Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells
Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells
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DOI：
10.1038/cdd.2009.115
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发表时间：
2010-01-01
影响因子：
12.4
通讯作者：
Romano, M. F.
中科院分区：
文献类型：
--
作者：
Romano, S.;D'Angelillo, A.;Romano, M. F.
fk506结合蛋白51 （FKBP51）是一种具有异构酶活性的亲免疫蛋白，在细胞中具有重要的生物学功能。它最近参与了恶性黑色素瘤的细胞凋亡抵抗。本研究的目的是探讨FKBP51在控制恶性黑色素瘤对电离辐射（Rx）反应中的可能作用。与非沉默细胞相比，fkbp51沉默细胞在辐照后表现出较低的克隆生成潜能。Rx后，我们观察到fkbp51沉默细胞的凋亡和非沉默细胞的自噬。FKBP51控制的辐射耐药机制涉及NF-kappa B。FKBP51是激活rx诱导的NF-kappa B所必需的，而NF-kappa B反过来通过刺激x连锁的凋亡蛋白抑制剂和促进自噬介导的Bax降解来抑制细胞凋亡。在肿瘤-异种移植小鼠模型中，用FKBP51-siRNA对肿瘤进行体内预处理，在照射后引起大量细胞凋亡。10例正常皮肤样本和80例恶性皮肤黑色素瘤的免疫组化分析显示，FKBP51是黑色素细胞恶性的标志物，与垂直生长期和病变厚度相关。最后，我们提供证据表明FKBP51靶向放射致敏癌症干细胞/起始细胞。总之，我们的研究确定了针对恶性黑色素瘤的放射增敏治疗策略的可能分子靶点。细胞死亡和分化（2010）17,145-157；doi: 10.1038 / cdd.2009.115;2009年8月21日在线发布
FK506-binding protein 51 (FKBP51) is an immunophilin with isomerase activity, which performs important biological functions in the cell. It has recently been involved in the apoptosis resistance of malignant melanoma. The aim of this study was to investigate the possible role of FKBP51 in the control of response to ionizing radiation (Rx) in malignant melanoma. FKBP51-silenced cells showed reduced clonogenic potential after irradiation compared with non-silenced cells. After Rx, we observed apoptosis in FKBP51-silenced cells and autophagy in non-silenced cells. The FKBP51-controlled radioresistance mechanism involves NF-kappa B. FKBP51 was required for the activation of Rx-induced NF-kappa B, which in turn inhibited apoptosis by stimulating X-linked inhibitor of apoptosis protein and promoting authophagy-mediated Bax degradation. Using a tumor-xenograft mouse model, the in vivo pretreatment of tumors with FKBP51-siRNA provoked massive apoptosis after irradiation. Immunohistochemical analysis of 10 normal skin samples and 80 malignant cutaneous melanomas showed that FKBP51 is a marker of melanocyte malignancy, correlating with vertical growth phase and lesion thickness. Finally, we provide evidence that FKBP51 targeting radiosensitizes cancer stem/initiating cells. In conclusion, our study identifies a possible molecular target for radiosensitizing therapeutic strategies against malignant melanoma. Cell Death and Differentiation (2010) 17, 145-157; doi:10.1038/cdd.2009.115; published online 21 August 2009