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Mol Pharmacol. 2014 Mar;85(3):441-50. doi: 10.1124/mol.113.090837. Epub 2013 Dec 23.

cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases inhibitor leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer's disease.

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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.).


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.

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