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.
Footnotes
- Received November 18, 2013.
- Accepted December 23, 2013.
This work was supported by grants from the Fonds Unique Interministériel (FUI) PharmaSea project; the European Union 7th Framework Programme (FP7) Micro-Therapy project; the European Union 7th Framework Programme Knowledge-Based Bio-Economy (FP7-KBBE)–BlueGenics 2012 grant; the Association France-Alzheimer (Finistère); Centre Régional d’Innovation et de Transfert de Technologie (CRITT)–Santé Bretagne; and Fondation Jérôme Lejeune.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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