Work

Exploiting the transcriptional specificity of the alpha-methylacyl-CoA racemase AMACR promoter for the molecular imaging of prostate cancer

Year: 2018

Type: article

Abstract: // Mariya Shapovalova 1 , Julia Davydova 2 , Christine Henzler 3 , Mark Daniel 4 , Scott M. Dehm 3 , Christopher A. Warlick 5 and Aaron M. LeBeau 1 1 Department of Pharmacology, University of Minnesota, Minneapolis 55455, MN, USA 2 Department of Surgery, University of Minnesota, Minneapolis 55455, MN, USA 3 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, MN, USA 4 Department of Microbiology and Immunology, University of Minnesota, Minneapolis 55455, MN, USA 5 Department of Urology, University of Minnesota, Minneapolis 55455, MN, USA Correspondence to: Aaron M. LeBeau, email: [email protected] Keywords: α-methylacyl-CoA racemase; molecular imaging; adenovirus; prostate cancer Received: October 17, 2018 Accepted: November 16, 2018 Published: November 30, 2018 ABSTRACT The metabolic protein alpha-methylacyl-CoA racemase (AMACR) is significantly overexpressed in prostate cancer compared to the normal prostate and other non-malignant tissue. Though an attractive target, there are no reports in the literature on leveraging the expression of AMACR for the molecular imaging of prostate cancer. Here, we used a molecular-genetic imaging strategy to exploit the transcriptional specificity of the AMACR promoter for the in vivo detection of prostate cancer using the reporter gene luciferase. We performed a stepwise truncation of the promoter and identified a 565 base pair minimal promoter for AMACR that retained both high activity and specificity. Following identification of the minimal promoter for AMACR, we used an advanced two-step transcriptional amplification system to maximize the promoter output. We showed that our optimized AMACR promoter can drive expression of luciferase for molecular imaging in subcutaneous xenograft models of androgen receptor-positive and androgen receptor-negative prostate cancer using a non-replicative adenovirus for gene delivery. Our results provide evidence that the AMACR promoter can be exploited to drive the cancer-specific expression of reporter genes and potentially even be incorporated into conditionally replicative adenoviruses for oncolytic therapy and other applications.

Source: Oncotarget

DOI: 10.18632/oncotarget.26401