title: Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Nicholes R
authors.initials: NR
authors.lastname: Candelaria
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Addanki
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Jine
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Trang
authors.initials: T
authors.lastname: Nguyen-Vu
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Husna
authors.initials: H
authors.lastname: Karaboga
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Dey
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbi
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Vedin
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Ka
authors.initials: K
authors.lastname: Liu
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Wanfu
authors.initials: W
authors.lastname: Wu
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Jonsson
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America; Center for Diabetes Research, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors.forename: Jean Z
authors.initials: JZ
authors.lastname: Lin
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Su
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Lakshmi Reddy
authors.initials: LR
authors.lastname: Bollu
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America; The Elkins Pancreas Center at Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Hodges
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America; The Elkins Pancreas Center at Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Amy L
authors.initials: AL
authors.lastname: McElhany
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America; The Elkins Pancreas Center at Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Mehdi A
authors.initials: MA
authors.lastname: Issazadeh
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America; The Elkins Pancreas Center at Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Fisher
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America; Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Chin-Yo
authors.initials: CY
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D008024:Ligands; D000071518:Liver X Receptors; D009363:Neoplasm Proteins; D057093:Orphan Nuclear Receptors; D003841:Deoxycytidine; D000093542:Gemcitabine