The ceramide pathway is involved in the survival, apoptosis and exosome functions of human multiple myeloma cells in vitro
The ceramide pathway is involved in the survival, apoptosis and exosome functions of human multiple myeloma cells in vitro
复制标题
神经酰胺途径参与人多发性骨髓瘤细胞体外的存活、凋亡和外泌体功能。
DOI：
10.1038/aps.2017.118
复制
发表时间：
2018-04-01
影响因子：
8.2
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Cheng, Qian;Li, Xin;Liu, Jing
多发性骨髓瘤（MM）以恶性浆细胞的克隆性增殖为特征，对传统治疗无效。已经表明，外泌体通过microRNA（miR）参与调节癌症的进展和转移。神经酰胺是一种鞘脂;外泌体分泌的神经酰胺途径已被证明会影响癌细胞的凋亡。但该途径在MM细胞功能、外泌体功能和miR调控中的作用仍不清楚。本研究发现，C6神经酰胺（一种外源性神经酰胺补充剂，1.25-40 μ mol/L）可剂量依赖性地抑制人MM OPM 2细胞系的增殖并促进其凋亡，这与caspase 3/9和PARP裂解增加有关。我们还发现，C6神经酰胺（5-20 μ mol/L）剂量依赖性地刺激外泌体分泌，并增加肿瘤抑制miR（miR 202，miR 16，miR 29 b和miR 15 a）的外泌体水平。值得注意的是，来自C6神经酰胺处理的OPM 2细胞的外来体可以影响受体OPM 2细胞的增殖和凋亡，这与肿瘤抑制性外来体miR增加相关。相反，GW 4869（一种神经酰胺抑制剂，5-20 μ mol/L）对MM功能、外泌体分泌和MM外泌体中miR水平的调节发挥相反的作用。然而，来自GW 4869处理的OPM 2细胞的外来体对这些miR和靶向的OPM 2细胞的存活没有影响。总之，我们的研究结果表明，神经酰胺途径调节MM生存，可能直接通过caspase途径和间接通过外泌体miR机制。
Multiple myeloma (MM) is characterized by the clonal proliferation of malignant plasma cells and refractoriness to traditional therapies. It has been shown that exosomes are involved in modulating the progression and the metastasis of cancers through microRNAs (miRs). Ceramide is a type of sphingolipid; the ceramide pathway of exosomal secretion has been shown to affect the apoptosis of cancer cells. But the role of this pathway in MM cell function, exosome function and miR regulation remains unknown. In this study, we showed that C6 ceramide (an exogenous ceramide supplement, 1.25-40 mu mol/L) dose-dependently inhibited the proliferation and promoted the apoptosis in human MM OPM2 cell line, which were associated with elevated caspase 3/9 and PARP cleavage. We also found that C6 ceramide (5-20 mu mol/L) dose-dependently stimulated exosome secretion and increased exosomal levels of tumor-suppressive miRs (miR 202, miR 16, miR 29b and miR 15a). Of note, exosomes from C6 ceramide-treated OPM2 cells could influence the proliferation and apoptosis of the recipient OPM2 cells, which correlated with increased tumor-suppressive exosomal miRs. In contrast, GW4869 (a ceramide inhibitor, 5-20 mu mol/L) exerted the opposite effects on the regulation of MM function, exosome secretion and miR levels in MM exosomes. However, exosomes from GW4869-treated OPM2 cells had no effect on these miRs and the survival of targeted OPM2 cells. Taken together, our findings reveal that the ceramide pathway modulates MM survival, probably directly via the caspase pathway and indirectly via exosomal miR mechanisms.