Journal
CELL CYCLE
Volume 14, Issue 15, Pages 2473-2483Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1005530
Keywords
drug resistance; exosomes; mesenchymal stem cells; gastric cancer
Categories
Funding
- Major Research Plan of National Natural Science Foundation of China [91129718]
- National Natural Science Foundation of China [81272481]
- Jiangsu Province's Project of Scientific and Technological Innovation and Achievements Transformation [BL2012055]
- Jiangsu Province for Outstanding Sci-tech Innovation Team in Colleges and Universities [SJK2013-10]
- Jiangsu Province's Outstanding Medical Academic Leader and Sci-tech Innovation Team Program [LJ201117]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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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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