RT Journal Article
SR Electronic
T1 cdc-Like/Dual-Specificity Tyrosine Phosphorylation–Regulated Kinases Inhibitor Leucettine L41 Induces mTOR-Dependent Autophagy: Implication for Alzheimer’s Disease
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 441
OP 450
DO 10.1124/mol.113.090837
VO 85
IS 3
A1 Xavier Fant
A1 Emilie Durieu
A1 Gaëtan Chicanne
A1 Bernard Payrastre
A1 Diego Sbrissa
A1 Assia Shisheva
A1 Emmanuelle Limanton
A1 François Carreaux
A1 Jean-Pierre Bazureau
A1 Laurent Meijer
YR 2014
UL http://molpharm.aspetjournals.org/content/85/3/441.abstract
AB 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.