cdc-Like/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases Inhibitor Leucettine L41 Induces mTOR-Dependent Autophagy: Implication for Alzheimer's Disease
cdc-Like/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases Inhibitor Leucettine L41 Induces mTOR-Dependent Autophagy: Implication for Alzheimer's Disease
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DOI：
10.1124/mol.113.090837
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发表时间：
2014-03-01
影响因子：
3.6
通讯作者：
Meijer, Laurent
中科院分区：
文献类型：
--
作者：
Fant, Xavier;Durieu, Emilie;Meijer, Laurent
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.
