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Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL

Cancer Gene Therapy volume 9, pages 164–172 (2002)Cite this article

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL/Apo2L) has been shown to induce apoptosis in malignant cells without harming normal cells. To determine the antitumor potential of TRAIL against prostate cells, we undertook a comprehensive study that included eight prostate cancer cells lines (CWR22Rv1, Du145, DuPro, JCA-1, LNCaP, PC-3, PPC-1, and TsuPr1) and primary cultures of normal prostate epithelial cells (PrEC). Cells were tested for susceptibility to soluble TRAIL in the presence or absence of the chemotherapeutic agent doxorubicin. TRAIL was also delivered by an adenoviral vector. Our results reveal that Du145, DuPro, LNCap, TsuPr1, and PrEC were resistant to 100 ng/mL TRAIL. JCA-1 and PPC-1 were slightly sensitive (20% killing) and PC-3 and CWR22Rv1 exhibited the highest sensitivity to TRAIL (30% and 50% killing, respectively). The combination of 10 ng/mL TRAIL with doxorubicin resulted in 60–80% cytotoxicity in seven of eight prostate cancer cells. TRAIL-mediated apoptosis involved cleavage of Bid, caspase-3, and PARP, and required caspase-8 and -9 activity. Full-length TRAIL delivered by an adenoviral vector (AdTRAIL-IRES-GFP) killed prostate cancer cell lines and PrEC without requisite doxorubicin cotreatment. Therefore, expression of the transgene from a tissue-specific promotor would make gene therapy with AdTRAIL-IRES-GFP a possibility.

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Acknowledgements

The authors thank Dr. Seymon Rubinchik for the construction of the adenoviral vectors and Dr. Margaret Kelly for critical reading of the manuscript. This research was supported by National Institutes of Health (NIH) RO1 CA69596 (to JSN) and Grant #IRG-97-151 from the American Cancer Society (to CV-J).

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  1. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, 29425, South Carolina, USA

    Christina Voelkel-Johnson & Deanne Lea King

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  1. Christina Voelkel-Johnson
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  2. Deanne Lea King
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  3. James Scott Norris
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Correspondence to Christina Voelkel-Johnson.

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Voelkel-Johnson, C., King, D. & Norris, J. Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL. Cancer Gene Ther 9, 164–172 (2002). https://doi.org/10.1038/sj.cgt.7700420

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