bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3686: Blocking fatty acid oxidation suggests a potential new therapeutic approach for pancreatic cancer
Authors: Woo Sang M. , Han Sung-Sik , Lee Ho , Kim Soo-Youl 
Published: April 2023

Abstract
Background: Glycolysis is known as the main pathway for ATP production in cancer cells. However, in pancreatic ductal adenocarcinoma (PDAC) cells, glucose deprivation for 24 h did not reduce ATP levels, whereas it suppressed lactate production. We found that ATP production in PDAC cells critically depended on fatty acid oxidation (FAO) while normal cells showed no dependency on fatty acid. Therefore, FAO inhibition significantly decrease oxygen consumption rate as well as ATP production only in cancer cells.
Methods: To test whether cancer depends on fatty acid for energy metabolism, high- or low-fat diet was tested in spontaneous PDAC cancer model (KPC mouse: Kras(G12D)/p53(R172H)/Pdx1-Cre model). To test whether FAO is absolute requirement for ATP production in cancer, overall survival (OS) was monitored in KPC mice by crossbreeding with FAO gene knock out mice.
Results: First, the effects of calorie balanced high- or low-fat diets were tested to determine whether cancer growth is modulated by fatty acid instead of calories. A low-fat diet caused a 70 % decrease in pancreatic preneoplastic lesions accompanying decrease of body weight 20% compared with the control, whereas high-fat diet caused a 2-fold increase in preneoplastic lesions accompanied with 25% increase of body mass index in Kras(G12D)/p53(R172H)/Pdx1-Cre model (KPC model; spontaneous PDAC model). Second, the effect of FAO gene knock down was tested to determine whether OS is increased in KPC model. The crossbreeding of FAO gene knockout (+/-) and KPC mice resulted in 2-fold increase of OS.
Conclusions: The two results suggest that controlling obesity by diet as well as targeting FAO can enhance anti-cancer effect of cancer therapeutics including conventional anti-cancer drug or immune-oncology drug.
Clinical Trial Identification: IND for PDAC therapy with drugs targeting FAO will be submitted in 2022.
Legal Entity Responsible for the Study: This study is legally under review by IRB in National Cancer Center, Korea, and sponsored by National Research Foundation of Korea (NRF) and NCC-Bio Co.
Funding: Funding source: Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2019M3A9G1104345)
Citation Format: Sang M. Woo, Sung-Sik Han, Ho Lee, Soo-Youl Kim. Blocking fatty acid oxidation suggests a potential new therapeutic approach for pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3686.
Abstract 3694: Metabolic response in human cervical cancer cells to modifications in bioavailable ATP
Authors: Jayaswal Parth K. , Muhammad Taha , Brown Ashley , Norris Jeffrey , Korch Shaleen B. 
Published: April 2023

