title: Retinoid resistance and multifaceted impairment of retinoic acid synthesis in glioblastoma.
abstract: Measuring concentrations of the differentiation-promoting hormone retinoic acid (RA) in glioblastoma tissues would help to understand the reason why RA treatment has been inefficient in clinical trials involving brain tumor patients. Here, we apply a recently established extraction and measurement protocol to screen glioblastoma tissues for the levels of the RA precursor retinol and biologically active RA. Combining this approach with mRNA analyses of 26 tumors and 8 normal brains, we identify a multifaceted disturbance of RA synthesis in glioblastoma, involving multiple aldehyde dehydrogenase 1 family and retinol dehydrogenase enzymes. Through database studies and methylation analyses, we narrow down chromosomal deletions and aberrant promoter hypermethylation as potential mechanisms accounting for these alterations. Employing chromatin immunoprecipitation analyses and cell-culture studies, we further show that chromatin at RA target genes is poised to RA substitution, but most glioblastoma cell cultures are completely resistant to RA treatment. This paradoxical RA response is unrelated to alternative RA signaling through the fatty acid-binding protein 5/peroxisome proliferator-activated receptor delta axis. Our data suggest a multifaceted disturbance of RA synthesis in glioblastoma and contribute to reconsider current RA treatment strategies.
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benito
authors.initials: B
authors.lastname: Campos
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weisang
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Osswald
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ramadan
authors.initials: R
authors.lastname: Ali
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Sedlmeier
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Bageritz
authors.affiliation: Research Group Genome Organization and Function, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Interdisciplinary Research Group Genome Organization and Function, BioQuant, Heidelberg, Germany.
authors.forename: Jan-Philipp
authors.initials: JP
authors.lastname: Mallm
authors.affiliation: Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.|Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Center, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Department of Neuropathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Center, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Odillia
authors.initials: O
authors.lastname: Popanda
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Violaine
authors.initials: V
authors.lastname: Goidts
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000150:complications*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005909:Glioblastoma / Q000150:complications*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D051142:Retinol O-Fatty-Acyltransferase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C082925:retinoic acid receptor beta; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D051142:Retinol O-Fatty-Acyltransferase
keywords: differentiation; glioma; retinoic acid