title: cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases inhibitor leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer's disease.
abstract: Leucettines, a family of pharmacological inhibitors of dual-specificity tyrosine phosphorylation regulated kinases and cdc-like kinases (CLKs), are currently under investigation for their potential therapeutic application to Down syndrome and Alzheimer's disease. We here report that leucettine L41 triggers bona fide autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 cells, characterized by microtubule-associated protein light chain 3 membrane translocation and foci formation. Leucettine L41-triggered autophagy requires the Unc-51-like kinase and is sensitive to the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the mammalian target of rapamycin (mTOR)/PI3K-dependent pathway. Leucettine L41 does not act by modifying the autophagic flux of vesicles. Leucettine L41-induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited phosphatidylinositol-3-phosphate 5-kinase, FYVE domain-containing activity as tested both in vitro and in vivo, which may also contribute to autophagy induction. Altogether these results demonstrate that leucettines can activate the autophagic mTOR/PI3K pathway, a characteristic that may turn advantageous in the context of Alzheimer's disease treatment.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), USR3151, "Protein Phosphorylation and Human Disease," Station Biologique, Roscoff cedex, France (X.F., E.D.); Institut National de la Santé et de la Recherche Médicale/Université Paul Sabatier Unité Mixte de Recherche (UMR) 1048, "Production et fonctions plaquettaires: signalisation et phosphoinositides" group, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Toulouse cedex, France (G.C., B.P.); Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan (D.S., A.S.); Laboratoire Sciences Chimiques de Rennes, UMR CNRS 6226, Groupe Ingénierie Chimique et Molécules pour le Vivant (ICMV), Université de Rennes, Campus de Beaulieu, Rennes cedex, France (E.L., F.C., J.-P.B.); and ManRos Therapeutics, Perharidy Research Center, Roscoff, Bretagne, France (L.M.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Fant
authors.forename: Emilie
authors.initials: E
authors.lastname: Durieu
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Chicanne
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.forename: Diego
authors.initials: D
authors.lastname: Sbrissa
authors.forename: Assia
authors.initials: A
authors.lastname: Shisheva
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Limanton
authors.forename: François
authors.initials: F
authors.lastname: Carreaux
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bazureau
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D004149:Dioxoles / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D004149:Dioxoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D014443:Tyrosine; D000097603:Dyrk Kinases; C578491:((5Z)5-(1,3-benzodioxol-5-yl)methylene-2-phenylamino-3,5-dihydro-4H-imidazol-4-one)