Characterization of Novel Liver X Receptor Ligands in Pancreatic Cancer

dc.contributor.advisorLin, Chin-Yo
dc.contributor.committeeMemberZhang, Weihua
dc.contributor.committeeMemberWidger, William R.
dc.contributor.committeeMemberŞen, Mehmet
dc.contributor.committeeMemberBailey, Jennifer M.
dc.creatorSrivastava, Shivangi
dc.date.accessioned2021-08-06T18:44:12Z
dc.date.createdDecember 2020
dc.date.issued2020-12
dc.date.submittedDecember 2020
dc.date.updated2021-08-06T18:44:15Z
dc.description.abstractPancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Efforts to directly target mutant KRAS found in >94% of PDACs have not been successful due to structural constraints. An alternative strategy to directly targeting KRAS is to identify and target druggable receptors involved in dysregulated cancer hallmarks such as metabolic reprogramming downstream of KRAS dysregulation. Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-modulated transcription factors and are involved in the regulation of genes which function in key cancer-related processes, including cholesterol transport, lipid and glucose metabolism, and inflammatory and immune responses. Modulation of LXRs via small molecule ligands has emerged as a promising approach in cancer therapeutics. Analysis of transcriptomic data from PDAC clinical samples reveals upregulation of LXR and its target genes in tumors. In a screen of a focused library of drug-like small molecules predicted to dock in the ligand-binding pocket of LXRβ, we identified two novel LXR ligands with more potent anti-tumor activity than current LXR agonists used in our published studies. Characterization of the two lead compounds (GAC0001E5 and GAC0003A4) indicates that they function as LXR inverse agonists which inhibit their transcriptional activity. Prolonged treatments with novel ligands further revealed their function as LXR “degraders” which significantly reduced LXR protein levels in all three PDAC cell lines tested. Using metabolomics approach, we discovered that GAC0001E5 inhibits glutamine anaplerosis and induces oxidative stress in PDAC cells. Furthermore, we revealed that high extracellular cystine concentration drives the antiproliferative effect of GAC0001E5 in PDAC cells. These findings support the idea of inhibiting LXR activity using inverse agonists and degraders for the treatment of advanced pancreatic cancer. This study also highlights a novel role for LXR in regulating glutamine metabolism and glutathione metabolism in pancreatic cancer. These novel LXR ligands can further be used to advance basic research on ligand design, allosteric mechanisms, and LXR functions in other cancer models.
dc.description.departmentBiology and Biochemistry, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.citationPortions of this document appear in: Karaboga, Husna, Wentao Huang, Shivangi Srivastava, Scott Widmann, Sridevi Addanki, Kasuni Thawalama Gamage, Zahra Mazhar et al. "Screening of focused compound library targeting liver X receptors in pancreatic cancer identified ligands with inverse agonist and degrader activity." ACS Chemical Biology 15, no. 11 (2020): 2916-2928.
dc.identifier.urihttps://hdl.handle.net/10657/8014
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. UH Libraries has secured permission to reproduce any and all previously published materials contained in the work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectPancreatic Cancer
dc.subjectLiver X Receptor
dc.subjectLigand
dc.subjectInverse Agonist
dc.subjectDegrader
dc.subjectGlutamine Metabolism
dc.subjectOxidative Stress
dc.subjectFerroptosis
dc.titleCharacterization of Novel Liver X Receptor Ligands in Pancreatic Cancer
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2022-12-01
local.embargo.terms2022-12-01
thesis.degree.collegeCollege of Natural Sciences and Mathematics
thesis.degree.departmentBiology and Biochemistry, Department of
thesis.degree.disciplineBiochemistry
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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