Abstract
Introduction: Cancer cells utilize a markedly reduced oxidative phosphorylation (OXPHOS) when experiencing conditions of high oxygen stress (Warburg Effect/aerobic glycolysis), a phenomenon first studied by Otto Warburg. While there have been many discoveries associated with metabolic differences across cancer cells, one of the most common alterations is the primary means of generating ATP. The importance of deciphering these cellular decisions will enable an understanding of the multifaceted role ATP has in cancer proliferation, senescence, and chemotherapeutic resistance. The use of synthetic protein DX, a man-made ATP chelator with high specificity and affinity, is a proposed method of investigating the metabolic response in cancer cells. Hypothesis: Following DX expression, HeLa cells respond to energy stress (reduced intracellular ATP) via metabolic adaptations, specifically inducing the spare respiratory capacity.
Methods: The impact of DX on cell viability was determined using a tetrazolium-based colorimetric cell viability assay and a caspase 3/7 assay. To correlate phenotypic/viability change with DX activity, bioavailable ATP levels were measured at specific time points following DX expression. Additionally, the relative contribution of glycolysis and OXPHOS to the total ATP production rate was measured using the label-free XF Real Time ATP Rate Assay and XF Cell Mito Stress Test (XFe96 Seahorse, Agilent Technologies) over time post DX expression. To determine the impact of ATP stress on mitochondrial and nuclear content, both were quantified following DX-expression.
Results: In a time- and dose- dependent manner, DX negatively impacted cell growth and induced cell death via apoptosis, at a time concomitant with a decrease in bioavailable ATP. In response to DX over time, the total ATP production rates in HeLa cells significantly decreased. Importantly, this reduction in the rate of ATP production was associated with a significant downregulation in both OXPHOS and glycolysis.
Conclusion: Advances in synthetic biology have allowed for the intentional design of artificial proteins that maintain function in vivo. These proteins can be developed into powerful investigative tools to study biological questions, such as cellular decisions involved in cancer cell metabolism. In response to DX-potentiated ATP stress, the significant reduction in both glycolysis and oxidative phosphorylation suggests metabolic downregulation is required to maintain HeLa cell viability.
Citation Format: Parth K. Jayaswal, Taha Muhammad, Ashley Brown, Jeffrey Norris, Shaleen B. Korch. Metabolic response in human cervical cancer cells to modifications in bioavailable ATP. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3694.
Abstract 3707: UXS1 is a synthetic lethal target in cancer
Authors: Cicchini Michelle Patricia , Wu Shuzhen , Peng Yang , Rao Yanhua 
Published: April 2023

Abstract
Studies presented here were conducted to validate UXS1 as a synthetic lethal target in UGDHhigh expressing cancer. In vitro and in vivo knockout studies were used to investigate the role of UXS1 in UGDH-high cancers. UXS1 has been validated as a synthetic lethal target in cancer cell lines highly expressing UGDH in vitro by CRISPR-mediated knockout of UXS1 in a panel of lung cancer cell lines. In addition to UGDH expression predicting UXS1 dependency, we have shown UGDH overexpression functional drives UXS1 dependency, such that knockout of UGDH rescues cellular growth defects seen with UXS1-knockout alone. Furthermore, catalytic activity of UXS1 was shown to be required, as wildtype but not catalytic deficient UXS1 was able to rescue cellular growth defects seen with endogenous UXS1 knockout in UGDH-high cancer cell lines. Together this data suggests that dysregulation of some metabolite(s) is driven by high expression of UGDH when knockout of UXS1 prevents normal pathway flux of UDP-Glucuronic Acid (UDP-GA) to be converted to UDP-Xylose (UDP-X), leading to the synthetic lethal effect observed as impaired cellular growth. To validate UXS1 as a target in vivo, an inducible genetic knockout system to knockout UXS1 showed impaired tumor growth, but no tumor regression. Sanger sequencing of UXS1 knockout efficiency at different time course suggested a slow and incomplete dropout of the UXS1-KO cells in vivo. Although in vitro efforts have shown UXS1 to a synthetic lethal target, the failure to induce a robust in vivo effect of UXS1 knockout have casted doubts on the promise of UXS1 being an effective target for the proposed indication.
Citation Format: Michelle Patricia Cicchini, Shuzhen Wu, Yang Peng, Yanhua Rao. UXS1 is a synthetic lethal target in cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3707.
Abstract 3709: Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: an in vitro and in vivo experiment
Authors: Liu Zhao , Hayashi Hiromitsu , Matsumura Kazuki , Ogata Yoko , Sato Hiroki , Shiraishi Yuta , Uemura Norio , Miyata Tatsunori , Higashi Takaaki , Nakagawa Shigeki , Mima Kosuke , Imai Katsunori , Baba Hideo 
Published: April 2023

