme. By combining these fluorescence assays, together with novel GAC mutants trapped in either the monomeric or dimeric state, we show that 968 has the highest affinity for monomeric GAC, and that the dose-dependent binding directly matches its dose-dependent inhibition of enzyme activity and cellular transformation. We then investigated the 968 structure-activity relationship, and to this end, characterized a robust real-time direct binding and inhibition assay for testing a panel of 968 derivatives. Additionally, we have developed novel 968-derivatives with unique functional moieties, such as fluorescent and photo-cross linking groups, to further elucidate the mechanism of GAC inhibition using recombinant GAC in vitro as well as in cancer cells. Together, these findings represent recent advances in our understanding of the regulation of GAC activity both in vitro and in cells, and highlight the potential future of targeting glutamine metabolism with novel small molecule therapeutics.
Citation Format: Clint Stalnecker, Scott Ulrich, Jon Erickson, Sekar Ramachandran, Ralph DeBerardinis, Rick Cerione. Regulation of glutamine metabolism: Allosteric activation and inhibition of mitochondrial glutaminase. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1155. doi:10.1158/1538-7445.AM2015-1155
Abstract 1159: Ketosis and hyperbaric oxygen elicit potent anti-cancer effects in vitro and in vivo
Authors: Poff Angela , Ward Nathan , Seyfried Thomas , D'Agostino Dominic 
Published: August 2015

Abstract
The Warburg effect and tumor hypoxia underlie a unique cancer metabolism characterized by glucose dependency and abnormal mitochondrial function. We have previously shown that this phenotype can be exploited therapeutically by glucose restriction with the ketogenic diet, dietary ketone supplementation, or hyperbaric oxygen (HBOT). We hypothesized that combining these therapies would be an effective non-toxic treatment regimen, so we tested this combination therapy in the VM-M3 mouse model of metastatic cancer. Treated mice exhibited decreased tumor growth rate, decreased metastatic spread to the lungs, kidneys, spleen, adipose, and liver, decreased liver tumor vascularization, and lived twice as long as controls. To further characterize the effects of these therapies, we measured proliferation, viability, ROS production, and expression of key signaling molecules in VM-M3 cells exposed to the following conditions: high glucose (control; 25mM), low glucose (LG; 3mM), ketone supplementation (βHB; 5mM), hyperbaric oxygen (HBOT; 90 min, 2.5 ATA), or combination therapy (LG+BHB+HBOT). Proliferation of VM-M3 cells was measured with trypan blue hemocytometry and was significantly decreased from controls at 24, 48, 72, and 96 hours. Viability of VM-M3 cells was measured by fluorescence microscopy with calcein and EthD-1 and was decreased by 19.2% in LG, 12.5% in βHB, and 38.2% in LG+βHB+HBOT treated cells compared to control. ROS (superoxide) production was measured by fluorescent microscopy with DHE and was increased by 46% in HBOT and by 48% in LG+βHB+HBOT treated cells. Treatment with βHB significantly decreased expression of HIF-1α and pAkt compared to control as measured with western blot. HBOT also inhibited HIF-1α expression but increased pAkt expression in vitro. This study strongly supports further investigation into mechanisms of action and the use of these metabolic therapies as a potential cancer treatment.
Citation Format: Angela Poff, Nathan Ward, Thomas Seyfried, Dominic D'Agostino. Ketosis and hyperbaric oxygen elicit potent anti-cancer effects in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1159. doi:10.1158/1538-7445.AM2015-1159
Abstract 1163: Phosphoserine aminotransferase 1 (PSAT1) as a novel anti-tumor target in hepatocellular carcinoma
Authors: Ding Zhaobing , Wee Kenneth , Kim Eung-Sam , Samanta Animesh , Steckel Michael , Raschke Marian , Velan Sendhil , Chang Young-Tae , Haegebarth Andrea , Ziegelbauer Karl , Gruenewald Sylvia , Han Weiping 
Published: August 2015

Abstract
With an estimated 700,000 new cases per year, hepatocellular carcinoma (HCC) represents the fifth commonest cancer and is the third leading cause of cancer death worldwide. Its 5-year survival rate after surgery is only 5-6%. Although HCC cases occur predominantly in the East and Southeast Asia and Sub-Saharan Africa, the incidence is rising in the West, largely due to an increasing incidence of Hepatitis C virus infection, alcoholic liver disease, and non-alcoholic steatohepatitis related to obesity and type II diabetes. Besides sorafenib, an oral multikinase inhibitor approved for the treatment of HCC, there is no other pharmacological agent in the treatment of HCC.
Cancer cells undergo dramatic metabolic reprogramming to sustain uncontrolled proliferation. Accumulating evidence supports abnormal metabolic pathways as an emerging hallmark of cancer. To identify metabolic genes required for HCC tumorigenesis, we compared gene expression profiles of a rat orthotopic and a mouse DEN (Diethylnitrosamine)-induced HCC model to a liver regeneration model and to normal liver by PCR arrays, transcriptomic analysis, and metabolomic profiling. Serine and glycine levels were increased in tumors of the HCC models as determined by NMR spectroscopy. PSAT1 (phosphoserine aminotransferase 1), an enzyme in the serine biosynthesis pathway, was identified as one of the top up-regulated genes in the HCC models. An increase in PSAT1 protein levels in tumor samples versus normal liver tissue was confirmed by Western blot. Knockdown of PSAT1 in rat hepatoma cells (MH3924a) led to a dramatic reduction in cell proliferation in vitro and in vivo. Moreover, a doxycycline-inducible knockdown approach confirmed the anti-proliferation effect of PSAT1 depletion. Interestingly, depletion of PSAT1 showed a variable effect on other HCC cells (e.g. Hep3B and Huh-7), suggesting the involvement of other genetic and metabolic factors. Detailed analysis of PSAT1 as a potential drug target for HCC is currently being addressed in in vivo studies.
Citation Format: Zhaobing Ding, Kenneth Wee, Eung-Sam Kim, Animesh Samanta, Michael Steckel, Marian Raschke, Sendhil Velan, Young-Tae Chang, Andrea Haegebarth, Karl Ziegelbauer, Sylvia Gruenewald, Weiping Han. Phosphoserine aminotransferase 1 (PSAT1) as a novel anti-tumor target in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1163. doi:10.1158/1538-7445.AM2015-1163