ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis.
ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis.
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ROS-p53-亲环蛋白-D信号介导盐霉素诱导的神经胶质瘤细胞坏死
DOI：
10.1186/s13046-015-0174-1
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发表时间：
2015-05-30
期刊：
影响因子：
--
通讯作者：
Zhang SM
中科院分区：
文献类型：
--
作者：
Qin LS;Jia PF;Zhang ZQ;Zhang SM
原发性多形性胶质母细胞瘤（GBM）是星形细胞肿瘤的最恶性形式，平均存活约12-14个月。寻找新的和更有效的化学药物治疗这种疾病是迫切的。盐霉素诱导广泛的抗癌作用;然而，其在GBM中的作用和潜在机制尚不清楚。在这里，我们发现，盐霉素诱导培养的胶质瘤细胞凋亡和坏死，坏死发挥了重要作用，贡献盐霉素的细胞毒性。盐霉素诱导p53易位到线粒体，在那里它与亲环素D（CyPD）形成复合物。这种复合是线粒体通透性转换孔（mPTP）开放和随后的程序性坏死所必需的。通过siRNA介导的耗竭或药理学抑制剂（环孢菌素A和sanglifehrin A）阻断Cyp-D可显著抑制盐霉素诱导的胶质瘤细胞坏死。同时，p53稳定敲低可减轻盐霉素诱导的胶质瘤细胞坏死。活性氧（Reactive oxygen species，ROS）的产生是盐霉素诱导的p53线粒体易位、mPTP开放和坏死所必需的，抗氧化剂N-乙酰半胱氨酸（n-acetylcysteine，NAC）和吡咯烷二硫代氨基甲酸酯（pyrrolidine dithiocarbamate，PDTC）可抑制p53易位、mPTP开放和胶质瘤细胞死亡。因此，盐霉素主要诱导培养的胶质瘤细胞程序性坏死。本文的在线版本（doi：10.1186/s13046-015-0174-1）包含补充材料，可供授权用户使用。
The primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor with an average survival of approximately 12–14 months. The search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects; however, its role in GBM and the underlying mechanism are not clear. Here we found that salinomycin induced both apoptosis and necrosis in cultured glioma cells, and necrosis played a major role in contributing salinomycin’s cytotoxicity. Salinomycin induced p53 translocation to mitochondria, where it formed a complex with cyclophilin-D (CyPD). This complexation was required for mitochondrial permeability transition pore (mPTP) opening and subsequent programmed necrosis. Blockade of Cyp-D by siRNA-mediated depletion or pharmacological inhibitors (cyclosporin A and sanglifehrin A) significantly suppressed salinomycin-induced glioma cell necrosis. Meanwhile, p53 stable knockdown alleviated salinomycin-induced necrosis in glioma cells. Reactive oxygen species (ROS) production was required for salinomycin-induced p53 mitochondrial translocation, mPTP opening and necrosis, and anti-oxidants n-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) inhibited p53 translocation, mPTP opening and glioma cell death. Thus, salinomycin mainly induces programmed necrosis in cultured glioma cells. The online version of this article (doi:10.1186/s13046-015-0174-1) contains supplementary material, which is available to authorized users.
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影响因子：
10.8
作者：
Hausenloy DJ;Lim SY;Ong SG;Davidson SM;Yellon DM
通讯作者：
Yellon DM
影响因子：
--
作者：
Naujokat C;Steinhart R
通讯作者：
Steinhart R
DOI：
10.1186/1756-9966-31-85
发表时间：
2012-10-11
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Matsutani T;Hiwasa T;Takiguchi M;Oide T;Kunimatsu M;Saeki N;Iwadate Y
通讯作者：
Iwadate Y
影响因子：
4.8
作者：
Clarke, SJ;McStay, GP;Halestrap, AP
通讯作者：
Halestrap, AP
影响因子：
4.1
作者：
Cassidy, L;Barry, P;Kennedy, S
通讯作者：
Kennedy, S