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

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.

MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMGB1-Mediated Autophagy

“…In NSCLC, the anti-tumor drug platycodin-D (PD) has been shown to induce autophagy in A549 cells by inhibiting the PI3K/Akt/mTOR and activating the JNK and p38 MAPK signaling pathways [35]. In this study, we found that inhibition of starvation-induced autophagy by miR-142-3p overexpression or HMGB1 knockdown in A549 cells was accompanied by increased PI3K, Akt, and mTOR phosphorylation ( P <0.01, Fig.…”

“…The PI3K/Akt/mTOR pathway has been implicated in drug-induced autophagy in cancer cells [33-35]. In NSCLC, the anti-tumor drug platycodin-D (PD) has been shown to induce autophagy in A549 cells by inhibiting the PI3K/Akt/mTOR and activating the JNK and p38 MAPK signaling pathways [35].…”

Chemomics‐Integrated Proteomics Analysis of Jie‐Geng‐Tang to Ameliorate Lipopolysaccharide‐Induced Acute Lung Injury in Mice

“…Most active compounds in PG and GU are pentacyclic triterpenoids; this type of compound inhibits IKK-mediated activation of the NF- κ B pathway [20]. Platycodin D was reported to modulate PI3K/Akt by inhibiting p-Akt (Ser473) [21].…”

Platycodin D exerts anti-tumor efficacy in H22 tumor-bearing mice via improving immune function and inducing apoptosis

“…Platycodin D (PD, Fig. 1), the major active constituent of P. grandiflorum, has received more and more attention due to its pharmaceutical effects, including anti-inflammation (Chung et al, 2008;Zhang et al, 2015), anti-obesity (Zhao et al, 2006), anti-atherosclerosis (Wu et al, 2012), hepatoprotective Li et al, 2015a), and anti-tumor (Luan et al, 2014;Zhao et al, 2015) effects. It is worth mentioning that PD exerts remarkable anti-cancer effects on different kinds of cancer cell lines, including HepG2, MDA-MB-231, U937, K562, PC3, and MCF-7, with main molecular mechanisms such as promoting apoptosis and inhibiting migration and invasion (Tang et al, 2014;Li et al, 2014;Yu and Kim, 2010;Shin et al, 2009;Kim et al, 2008).…”