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.
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Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2014, 85 (3), pp.441-50. 〈10.1124/mol.113.090837〉
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Contributeur : Marie Francoise Simon <>
Soumis le : mercredi 25 juin 2014 - 14:15:34
Dernière modification le : vendredi 25 mai 2018 - 01:27:14

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Xavier Fant, Emilie Durieu, Gaëtan Chicanne, Bernard Payrastre, Diego Sbrissa, et al.. cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases inhibitor leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer's disease.. Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2014, 85 (3), pp.441-50. 〈10.1124/mol.113.090837〉. 〈inserm-01012086〉

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