ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect in human stomach adenocarcinoma

Na Li,Kaping Lee,Jieyao Li,Liping Wang,Xiaohan Yao,Zhuoyu Gu,Dongli Yue,Qian Long,Yanfen Liu,Shuangning Yang,Yixin Li

doi:10.1038/s41419-020-03107-3

Abstract

Currently, only a few available targeted drugs are considered to be effective in stomach adenocarcinoma (STAD) treatment. The PARP inhibitor olaparib is a molecularly targeted drug that continues to be investigated in BRCA-mutated tumors. However, in tumors without BRCA gene mutations, particularly in STAD, the effect and molecular mechanism of olaparib are unclear, which largely restricts the use of olaparib in STAD treatment. In this study, the in vitro results showed that olaparib specifically inhibited cell growth and migration, exerting antitumor effect in STAD cell lines. In addition, a ClC-3/SGK1 regulatory axis was identified and validated in STAD cells. We then found that the down-regulation of ClC-3/SGK1 axis attenuated olaparib-induced cell growth and migration inhibition. On the contrary, the up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced cell growth and migration inhibition, and the enhancement effect could be attenuated by SGK1 knockdown. Consistently, the whole-cell recorded chloride current activated by olaparib presented the same variation trend. Next, the clinical data showed that ClC-3 and SGK1 were highly expressed in human STAD tissues and positively correlated (r = 0.276, P = 0.009). Furthermore, high protein expression of both ClC-3 (P = 0.030) and SGK1 (P = 0.006) was associated with poor survival rate in STAD patients, and positive correlations between ClC-3/SGK1 and their downstream molecules in STAD tissues were demonstrated via the GEPIA datasets. Finally, our results suggested that olaparib inhibited the PI3K/AKT pathway in STAD cells, and up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced PI3K/AKT pathway inhibition. The animal experiments indicated that olaparib also exerted antitumor effect in vivo. Altogether, our findings illustrate that olaparib exerts antitumor effect in human STAD, and ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect. Up-regulation of the ClC-3/SGK1 axis may provide promising therapeutic potential for the clinical application of olaparib in STAD treatment.

Highlights

Gastric cancer (GC) is one of the most common malignant tumors worldwide
In the clone formation assay, we found that the formation number of cell clones was decreased in stomach adenocarcinoma (STAD) cells treated with olaparib, and the decreased colony number was exhibited in a dosedependent manner (Fig. 1B, C, S1a)
These findings proved that olaparib exerted antitumor effect in STAD cell lines

Summary

Introduction

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Official journal of the Cell Death Differentiation Association. Olaparib has been effectively used as an anticancer agent and is mainly evaluated in BRCA-associated tumors[4]. The potential antitumor mechanisms of olaparib are mostly involved in BRCA-mutated tumors, including transcriptional regulation, cell apoptosis promotion, and DNA repair abnormality[7,8,9]. The role of olaparib and its specific molecular mechanism in tumors without BRCA gene mutations, especially in digestive system tumors, has not been fully elucidated. The action mechanism and clinical application value of olaparib in STAD remain unclear, which is of importance to the current targeted therapy of STAD patients

Objectives

Methods

Results

Conclusion