title: All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation.
abstract: All trans retinoic acid (atRA) is one of the most potent therapeutic agents, but extensive toxicity caused by nuclear RA receptors (RARs) limits its clinical application in treating cancer. AtRA also exerts non-genomic activities for which the mechanism remains poorly understood. We determine that cellular retinoic acid binding protein 1 (Crabp1) mediates the non-genomic activity of atRA, and identify two compounds as the ligands of Crabp1 to rapidly and RAR-independently activate extracellular signal regulated kinase 1/2 (ERK1/2). Non-canonically activated ERK activates protein phosphatase 2A (PP2A) and lengthens cell cycle duration in embryonic stem cells (ESC). This is abolished in Crabp1-null ESCs. Re-expressing Crabp1 in Crabp1-negative cancer cells also sensitizes their apoptotic induction by atRA. This study reveals a physiological relevance of the non-genomic action of atRA, mediated by Crabp1, in modulating cell cycle progression and apoptosis induction, and provides a new cancer therapeutic strategy whereby compounds specifically targeting Crabp1 can modulate cell cycle and cancer cell apoptosis in a RAR-independent fashion, thereby avoiding atRA's toxicity caused by its genomic effects.
authors.affiliation: Department of Pharmacology University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Shawna D
authors.initials: SD
authors.lastname: Persaud
authors.affiliation: Department of Pharmacology University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Park
authors.affiliation: Tokyo Medical and Dental University (TMDU), Institute of Biomaterials and Bioengineering, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JAPAN.
authors.forename: Mari
authors.initials: M
authors.lastname: Ishigami-Yuasa
authors.affiliation: Department of Medicine, University of Minnesota, MN 55455, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Koyano-Nakagawa
authors.affiliation: Tokyo Medical and Dental University (TMDU), Institute of Biomaterials and Bioengineering, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JAPAN.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Department of Pharmacology University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; C082927:retinoic acid binding protein I, cellular; D014212:Tretinoin; D048052:Mitogen-Activated Protein Kinase 3