Abstract
Background: Pancreatic cancer is a serious life-threatening disease due to its highly invasive and metastatic potential. Hyperglycemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). In this study, we elucidate the biological and clinical impact of hyperglycemia in PDAC progression.
Methods: Biological impact of hyperglycemia on malignant behavior in PDAC was examined by in vitro and in vivoexperiment.
Results: Hyperglycemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycemia enhanced chemoresistance by upregulating ABCB1 expression, and triggered PDAC switch into pure-basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterized by abundant stroma that harbors tumor-promoting properties and chemoresistance. Hyperglycemia promotes production of collagen fiber-related proteins (fibronectin, fibroblast activation protein, COL1A1, and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance, and a favorable tumor microenvironment even under hyperglycemic conditions in vitro and in vivo. Indeed, YAP/TAZ overexpression was significantly associated with worse prognostic outcomes in human PDAC patients.
Conclusion: Hyperglycemia induce metabolic reprogramming into a glycolytic phenotype and promote EMT via the YAP/TAZ-Hedgehog signaling axis in PDAC. Hyperglycemia as an initial symptom may be the cause of highly invasive and metastatic potential by inducing YAP/TAZ overexpression, while YAP/TAZ could be a novel therapeutic target in PDAC patients.
Citation Format: Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Hideo Baba. Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: an in vitro and in vivo experiment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3709.
Abstract 3735: N-terminal and C-terminal elephant-to-human p53 variants and truncations alter p53 transactivation
Authors: Yang William H. , Yang Wei-Hsiung 
Published: April 2023

Abstract
Cancer is one of the most dreaded diseases of the 21st century for humans. Currently, the human cancer mortality rate is approximately 11-25%. However, for some animals, such as elephants, the cancer mortality rate is lower than 5%. p53 is a significant cellular regulator in human cancers, and its important role in response to DNA damage has been highlighted by the discovery of p53 retrogene found in elephants (19 copies) but not humans (0 copies). Therefore, the main question is whether (1) more copies of p53 are better at combating cancer development or (2) is elephant p53 is better than human p53 in p53-mediated function? Herein, we demonstrate for the first time that N-terminal and C-terminal elephant-to-human p53 variants and truncations alter p53 transactivation. First, we created elephant-to-human p53 variants (such as T387R, L383P, LSTEL, etc.) and truncations at the N-terminus and C-terminus of human p53. Secondly, R175H and R273H p53 mutants (conformational and contact mutants, respectively) were used as negative control. Using a p53 (14X) response element LUC and several natural p53 downstream gene promoters, we demonstrated that several N-terminal and C-terminal p53 variants and truncations increases p53 transactivation compared to WT p53. Moreover, we found that deletion of the region between aa374 and aa382 is integral for p53 transactivation. Taken together, our preliminary results demonstrate that several N-terminal and C-terminal elephant-to-human p53 variants enhance p53 transactivation and possible stability. This data is the first step to support the notion that elephant p53 is better than human p53 in p53-mediated function.
Citation Format: William H. Yang, Wei-Hsiung Yang. N-terminal and C-terminal elephant-to-human p53 variants and truncations alter p53 transactivation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3735.
Abstract 3745: GRAS1 long non-coding RNA binds and stabilizes NF-kB activating protein to protect lung cancer cells from DNA damage
Authors: Su Tong , Kong Bobby , Zhu Jonathan , McHugh Colleen A. 
Published: April 2023

