RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling.
RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling.
复制标题
RPS3 通过靶向 Cyto C/Ca2 /MICU1 依赖的线粒体信号传导来调节黑色素瘤细胞的生长和凋亡。
DOI：
10.18632/oncotarget.4868
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发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Deng W
中科院分区：
文献类型：
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作者：
Tian Y;Qin L;Qiu H;Shi D;Sun R;Li W;Liu T;Wang J;Xu T;Guo W;Kang T;Huang W;Wang G;Deng W
黑色素瘤是最具侵袭性和致命性的癌症之一。因此，迫切需要发现和鉴定新的治疗靶点。在这项研究中，我们证明了核糖体蛋白S3（RPS 3）是一个潜在的目标参与黑色素瘤的生长。通过siRNA敲低RPS 3抑制黑色素瘤细胞的生长并诱导细胞凋亡。进一步的机制研究表明，RPS 3在黑色素瘤细胞中的敲低触发了线粒体细胞色素C（Cyto C）的释放，增加了BID在线粒体膜上的定位和促凋亡蛋白的切割（PARP，半胱天冬酶-3和-9），促进线粒体通透性转换孔的开放和钙离子（Ca 2+）向线粒体的涌入，降低了钙门控细胞MICU 1的表达及其在线粒体上的定位。我们还发现RPS 3的敲低显著抑制了黑素瘤异种移植小鼠模型中的肿瘤生长。此外，我们发现RPS 3在黑色素瘤细胞系和黑色素瘤肿瘤组织中高度表达，并且RPS 3的过表达与黑色素瘤患者的不良预后相关。因此，我们的研究结果表明，RPS 3调节黑色素瘤的生长，通过调节细胞色素C/Ca 2 +/MICU 1依赖的线粒体信号转导，并表明，RPS 3是一个潜在的治疗黑色素瘤治疗的目标。
Melanoma is one of the most aggressive and lethal cancers. Discovery and identification of novel therapeutic targets is urgently needed. In this study, we demonstrated that ribosomal protein S3 (RPS3) was a potential target involved in melanoma growth. Knockdown of RPS3 by siRNA suppressed cell growth and induced apoptosis in melanoma cells. Further mechanism studies showed that RPS3 knockdown in melanoma cells triggered the release of cytochrome C (Cyto C) from mitochondrial, increased the location of BID on mitochondrial membrane and the cleavage of the pro-apoptotic proteins (PARP, caspase-3 and -9), promoted the opening of mitochondrial permeability transition pore and the flooding of calcium ions (Ca2+) into the mitochondrial, and decreased the expression of the Ca2+ gatekeeper MICU1 and its location on the mitochondrial. We also found that knockdown of RPS3 significantly inhibited tumor growth in a melanoma xenograft mouse model. Furthermore, we showed that RPS3 was highly expressed in melanoma cell lines and melanoma tumor tissues, and overexpression of RPS3 was associated with the poor prognosis of melanoma patients. Our results therefore demonstrate that RPS3 regulates melanoma growth through the modulation of the Cyto C/Ca2+/MICU1 dependent mitochondrial signaling and suggest that RPS3 is a potential therapeutic target for melanoma treatment.