title: 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.
abstract: 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 [124I]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 [124I]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.
authors.affiliation: Department of Neurology, Memorial Hospital,Sloan-KetteringInstitute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Doubrovin
authors.forename: Jian T
authors.initials: JT
authors.lastname: Che
authors.forename: Inna
authors.initials: I
authors.lastname: Serganova
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Moroz
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Ageyeva
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kochetkova
authors.forename: Nagavarakishore
authors.initials: N
authors.lastname: Pillarsetti
authors.forename: Ronald
authors.initials: R
authors.lastname: Finn
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D003952:Diagnostic Imaging / Q000379:methods*; D017930:Genes, Reporter / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D014157:Transcription Factors; C112765:tanespimycin