Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer |
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Authors: | Runbi Ji Bin Zhang Xu Zhang Jianguo Xue Xiao Yuan Yongmin Yan Mei Wang Wei Zhu Hui Qian Wenrong Xu |
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Institution: | 1.Jiangsu Key Laboratory of Medical Science and Laboratory Medicine; School of Medicine; Jiangsu University; Zhenjiang, Jiangsu, PR China;2.The Affiliated Hospital; Jiangsu University; Zhenjiang, Jiangsu, PR China |
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Abstract: | Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer. |
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Keywords: | drug resistance exosomes mesenchymal stem cells gastric cancer |
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