Monitoring the Induction of Heat Shock Factor 1/Heat Shock Protein 70 Expression following 17-Allylamino-Demethoxygeldanamycin Treatment by Positron Emission Tomography and Optical Reporter Gene Imaging
Monitoring the Induction of Heat Shock Factor 1/Heat Shock Protein 70 Expression following 17-Allylamino-Demethoxygeldanamycin Treatment by Positron Emission Tomography and Optical Reporter Gene Imaging
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DOI：
10.2310/7290.2011.00028
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发表时间：
2012-01-01
影响因子：
2.8
通讯作者：
Blasberg, Ronald G.
中科院分区：
文献类型：
--
作者：
Doubrovin, Mikhail;Che, Jian T.;Blasberg, Ronald G.
细胞对蛋白毒性细胞应激的反应主要是通过激活热休克因子1 （HSF1）介导的。该转录因子在热休克蛋白（HSPs）的调控中起主要作用，包括HSP70。我们证明了一个包含诱导型HSP70启动子的[I-124]碘化- pqhnig70正电子发射层析成像（PET）报告系统可用于成像和监测HSF1/HSP70转录因子对药物治疗（17-烯丙基氨基-去甲氧基格尔达霉素[17-AAG]）的激活。我们开发了一种双成像报告基因（pQHNIG70），用于对细胞培养和活体动物的热休克反应进行无创成像，目前正在研究暴露于17-AAG后细胞培养和肿瘤动物中HSF1/HSP70报告基因的激活。17-AAG （10- 1000 nM）诱导报告基因表达；60小时后观察到23倍的增长。报告基因表达与HSP70蛋白水平呈良好的对应关系。基于pqhnig70介导的RG2异种移植物中[I-124]碘积累的MicroPET成像显示，17-AAG对肿瘤HSP70、肿瘤人碘化钠同向转运体和绿色荧光蛋白报告蛋白的反应显著增加6.2倍。HSF1报告系统可用于体外和体内筛选诱导细胞毒性应激和HSF1激活的抗癌药物。
The cell response to proteotoxic cell stresses is mediated primarily through activation of heat shock factor 1 (HSF1). This transcription factor plays a major role in the regulation of the heat shock proteins (HSPs), including HSP70. We demonstrate that an [I-124] iodide-pQHNIG70 positron emission tomography (PET) reporter system that includes an inducible HSP70 promoter can be used to image and monitor the activation of the HSF1/HSP70 transcription factor in response to drug treatment (17-allylamino-demethoxygeldanamycin [17-AAG]). We developed a dual imaging reporter (pQHNIG70) for noninvasive imaging of the heat shock response in cell culture and living animals previously and now study HSF1/HSP70 reporter activation in both cell culture and tumor-bearing animals following exposure to 17-AAG. 17-AAG (10-1,000 nM) induced reporter expression; a 23-fold increase was observed by 60 hours. Good correspondence between reporter expression and HSP70 protein levels were observed. MicroPET imaging based on [I-124] iodide accumulation in pQHNIG70-transduced RG2 xenografts showed a significant 6.2-fold reporter response to 17-AAG, with a corresponding increase in tumor HSP70 and in tumor human sodium iodide symporter and green fluorescent protein reporter proteins. The HSF1 reporter system can be used to screen anticancer drugs for induction of cytotoxic stress and HSF1 activation both in vitro and in vivo.