Cisplatin-Resistant Gastric Cancer Cells Promote the Chemoresistance of Cisplatin-Sensitive Cells via the Exosomal RPS3-Mediated PI3K-Akt-Cofilin-1 Signaling Axis.

Meng-Yao Sun,Hui Zhang,Bo Xu,Qiu-Xue Wu,Si Cai,Qing-Feng Tang,Wen-Lian Chen

doi:10.3389/fcell.2021.618899

Abstract

Cisplatin is an important agent in first-line chemotherapy against gastric cancer (GC). However, consequential drug resistance limits its effectiveness for the treatment of GC. In this study, a cisplatin resistant gastric cancer cell line SGC7901R was determined by LC-MS/MS with increased exosomal levels of RPS3 protein. SGC7901R cell-derived exosomes were readily taken up by cisplatin-sensitive SGC7901S cells, thus triggering off a phenotype of chemoresistance in the receptor cells. Subsequently, it was demonstrated that exosomal RPS3 was essential for inducing chemoresistance of receptor cells as shown by the acquisition of this phenotype in SGC7901S cells with enforced expression of RPS3. Further mechanism study demonstrated that cisplatin-resistant gastric cancer cell-derived exosomal RPS3 enhanced the chemoresistance of cisplatin-sensitive gastric cancer cells through the PI3K-Akt-cofilin-1 signaling pathway. All these findings demonstrated that cisplatin-resistant gastric cancer cells communicate with sensitive cells through the intercellular delivery of exosomal RPS3 and activation of the PI3K-Akt-cofilin-1 signaling pathway. Targeting exosomal RPS3 protein in cisplatin-resistant gastric cancer cells may thus be a promising strategy to overcome cisplatin resistance in gastric cancer.

Highlights

Gastric cancer ranks as the second most common malignant disease and the third leading cause of cancer-associated mortality in developing countries (Bray et al, 2018)
Using inductively coupled with mass spectrometry (ICP-MS) for determination of the changed intracellular cisplatin concentration in SGC-7901S cells, we found that, when 6.73 μg/mL cisplatin exposed to above cells for 48 h, the intracellular accumulation of cisplatin increased in SGC7901S cells pretreated with RPS3-silencing SGC7901R cell exosomes but reduced in SGC7901S cells pretreated with RPS3-overexpressing SGC7901R cell exosomes compared with the control exosomes (Figure 3F)
The results showed that pretreatment of exosomes derived from RPS3-silencing SGC7901R cells led to the reduction of SGC-7901S cells in G2/M phages compared with the control exosomes, while the exosomes derived from RPS3-overexpressing SGC7901R cells did the opposite effect (Figures 4A,B)

Summary

Introduction

Gastric cancer ranks as the second most common malignant disease and the third leading cause of cancer-associated mortality in developing countries (Bray et al, 2018). Chemotherapy is one of the principal therapeutic approaches used for the treatment of gastric cancer. Chemoresistance has been identified as a major problem in the process of cancer treatment. Cisplatin (DDP) is widely used as a front-line chemotherapeutic agent for gastric cancer; chemoresistance limits the effectiveness of chemotherapy and results in treatment failure in the majority of cases (Guo et al, 2015; Zhang and Fan, 2017). In the past few years, some reports have partly shown. Exosomal RPS3 Transmitted Chemoresistance the underlying mechanisms of cisplatin resistance in gastric cancer. The molecular mechanisms underlying cisplatin resistance remain to be further investigated

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Conclusion