Platycodin-D Induced Autophagy in Non-Small Cell Lung Cancer Cells via PI3K/Akt/mTOR and MAPK Signaling Pathways.

• Type of Material: Article
• Authors: Ruolin Zhao, Nanjing University; Meijuan Chen, Nanjing University; Zequn Jiang, Nanjing University; Fengming Zhao, Nanjing University; Beili Xi, Nanjing University; Xu Zhang, Nanjing University; Haian Fu, Emory University; Kunfu Zhou, Nanjing University
• Language: English
• Date: 2015
• Publisher: Ivyspring International Publisher
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Ivyspring International Publisher
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7150/jca.11291
• Title of Journal or Parent Work: Journal of Cancer
• ISSN: 1837-9664
• Volume: 6
• Issue: 7
• Start Page: 623
• End Page: 631
• Grant/Funding Information: U.S. National Institutes of Health grants P01 CA116676 and the Natural Science Foundation of Jiangsu Province (BK20131415).; People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013/ under REA grant agreement n° PIR SES-GA-2013-612589"; Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
• Keywords: autophagy; MAPK signaling pathways; Platycodin-D; non-small cell lung cancer; PI3K/Akt/mTOR
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Platycodin-D (PD) is an effective triterpene saponin extracted from the root of Platycodon grandiflorum which has been used clinically to treat pulmonary diseases in traditional Chinese medicine. Recently, it has been reported that PD has anti-tumor effects in various cancer models through the induction of apoptosis. However, whether PD induces autophagy in both cell lines and its molecular mechanisms have not been elucidated. Here, our present study confirmed that PD induced autophagy in both NCI-H460 and A549 cells via up-regulating the expression levels of Atg-3, Atg-7 and Beclin-1. Meanwhile, PD contributed to the up-regulation of LC3-II at both protein and mRNA levels. Further detection of the PI3K/Akt/mTOR signaling pathway compared to LY294002 (PI3K kinase inhibitor), RAP (mTOR kinase inhibitor) and insulin (an activator of PI3K/Akt/mTOR signaling pathway) showed that PD induced autophagy through inhibiting the pathway at p-Akt (Ser473), p-p70S6K (Thr389) and p-4EBP1 (Thr37/46) in both cell lines. Moreover, the examination of MAPK signaling pathway showed that PD treatment increased the phosphorylation of JNK and p38 MAPK, while decreased the phosphorylation of Erk1/2 in both cell lines. Additionally, the effects assessed with a panel of pharmacologic inhibitors, including U0126 (Erk1/2 kinase inhibitor), SP600125 (JNK kinase inhibitor) and SB203580 (p38 MAPK kinase inhibitor) suggested that the activation of JNK and p38 MAPK participated in PD-induced autophagy. Taken together, these findings suggested that PD induced autophagy in NCI-H460 and A549 cells through inhibiting PI3K/Akt/mTOR signaling pathway and activating JNK and p38 MAPK signaling pathways. Therefore, PD may be an alternative compound for NSCLC therapy.