Sun Meng-Yao, Xu Bo, Wu Qiu-Xue, Chen Wen-Lian, Cai Si, Zhang Hui, Tang Qing-Feng
Department of Clinical Laboratory and Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Cell Dev Biol. 2021 Feb 11;9:618899. doi: 10.3389/fcell.2021.618899. eCollection 2021.
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.
顺铂是一线治疗胃癌（GC）的重要药物。然而，随之而来的耐药性限制了其治疗GC的效果。在本研究中，通过液相色谱-串联质谱法（LC-MS/MS）确定了一种顺铂耐药胃癌细胞系SGC7901R，其外泌体中RPS3蛋白水平升高。SGC7901R细胞来源的外泌体很容易被顺铂敏感的SGC7901S细胞摄取，从而在受体细胞中引发化疗耐药表型。随后，研究表明外泌体RPS3对于诱导受体细胞的化疗耐药至关重要，这在过表达RPS3的SGC7901S细胞中获得该表型得到了证实。进一步的机制研究表明，顺铂耐药胃癌细胞来源的外泌体RPS3通过PI3K-Akt-丝切蛋白-1信号通路增强了顺铂敏感胃癌细胞的化疗耐药性。所有这些发现表明，顺铂耐药胃癌细胞通过细胞间传递外泌体RPS3和激活PI3K-Akt-丝切蛋白-1信号通路与敏感细胞进行通讯。因此，靶向顺铂耐药胃癌细胞中的外泌体RPS3蛋白可能是克服胃癌顺铂耐药的一种有前景的策略。