Abstract
Long non-coding RNAs (lncRNAs) control numerous biological processes, including epigenetic regulation, gene expression, proliferation and metabolism. However, the detailed biological mechanisms by which lncRNAs regulate cellular processes are still poorly understood. We identified a set of growth regulator non-coding RNAs based on data mining of CRISPR/Cas9 screens and high-throughput sequencing studies from patient normal and tumor cells. We hypothesized that growth regulator lncRNAs play a role in cancer development by recruiting effector proteins to regulate gene expression. In our screen, the Growth Regulator Antisense 1 RNA (GRAS1) was identified as a key factor controlling growth in non-small cell lung cancer cells. Loss of GRAS1 resulted in altered expression of genes involved in DNA repair, cell cycle progression, and p53 and NF-ΚB signaling pathways. Extensive DNA damage occurred within 48 hours after GRAS1 knockdown, with a significant increase in the number of γH2AX loci visualized by immunofluorescence assay. We used RNA antisense purification combined with mass spectrometry to identify the NF-ΚB activating protein (NKAP) as the top directly interacting partner of GRAS1 lncRNA. NKAP stability decreased after GRAS1 knockdown, and this phenotype could be reversed with proteasome inhibition. Further, RelA levels were decreased in GRAS1 knockdown cells. We found that GRAS1 lncRNA binds and stabilizes NKAP to enable survival and protect against DNA damage in lung cancer cells.
Citation Format: Tong Su, Bobby Kong, Jonathan Zhu, Colleen A. McHugh. GRAS1 long non-coding RNA binds and stabilizes NF-kB activating protein to protect lung cancer cells from DNA damage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3745.
Abstract 376: DKK1 inhibition can overcome sorafenib resistance in hepatocellular carcinoma cells through beta-catenin suppression
Authors: Li Lin , Hsu Chia-Lang , Lin Liang-In , Lee Bin-Shyun , Ou Ping-Yun , Cheng Ann-Lii , Hsu Chiun , Ou Da-Liang 
Published: April 2023

Abstract
As part of our previous studies on the anti-tumor mechanisms of sorafenib, one of the primary treatments for advanced hepatocellular carcinoma (HCC), we found that suppression of cyclin E1 in HCC cells correlates with sensitivity to sorafenib (Chiun Hsu et al. Clin Cancer Res. 2016:2555). Furthermore, the combination of sorafenib and a cyclin-dependent kinase inhibitor was found to have synergistic anti-tumor effects. Specifically, we found that inhibiting DKK1 (dickkopf1), an essential regulator of Wnt signaling, had a synergistic effect. In sorafenib-sensitive HCC cells, DKK1 mRNA and protein expressions were suppressed following treatment with sorafenib, but not in sorafenib-resistant cells. HCC cells resistant to sorafenib were induced to apoptosis with knockdown of DKK1 expression. The apoptosis-inducing effects of sorafenib were enhanced by DKK1 inhibitors, and beta-catenin suppression was found to be crucial to this effect. In addition, mouse tumors secrete DKK1 into the blood and its presence correlates positively with tumor size and survival during sorafenib treatment. Suppression of DKK1 in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib or CDK inhibitor efficacy. Sorafenib combined with a DKK1 inhibitor may improve sorafenib's efficacy in hepatocellular carcinoma. (Supported by MOST 106-2314-B-002-229-MY3, MOST 109-2634-F-002-043, MOST 109-2314-B-002-229 -MY3, MOST 110-2634-F-002-044 from Ministry of Science and Technology, Taiwan)
Citation Format: Lin Li, Chia-Lang Hsu, Liang-In Lin, Bin-Shyun Lee, Ping-Yun Ou, Ann-Lii Cheng, Chiun Hsu, Da-Liang Ou. DKK1 inhibition can overcome sorafenib resistance in hepatocellular carcinoma cells through beta-catenin suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 376.
Abstract 3831: The molecular composition of a water-soluble extract from the leaves of the indigenous Southern African plant Tulbaghia violacea that displays anti-cancer activity against a triple negative breast cancer cell line
Authors: Alaouna Mohammed , Penny Clement , Ulll Rodney , Dlamini Zodwa 
Published: April 2023

