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

Abstract

Background: 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. Exosomes which are loaded with proteins, lipids and RNAs, have been proven to transfer malignant phenotype. This study aims to explore the role and mechanism of exosomal RPS3 protein in transmitting a chemoresistance phenotype from cisplatin resistant to cisplatin sensitive gastric cancer cells.Methods: A cisplatin resistant gastric cancer cell line SGC7901R was established by continuously grafting SGC7901S cells into cisplatin-containing culture medium. Exosomes from SGC7901R and SGC7901S were obtained and confirmed through ultracentrifuge and Nano Analyzer. By LC-MS/MS analysis methods, we detected the differentially expressed proteins in SGC7901R cells exosomes and SGC7901S cells exosomes. Western blotting was used to verify the differential expression of exosomal RPS3 between cisplatin resistant and parental cell lines. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of exosomal RPS3 protein in GC.Results: 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 cells-derived exosomal RPS3 enhanced the chemoresistance of cisplatin‑sensitive gastric cancer cells through the PI3K-Akt-cofilin-1 signaling pathway.Conclusion: 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.

Exosome-derived noncoding RNAs in gastric cancer: functions and clinical applications

“…Furthermore, exosome-mediated molecular transfers decreased the accumulation of loaded ncRNA in nontarget tissues, therefore reducing off-target toxicity [142]. Recently, Sun and coworkers found that chemoresistant GC cells promoted the chemoresistance of chemosensitive GC cells via exosome-mediated substance exchange [143].Inhibiting this substance exchange mediated by exosomes or associated molecules may exert an antitumor role in GC. In 2018, Wand and colleagues found that transferring exosomes carrying anti-miR-214 into GC cells reversed cisplatin resistance [144].…”

The role and application of small extracellular vesicles in gastric cancer

“…Platinum drugs are one of the most common chemotherapy drugs used for GC, and cisplatin and oxaliplatin have been included as first-line treatments. Cisplatin-resistant gastric cancer cells communicate with sensitive cells through RPS3 in sEVs and activation of the PI3K-Akt-cofilin-1 signalling pathway [ 98 ]. Zheng et al [ 99 ] found that M2-polarized macrophages can promote resistance to cisplatin in GC cells.…”

Exosomes and Exosomal circRNAs: The Rising Stars in the Progression, Diagnosis and Prognosis of Gastric Cancer

“…Drug resistance is a major clinical problem, which partially leads to poor survival rate of GC patients. 31 However, drug resistance limits its effectiveness for the treatment of GC. Sun et al demonstrated that cisplatin-resistant GC cells derived exosomes enhanced the chemoresistance of cisplatin-sensitive GC cells through exosomal RPS3 mediated PI3K/Akt/cofilin-1 pathway.…”

“…Sun et al demonstrated that cisplatin-resistant GC cells derived exosomes enhanced the chemoresistance of cisplatin-sensitive GC cells through exosomal RPS3 mediated PI3K/Akt/cofilin-1 pathway. 31 Therefore, targeting exosomal RPS3 in cisplatin resistant GC cells may be a promising strategy to overcome cisplatin resistance. The findings of Zheng et al suggested that exosomal transfer of cancer-associated macrophages derived miR-21 mediates cisplatin resistance in GC.…”