Cord blood stem cell-mediated induction of apoptosis in glioma downregulates X-linked inhibitor of apoptosis protein (XIAP).
Cord blood stem cell-mediated induction of apoptosis in glioma downregulates X-linked inhibitor of apoptosis protein (XIAP).
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DOI：
10.1371/journal.pone.0011813
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发表时间：
2010-07-28
期刊：
影响因子：
3.7
通讯作者：
Rao JS
中科院分区：
文献类型：
--
作者：
Dasari VR;Velpula KK;Kaur K;Fassett D;Klopfenstein JD;Dinh DH;Gujrati M;Rao JS
XIAP（X-linked inhibitor of apoptosis protein）是凋亡抑制蛋白家族中最重要的成员之一。XIAP在各种恶性肿瘤中上调，包括人胶质母细胞瘤。它促进恶性细胞的侵袭、转移、生长和存活。我们假设，下调XIAP的人脐带血间充质干细胞（hUCBSC）在胶质瘤细胞将导致他们经历凋亡死亡。我们观察了hUCBSC对两种恶性胶质瘤细胞系（SNB 19和U251）和两种胶质瘤异种移植细胞系（4910和5310）的作用。在胶质瘤细胞与hUCBSC的共培养中，胶质瘤细胞的增殖被显著抑制。这与胶质瘤细胞的细胞毒性增加有关，这导致胶质瘤细胞死亡。干细胞诱导胶质瘤细胞凋亡，通过TUNEL测定、流式细胞仪分析和免疫印迹进行评价。细胞凋亡的诱导与hUCBSC的共培养物中XIAP的抑制相关。通过用shRNA处理胶质瘤细胞以下调XIAP（siXIAP）获得了类似的结果。XIAP的下调导致caspase-3和caspase-9的激活，从而触发胶质瘤细胞的凋亡。细胞凋亡的特征在于线粒体膜电位的丧失和线粒体凋亡蛋白Bax和Bad的上调。胶质瘤细胞的细胞死亡的标志是Akt和磷酸化Akt分子的下调。我们在体内条件下在注射U251和5310的裸小鼠大脑中观察到类似的结果，这些小鼠大脑用hUCBSC处理。在体内条件下，发现Smac/DIABLO共定位于细胞核中，表明hUCBSC诱导的凋亡是通过抑制XIAP和激活Smac/DIABLO介导的。我们的研究结果表明，下调XIAP通过hUCBSC处理诱导凋亡，这导致胶质瘤细胞和异种移植细胞的死亡。本研究证明了XIAP和hUCBSC治疗恶性胶质瘤的治疗潜力。
XIAP (X-linked inhibitor of apoptosis protein) is one of the most important members of the apoptosis inhibitor family. XIAP is upregulated in various malignancies, including human glioblastoma. It promotes invasion, metastasis, growth and survival of malignant cells. We hypothesized that downregulation of XIAP by human umbilical cord blood mesenchymal stem cells (hUCBSC) in glioma cells would cause them to undergo apoptotic death. We observed the effect of hUCBSC on two malignant glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310). In co-cultures of glioma cells with hUCBSC, proliferation of glioma cells was significantly inhibited. This is associated with increased cytotoxicity of glioma cells, which led to glioma cell death. Stem cells induced apoptosis in glioma cells, which was evaluated by TUNEL assay, FACS analyses and immunoblotting. The induction of apoptosis is associated with inhibition of XIAP in co-cultures of hUCBSC. Similar results were obtained by the treatment of glioma cells with shRNA to downregulate XIAP (siXIAP). Downregulation of XIAP resulted in activation of caspase-3 and caspase-9 to trigger apoptosis in glioma cells. Apoptosis is characterized by the loss of mitochondrial membrane potential and upregulation of mitochondrial apoptotic proteins Bax and Bad. Cell death of glioma cells was marked by downregulation of Akt and phospho-Akt molecules. We observed similar results under in vivo conditions in U251- and 5310-injected nude mice brains, which were treated with hUCBSC. Under in vivo conditions, Smac/DIABLO was found to be colocalized in the nucleus, showing that hUCBSC induced apoptosis is mediated by inhibition of XIAP and activation of Smac/DIABLO. Our results indicate that downregulation of XIAP by hUCBSC treatment induces apoptosis, which led to the death of the glioma cells and xenograft cells. This study demonstrates the therapeutic potential of XIAP and hUCBSC to treat malignant gliomas.
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影响因子：
3.7
作者：
Dasari VR;Kaur K;Velpula KK;Gujrati M;Fassett D;Klopfenstein JD;Dinh DH;Rao JS
通讯作者：
Rao JS
影响因子：
82.9
作者：
Fulda, S;Wick, W;Debatin, KM
通讯作者：
Debatin, KM
影响因子：
4.2
作者：
Dasari, Venkata Ramesh;Spomar, Daniel G.;Dinh, Dzung H.
通讯作者：
Dinh, Dzung H.
影响因子：
5.2
作者：
Jeong, JA;Hong, SH;Kim, H
通讯作者：
Kim, H
影响因子：
11.4
作者：
Deveraux, QL;Leo, E;Reed, JC
通讯作者：
Reed, JC