Abstract
Approximately 20% of all breast cancer cases are Triple negative breast cancer (TNBC), whichis more difficult to treat and has a higher mortality rate than other types of breast cancer. Thereis an active practice of traditional medicine in in South Africa, in the form of infusions madeusing plant material. Previously we demonstrated that water soluble extracts from the leaves ofone of these plants, African garlic (Tulbaghia violacea), is able to induce apoptosis in TNBCcell lines, while also inhibiting the ability of these cells to migrate or penetrate a basementmembrane. In an attempt to isolate the molecular compounds that are present in this extract,water soluble leaf extracts were subjected to Fourier transform infrared spectroscopy (FITR),Gas chromatography–mass spectrometry (GC-MS) and Nuclear magnetic resonance (NMR)spectroscopy. Identified compounds of interest were then used in computational dockingstudies with the anti-apoptotic protein Cox2. The FITR analysis indicated that the extractconsisted of multiple compounds, belonging to a variety of classes. GC-NS and NMRspectroscopy identified 36 and 61 separate compounds respectively. Many of these compoundswere similar in structure to compounds with known anti-cancer properties. Many compoundswith established medical uses were also identified in the extract. Five compounds identified inthe extract, d-Glycero-d-galacto-heptose, H-Pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, and Benzaldehyde and 4-(1-methylethyl)- demonstrated high binding affinity towardsCOX2. With d-Glycero-d-galacto-heptose having a higher docking score than manycommercially available COX2 inhibitors. Based on our findings, the compounds within theextract could be used as the basis for the development of safe and effective drugs for thetreatment of TNBC and other cancers. In order to fulfil this potential, future work shouldexamine the molecular pathways affected by the treatment of TNBC cells with this extract orindividual compounds.
Citation Format: Mohammed Alaouna, Clement Penny, Rodney Ulll, Zodwa Dlamini. The molecular composition of a water-soluble extract from the leaves of the indigenous Southern African plant Tulbaghia violacea that displays anti-cancer activity against a triple negative breast cancer cell line. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3831.
Abstract 3926: Activating missense mutations in ROS1 receptor harbor oncogenic potential and are sensitive to tyrosine kinase inhibition
Authors: Iyer Sudarshan R. , Nusser Kevin , Jones Kristen , Shinde Pushkar , Beach Catherine Z. , Keddy Clare , Aguero Erin , Force Jeremy , Shinde Ujwal , Davare Monika A. 
Published: April 2023

Abstract
ROS1 encodes the largest receptor tyrosine kinase (RTK) in the human genome. Chromosomal rearrangements of the ROS1 gene generate oncogenic ROS1 fusion proteins that have been successfully targeted with tyrosine kinase inhibitors (TKIs), most notably in lung cancer. To date, ROS1 fusions are the only known biomarkers for therapeutic implementation of ROS1 TKIs. However, unlike known oncogenic mutations in EGFR and ALK RTKs, the functional impact of point mutations within the full-length ROS1 RTK is unknown. Here we queried the AACR Genie database, which consists of pan-cancer clinical genomic sequencing data from thousands of patient samples, for ROS1 aberrations and nominated thirty-four missense mutations residing in the ROS1 tyrosine kinase domain for functional interrogation. Immunoblotting revealed distinct impact of the mutations on kinase function, ranging from complete loss to significant increase in catalytic activity. Notably, Asp and Gly substitutions at the D2113 position within the ROS1 kinase domain dramatically increased autophosphorylation and activation of downstream signaling pathways. ROS1D2113N/G were found to be ROS1 TKI-sensitive transformative oncogenes in independent cell-based models. Molecular dynamic simulations of ROS1D2113N kinase revealed dramatic alterations in the activation loop of the mutant kinase as compared to wildtype. Global proteomics and phosphoproteomics showed that ROS1D2113N upregulates signaling via phosphorylation of known effectors (SHP2 and STAT3) similar to ROS1 fusions, but also upregulates other pathways, including mTORC2, JNK1/2, AP-1 and TGFB1. In vivo, ROS1D2113N drove tumor formation that was inhibited with ROS1 TKIs. Taken together, these data demonstrate for the first time that select point mutations within ROS1 drive tumorigenesis and can be therapeutically targetable with existing FDA-approved ROS1-TKIs.
Citation Format: Sudarshan R. Iyer, Kevin Nusser, Kristen Jones, Pushkar Shinde, Catherine Z. Beach, Clare Keddy, Erin Aguero, Jeremy Force, Ujwal Shinde, Monika A. Davare. Activating missense mutations in ROS1 receptor harbor oncogenic potential and are sensitive to tyrosine kinase inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3926.