OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing
OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing
复制标题
DOI：
10.4161/cbt.13.4.18877
复制
发表时间：
2012-02-15
影响因子：
3.6
通讯作者：
Dent, Paul
中科院分区：
文献类型：
--
作者：
Booth, Laurence;Cazanave, Sophie C.;Dent, Paul
我们进一步定义了药物OSU-03012（OSU）杀死肿瘤细胞的机制。OSU致死性通过敲低PERK而被抑制，并且通过敲低ATF 6和IRE 1 α而被增强。OSU处理抑制了伴侣蛋白BiP/GRP 78的表达，并通过降低蛋白质的稳定性来实现。BiP/GRP 78的敲低进一步增强了OSU致死性。BiP/GRP 78的过表达消除了OSU毒性。用OSU预处理细胞比伴随或顺序的药物治疗与辐射暴露在更大程度上增强了辐射敏感性。GBM细胞中突变型活性p110 PI 3 K或突变型活性EGFR的表达对OSU杀伤没有差异性抑制作用。相比之下，PTEN功能的丧失降低了OSU的致死率，而不改变AKT、p70 S6 K或mTOR活性，或药物对GBM细胞放射增敏的能力。敲低PTEN保护细胞免受OSU和放射治疗，而重新表达PTEN促进药物致死和放射增敏。OSU以剂量依赖性方式延长了携带GBM肿瘤的小鼠的存活，并与放疗相互作用以进一步延长存活。总的来说，我们的数据显示，降低的BiP/GRP 78水平在GBM细胞中的OSU-3012毒性中起关键作用，并且该药物具有针对侵袭性原代人GBM分离株的体内活性。
We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills tumor cells. OSU lethality was suppressed by knock down of PERK and enhanced by knock down of ATF6 and IRE1 alpha. OSU treatment suppressed expression of the chaperone, BiP/GRP78, and did so through reduced stability of the protein. Knock down of BiP/GRP78 further enhanced OSU lethality. Overexpression of BiP/GRP78 abolished OSU toxicity. Pre-treatment of cells with OSU enhanced radiosensitivity to a greater extent than concomitant or sequential drug treatment with radiation exposure. Expression of a mutant active p110 PI3K, or mutant active forms of the EGFR in GBM cells did not differentially suppress OSU killing. In contrast loss of PTEN function reduced OSU lethality, without altering AKT, p70 S6K or mTOR activity, or the drug's ability to radiosensitize GBM cells. Knock down of PTEN protected cells from OSU and radiation treatment whereas re-expression of PTEN facilitated drug lethality and radiosensitization. In a dose-dependent fashion OSU prolonged the survival of mice carrying GBM tumors and interacted with radiotherapy to further prolong survival. Collectively, our data show that reduced BiP/GRP78 levels play a key role in OSU-3012 toxicity in GBM cells, and that this drug has in vivo activity against an invasive primary human GBM isolate.