1. Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway.
- Author
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Wong CP, Seki A, Horiguchi K, Shoji T, Arai T, Nugroho AE, Hirasawa Y, Sato F, Kaneda T, and Morita H
- Subjects
- Annexin A5 metabolism, Apoptosis drug effects, Apoptosis Regulatory Proteins metabolism, Autophagy, Cell Line, Tumor, Cytostatic Agents chemistry, Cytostatic Agents pharmacology, Down-Regulation, Female, Humans, Indole Alkaloids chemistry, Indole Alkaloids isolation & purification, Malaysia, Molecular Structure, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, TOR Serine-Threonine Kinases drug effects, Vinblastine pharmacology, Indole Alkaloids pharmacology
- Abstract
We have previously reported that bisleuconothine A (Bis-A), a novel bisindole alkaloid isolated from Leuconotis griffithii, showed cytostatic activity in several cell lines. In this report, the mechanism of Bis-A-induced cytostatic activity was investigated in detail using A549 cells. Bis-A did not cause apoptosis, as indicated by analysis of annexin V and propidium iodide staining. Expression of all tested apoptosis-related proteins was also unaffected by Bis-A treatment. Bis-A was found to increase LC3 lipidation in MCF7 cells as well as A549 cells, suggesting that Bis-A cytostatic activity may be due to induction of autophagy. Subsequent investigation via Western blotting and immunofluorescence staining indicated that Bis-A induced formation but prevented degradation of autophagosomes. Mechanistic studies showed that Bis-A down-regulated phosphorylation of protein kinase B (AKT) and its downstream kinase, PRAS40, which is an mTOR repressor. Moreover, phosphorylation of p70S6K, an mTOR-dependent kinase, was also down-regulated. Down-regulation of these kinases suggests that the increase in LC3 lipidation may be due to mTOR deactivation. Thus, the cytostatic activity shown by Bis-A may be attributed to its induction of autophagosome formation. The Bis-A-induced autophagosome formation was suggested to be caused by its interference with the AKT-mTOR signaling pathway.
- Published
- 2015
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