Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma
Bortezomib stabilizes NOXA and triggers ROS-associated apoptosis in medulloblastoma
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DOI：
10.1007/s11060-011-0619-0
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发表时间：
2011-12-01
影响因子：
3.9
通讯作者：
Keller, Charles
中科院分区：
文献类型：
--
作者：
Ohshima-Hosoyama, Sachiko;Davare, Monika A.;Keller, Charles
我们以前已经证明，硼替佐米，26 S蛋白酶体抑制剂，有效地抑制髓母细胞瘤生长在体内的基因工程Ptch 1，p53小鼠模型，然而，硼替佐米也与严重的周围神经病变，这将是不利的中枢神经系统恶性肿瘤患者的临床。本研究的目的是确定硼替佐米在髓母细胞瘤中的疗效机制，以便更特异地复制靶向泛素-蛋白酶体系统的治疗优势。在我们对泛素-蛋白酶体系统的上游组分的研究中，我们将促凋亡蛋白NOXA鉴定为通过硼替佐米稳定并在反应性氧化应激诱导的细胞死亡的背景下诱导半胱天冬酶裂解的后修饰靶。这些临床前的结果可能适用于相当大的部分Shh驱动的人髓母细胞瘤，也许其他髓母细胞瘤亚型，独立于p53状态。
We have previously demonstrated that bortezomib, a 26S proteasome inhibitor, effectively inhibits medulloblastoma growth in vivo in a genetically engineered Ptch1, p53 mouse model; however, bortezomib is also associated clinically with severe peripheral neuropathy, which would be disadvantageous for patients with central nervous system malignancy. The purpose of this study was to determine the mechanism of bortezomib efficacy in medulloblastoma in order to replicate more specifically the therapeutic advantage of targeting the ubiquitin-proteosome system. In our studies of upstream components of the ubiquitin-proteasome system, we identified the pro-apoptotic protein NOXA as a post-translationally modified target that is stabilized by bortezomib and induces caspase cleavage in the context of reactive oxidative stress induced cell death. These preclinical results may apply to the sizable fraction of Shh-driven human medulloblastoma and perhaps other medulloblastoma subtypes, independent of p53 status.