Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells.

Huahong Yang,Xingkai Liu,Xinxin Ci,Xiaoye Fan,Liping Peng,Yun Gao

doi:10.3389/fonc.2019.00769

Huahong Yang, Xingkai Liu + Show 4 more

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https://doi.org/10.3389/fonc.2019.00769

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Abstract

AMPK-mediated autophagy and Akt/mTOR pathways play important roles in current cancer treatments. Oridonin (Ori), an ent-kaurane diterpenoid isolated from Isodon rubescens, exerts extensive anti-tumor potential and controversial effects on autophagy. In this study, we investigated the effect of Ori on the autophagy, apoptosis, and AMPK/Akt/mTOR pathways and determined whether Ori was related to the increased cisplatin sensitivity observed in A549 cells. First, we found that Ori suppressed Akt/mTOR, Bcl2 and autophagy flux with enhanced levels of Atg3, P62, and LC3II, which was also shown as the accumulation of autophagosomes. AMPK and pro-apoptotic proteins (caspase3, Bax, and PARP) were activated in Ori-treated cells. With the pretreatment of compound c (AMPK inhibitor), the activation of autophagosomes, apoptosis and the inhibition of Akt/mTOR pathways induced by Ori were all reversed. The Ori-activated apoptosis-related markers mentioned previously and the cell-killing effect were restrained by 3-MA (inhibitor of autophagosomes) treatment. Therefore, we hypothesized that the Ori-induced pro-apoptotic effect was mediated by AMPK/Akt/mTOR-dependent accumulation of impaired autophagosomes. Furthermore, Ori could increase the sensitivity of cisplatin through its increased cell-killing, autophagy-suppressing and apoptosis-inducing activities. In addition to sensitizing cisplatin, Ori also alleviated cisplatin-induced acute renal injury in vivo, manifested as depleted BUN, CRE, kidney index, and weight loss compared to the cisplatin group. In summary, apart from its protective effect on cisplatin-induced nephrotoxicity, Ori enhanced cisplatin sensitivity via its pro-apoptotic activity mediated by AMPK/Akt/mTOR-dependent autophagosome activation, which may be a potential therapeutic target for non-small cell lung cancer.

Highlights

With the highest morbidity and mortality, lung cancer is a serious disease affecting public health [1]
We aimed to explore the role and correlation of autophagy, apoptosis and AMPK/Akt/mammalian target of rapamycin (mTOR) induced by Ori in cisplatintreated A549 cells, and provided a new therapeutic target against carcinogenesis and cisplatin resistance in lung cancer
As autophagy and related pathways play a vital role in cancer treatment, we investigated whether Ori had the corresponding regulatory effects in A549 cells

Summary

Introduction

With the highest morbidity and mortality, lung cancer is a serious disease affecting public health [1]. In terms of biological characteristics, lung cancer is divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 80–85% of all lung cancers with poor prognosis [2]. Cisplatin remains the first-line chemotherapy drug for NSCLC, despite the occurrence of cisplatin resistance. Numerous studies show that some cytotoxic agents can reverse the cisplatin resistance of NSCLC patients, the survival rates are still low [3,4,5]. There is an urgent need to develop new effective adjuvant therapies against NSCLC

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