cdc-Like/Dual-Specificity Tyrosine Phosphorylation–Regulated Kinases Inhibitor Leucettine L41 Induces mTOR-Dependent Autophagy: Implication for Alzheimer’s Disease

• Published in: Molecular pharmacology Vol. 85; no. 3; pp. 441 - 450
• Main Authors: Fant, Xavier, Durieu, Emilie, Chicanne, Gaëtan, Payrastre, Bernard, Sbrissa, Diego, Shisheva, Assia, Limanton, Emmanuelle, Carreaux, François, Bazureau, Jean-Pierre, Meijer, Laurent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2014; American Society for Pharmacology and Experimental Therapeutics; American Society for Pharmacology and Experimental Therapeutics (ASPET); The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Alzheimer Disease; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Animals; Autophagy; Autophagy - drug effects; Autophagy - genetics; Autophagy - immunology; Cell Line; Cell Line, Tumor; Chemical Sciences; Dioxoles; Dioxoles - pharmacology; Dyrk Kinases; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Humans; Imidazoles; Imidazoles - pharmacology; Mice; Microtubule-Associated Proteins; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - metabolism; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - genetics; Phosphorylation - immunology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; TOR Serine-Threonine Kinases; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tyrosine; Tyrosine - genetics; Tyrosine - metabolism; DYRKs; PtdIns5P; DMSO; PtdIns3P; BiP; S-CR8; EGFP; SB203580; YM201636; GFP; PI3K; ULK; mTOR; EBSS; LC3; HPLC; U0126; PIKfyve; PtdIns(3,5)P2; GroPIns; siRNA; ER; IP3; CLKs; SB600125; SR proteins; Z-PP-CHO; PE; PI; mRFP
• ISSN: 0026-895X; 1521-0111; 1521-0111
• DOI: 10.1124/mol.113.090837

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.