title: Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA.
abstract: Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Jin-Chul
authors.initials: JC
authors.lastname: Heo
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.|Pharmacology Research Medicinal and Pharmaceutical Chemistry, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Jung
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Hyun Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Gildon
authors.initials: G
authors.lastname: Choi
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Myungeun
authors.initials: M
authors.lastname: Jung
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Daeyoung
authors.initials: D
authors.lastname: Jung
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Heung Kyoung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea.
authors.forename: Jung-Ok
authors.initials: JO
authors.lastname: Lee
authors.affiliation: Department of Chemical Engineering, POSTECH, Pohang, 790-784, Republic of Korea.
authors.forename: Ji-Hwan
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, Daegu, 42988, Republic of Korea.|Department of Chemical Engineering, POSTECH, Pohang, 790-784, Republic of Korea.
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Department of Neurosurgery, Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea.
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Seol
authors.affiliation: Drug Discovery Division, Pharmacology Research Group, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea. hycho@krict.re.kr.|Pharmacology Research Medicinal and Pharmaceutical Chemistry, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea. hycho@krict.re.kr.
authors.forename: Heeyeong
authors.initials: H
authors.lastname: Cho
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis; D000818:Animals; D000077610:Bexarotene; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D051379:Mice; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020710:RGS Proteins / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D047488:Retinoid X Receptors / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D011503:Transglutaminases / Q000096:biosynthesis / Q000235:genetics*; D014212:Tretinoin / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C527276:CXCR4 protein, human; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D020710:RGS Proteins; D019718:Receptors, CXCR4; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; C098799:RGS4 protein; D014212:Tretinoin; D000077610:Bexarotene; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: All-trans retinoic acid; Bexarotene; GBM; Glioblastoma multiforme; Transglutaminase 2