Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene.
Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene.
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DOI：
10.18632/oncotarget.9105
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发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Kaneda Y
中科院分区：
文献类型：
--
作者：
Jiang Y;Saga K;Miyamoto Y;Kaneda Y
由于耐药性的出现是目前多发性骨髓瘤（MM）治疗的主要限制，因此有必要不断开发新的抗癌策略。在这里，使用灭活的仙台病毒（日本血凝病毒; HVJ）包膜（HVJ-E），我们发现，通过病毒-细胞融合增加细胞质Ca2+显著诱导针对人MM细胞的凋亡，但不诱导来自健康供体的外周血单核细胞的凋亡。HVJ-E的F蛋白与MM细胞的相互作用通过诱导内质网的Ca~（2+）流出而不是胞外区的Ca~（2+）内流来增加MM细胞内Ca~（2+）水平。胞浆Ca~（2+）水平升高可诱导SMAD1/5/8磷酸化并转位入核，SMAD1/5/8和SMAD4复合物抑制c-Myc转录。同时，HVJ-E降低c-Myc的S62磷酸化，促进c-Myc蛋白降解。因此，HVJ-E诱导的MM细胞死亡是由于c-Myc蛋白不稳定和c-Myc转录下调导致的c-Myc抑制。该研究表明HVJ-E将成为MM治疗的有前途的工具。
Because the emergence of drug resistance is a major limitation of current treatments for multiple myeloma (MM), it is necessary to continuously develop novel anticancer strategies. Here, using an inactivated Sendai virus (Hemagglutinating Virus of Japan; HVJ) envelope (HVJ-E), we discovered that increase of cytoplasmic Ca2+ by virus-cell fusion significantly induced apoptosis against human MM cells but not peripheral blood mononuclear cells from healthy donors. Interaction of F protein of HVJ-E with MM cells increased intracellular Ca2+ level of MMs by the induction of Ca2+ efflux from endoplasmic reticulum but not influx from extracellular region. The elevation of the Ca2+ cytoplasmic level induced SMAD1/5/8 phosphorylation and translocation into the nucleus, and SMAD1/5/8 and SMAD4 complex suppressed c-Myc transcription. Meanwhile, HVJ-E decreases S62 phosphorylation of c-Myc and promotes c-Myc protein degradation. Thus, HVJ-E-induced cell death of MM resulted from suppression of c-Myc by both destabilization of c-Myc protein and downregulation of c-Myc transcription. This study indicates that HVJ-E will be a promising tool for MM therapy.
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