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Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway

2015; American Chemical Society; Volume: 78; Issue: 7 Linguagem: Inglês

10.1021/acs.jnatprod.5b00258

1520-6025

Chin Piow Wong, Ari Seki, Kaori Horiguchi, Tomokazu Shoji, Takashi Arai, Alfarius Eko Nugroho, Yusuke Hirasawa, Fumiaki Sato, Toshio Kaneda, Hiroshi Morita,

Calcium signaling and nucleotide metabolism

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.