Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells.

Ting Li,Chung Hang Leung,Xin Chen,Jin Jian Lu,Xiuping Chen,Dik Lung Ma

doi:10.1038/srep37997

Abstract

AKT is the frequently overexpressed and constitutively active kinase within NSCLC cells and recognized as a promising target for NSCLC treatment. However, AKT inhibition relieves the feedback inhibition of upstream receptor tyrosine kinases (RTKs) that may weaken the efficiency of AKT inhibitors. Platycodin D (PD), isolated from widely-used traditional Chinese medicine Platycodonis Radix, is now found to remarkably enhance the anti-proliferative effect of AKT inhibitors. In this study, combinatorial activity of AKT inhibitor MK2206 and PD on cell proliferation, apoptosis and related signaling were disclosed. Long-term AKT inhibition induced up-regulation of RTKs, including EGFR and HER-2. Co-treatment of MK2206 with PD could abolish this feedback survival through decrease of EGFR, HER-2, and p-AKT, and profound inhibition of 4E-BP1, leading to an amplified anti-proliferative and apoptotic activity in NSCLC cells. Similarly, feedback activation in response to reduction of AKT expression by small interfering RNA (siRNA) was also blocked by PD and apoptotic effect was further enhanced. Thus, PD potentiated proliferative inhibition and apoptotic induction of both AKT inhibitor and siRNA. These findings also reveal the limitations of suppressing feedback-regulated pathways by monotherapy and establish a mechanistic rationale for a novel combination approach targeting AKT for the treatment of NSCLC.

Highlights

Lung cancer is the most common incident cancer and the chief cause of cancer death worldwide[1,2,3]
These results indicated that inhibition of AKT led to the relief of feedback regulation of EGFR and HER-2
Combined treatment of MK2206 and Platycodin D (PD) caused a further decrease of 4E-BP1 phosphorylation (Fig. 5A), abrogated the consequential survival signals, and enhanced the apoptotic response. These results suggested that PD decreased EGFR and HER-2 levels after treatment with MK2206 together, followed by the decrease of p-AKT, against Non-small cell lung cancer (NSCLC) cells irrespective their EGFR status

Summary

Introduction

Lung cancer is the most common incident cancer and the chief cause of cancer death worldwide[1,2,3]. We have observed that PD could decrease the level of EGFR, an all-important upstream RTK of AKT pathway and an attractive target for NSCLC therapy, indicating a potential inhibiton of negative feedback by AKT inhibitors This finding encourages us to combine an AKT inhibitor with PD. We developed a novel and potential combination approach that targeting AKT by co-treatment of MK2206 with PD for the treatment of NSCLC cells This combination revealed a fully abolishment of the feedback survival stimulated by the AKT inhibitor through the decrease of EGFR, HER-2, and p-AKT, as well as a profound inhibition of 4E-BP1, resulting in amplified anti-proliferative and apoptotic effect in NSCLC cells

Methods

Results

Conclusion