C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway
- J Transl Med. 2020 Aug 3;18(1):298. doi: 10.1186/s12967-020-02468-9.
- 1. Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
- 2. Department of Physiology and Cell Biology, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
- 3. Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, 45435, USA.
- 4. Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. [email protected].
- 5. Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, 45435, USA. [email protected].
- 6. Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China. [email protected].
Background: The increased bone marrow angiogenesis is involved in the progression of multiple myeloma (MM) with the underlying mechanism poorly understood. Cancer-released exosomes could play an important role in the pathological angiogenesis through exosomal MicroRNAs (miRs) delivery. It is reported that miR-29b played an important role in regulating the tumor angiogenesis.
Methods: In this study, we explored the role of C6-ceramide (C6-cer, a Ceramide pathway activator) in the angiogenic effect of MM exosomes and its potential mechanism. MM cells (OPM2 and RPMI-8226) treated with C6-cer were studied for its effects on the endothelial cell (EC) functions.
Results: Our results showed that exosomes released from MM cells treated by C6-cer (ExoC6-cer) significantly inhibited the proliferation, migration and tube formation of ECs. For mechanism studies, we found that the level of miR-29b was increased in ECs treated by ExoC6-cer, while mRNA and protein expressions of Akt3, PI3K and VEGFA were decreased in ECs, indicating the involvement of Akt pathway. Furthermore, downregulation of miR-29b by inhibitor administration could prevent the ExoC6-cer-induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA.
Conclusions: Collectively, our data suggest that ExoC6-cer-mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.