BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells.
BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells.
复制标题
BMPR2 抑制通过人软骨肉瘤细胞中 XIAP 的不稳定诱导细胞凋亡和自噬
DOI：
10.1038/cddis.2014.540
复制
发表时间：
2014-12-11
影响因子：
9
通讯作者：
Sun K
中科院分区：
文献类型：
--
作者：
Jiao G;Guo W;Ren T;Lu Q;Sun Y;Liang W;Ren C;Yang K;Sun K
骨形态发生蛋白（BMPs）是一种多功能蛋白质，其受体（BMPRs）在信号传导过程中起着重要作用。然而，它们在癌症中的功能有点不一致。研究表明，在去分化软骨肉瘤中，骨形态发生蛋白受体2（BMPR 2）的表达比传统软骨肉瘤更为普遍。在这里，我们发现BMPR 2抑制诱导软骨肉瘤细胞凋亡和自噬。我们发现BMPR 2的表达与软骨肉瘤的临床病理特征相关，并可预测治疗结果。小干扰RNA敲低BMPR 2导致软骨肉瘤细胞生长抑制。沉默BMPR 2可促进软骨肉瘤细胞G2/M期阻滞，通过抑制X连锁凋亡抑制蛋白（XIAP）通过caspase-3依赖的途径诱导软骨肉瘤细胞凋亡，通过XIAP-Mdm 2-p53途径诱导软骨肉瘤细胞自噬。BMPR 2小干扰RNA（siBMPR 2）诱导的自噬抑制使软骨肉瘤细胞对siBMPR 2诱导的凋亡性细胞死亡敏感，表明自噬在siBMPR 2诱导的凋亡性细胞死亡的背景下对软骨肉瘤细胞具有保护作用。小鼠体内致瘤性试验表明，抑制BMPR 2可降低肿瘤生长。综上所述，我们的研究结果表明，BMPR 2在软骨肉瘤的肿瘤发生中具有重要作用，并可能是软骨肉瘤的重要预后标志物。BMPR 2抑制可能最终为软骨肉瘤治疗提供有希望的疗法。
Bone morphogenetic proteins (BMPs) are multifunctional proteins, and their receptors (BMPRs) have crucial roles in the process of signaling. However, their function in cancer is somewhat inconsistent. It has been demonstrated that more prevalent expression of bone morphogenetic protein receptor 2 (BMPR2) has been detected in dedifferentiated chondrosarcomas than conventional chondrosarcomas. Here, we find that BMPR2 inhibition induces apoptosis and autophagy of chondrosarcoma. We found that BMPR2 expression was correlated with the clinicopathological features of chondrosarcomas, and could predict the treatment outcome. Knockdown of BMPR2 by small interfering RNA results in growth inhibition in chondrosarcoma cells. Silencing BMPR2 promoted G2/M cell cycle arrest, induced chondrosarcoma cell apoptosis through caspase-3-dependent pathway via repression of X-linked inhibitor of apoptosis protein (XIAP) and induced autophagy of chondrosarcoma cells via XIAP-Mdm2-p53 pathway. Inhibition of autophagy induced by BMPR2 small interfering RNA (siBMPR2) sensitized chondrosarcoma cells to siBMPR2-induced apoptotic cell death, suggesting that autophagy has a protective role for chondrosarcoma cells in context of siBMPR2-induced apoptotic cell death. In vivo tumorigenicity assay in mice indicated that inhibition of BMPR2 reduced tumor growth. Taken together, our results suggest that BMPR2 has a significant role in the tumorigenesis of chondrosarcoma, and could be an important prognostic marker for chondrosarcoma. BMPR2 inhibition could eventually provide a promising therapy for chondrosarcoma treatment.