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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 Therapy volume 13, pages 32–43 (2006)Cite this article

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.

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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.

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Authors and Affiliations

  1. 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

  2. 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

  3. Department of Urology, Louisiana State University Medical Center, Shreveport, LA, USA

    A De Benedetti & B J Williams

  4. Department of Biochemistry/Molecular Biology, Louisiana State University Medical Center, Shreveport, LA, USA

    A De Benedetti & B J Williams

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  1. D Yu
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Correspondence to P S Rennie.

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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

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  • DOI: https://doi.org/10.1038/sj.cgt.7700885

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