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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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https://www.hal.inserm.fr/inserm-01012086
Contributor : Marie Francoise Simon <>
Submitted on : Wednesday, June 25, 2014 - 2:15:34 PM
Last modification on : Friday, October 16, 2020 - 3:41:10 AM

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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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