Targeting and killing of prostate cancer cells using lentiviral constructs containing a sequence recognized by translation factor eif4e and a prostate-specific promoter

ABSTRACT To develop a gene therapy that would selectively kill prostate cancer cells while sparing normal cells, we have constructed lentiviral vectors that contain a therapeutic gene with a

short DNA sequence in the 5′-untranslated region (UTR) that is recognized by the translation initiation factor, eIF4E, which is often overexpressed in malignant cells. Infection of cancer

(LNCaP, PC-3M, DU145, and MCF-7 cells) and noncancer cell lines (BPH-1, 267-B1, Plat-E, and Huvec-c cells) with lentivirus having a CMV-promoter and EGFP reporter resulted in high levels of

EGFP expression in all cells, whereas, inclusion of the eIF4E UTR recognition sequence restricted high expression to cancer cells and Plat-E cells, which also express substantial levels of

eIF4E. Infection of the cells with lentiviral vectors having this UTR in front of the HSV thymidine kinase suicide gene resulted in differential sensitivity to the killing effects of

ganciclovir, with at least 100-fold more drug required to kill noncancer cells than cancer cells. Furthermore, in experiments where the CMV promoter was replaced by the prostate-specific

ARR2PB promoter, the killing effects of ganciclovir were restricted to prostate cancer cells and not seen in nonprostate cancer cells. Our results indicate that combined translational

regulation, by incorporation of an eIF4E-UTR recognition sequence into a therapeutic gene, together with transcriptional regulation with a prostate-specific promoter, may provide a means to

selectively destroy prostate cancer cells while sparing normal prostate cells. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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ACKNOWLEDGEMENTS This research was supported by grants from the Terry Fox Foundation/National Cancer Institute of Canada. DY was supported in part by a Canadian Prostate Cancer Research

Initiative Training Centre award and CCN was supported by a scholarship from the Michael Smith Foundation for Health Research. We thank Mr Robert Bell, Head of Bioinformatics at the Prostate

Centre, for help with the statistical analyses. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * The Prostate Center at Vancouver General Hospital, University of British Columbia, Vancouver,

BC, Canada D Yu, C Scott, W W Jia, L Fazli, Y Wen, M Gleave, C Nelson & P S Rennie * Department of Surgery, University of British Columbia, Vancouver, BC, Canada D Yu, C Scott, W W Jia, 

L Fazli, Y Wen, M Gleave, C Nelson & P S Rennie * Department of Urology, Louisiana State University Medical Center, Shreveport, LA, USA A De Benedetti & B J Williams * Department of

Biochemistry/Molecular Biology, Louisiana State University Medical Center, Shreveport, LA, USA A De Benedetti & B J Williams Authors * D Yu View author publications You can also search

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to P S Rennie. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Yu, D., Scott, C., Jia, W. _et al._ Targeting and killing of prostate cancer cells using

lentiviral constructs containing a sequence recognized by translation factor eIF4E and a prostate-specific promoter. _Cancer Gene Ther_ 13, 32–43 (2006).

https://doi.org/10.1038/sj.cgt.7700885 Download citation * Received: 22 August 2004 * Revised: 07 April 2005 * Accepted: 12 April 2005 * Published: 29 July 2005 * Issue Date: 01 January 2006

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not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * prostate cancer * EIF4E * translational control *

probasin promoter * lentivirus