1. ¹Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
2. ²Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
3. ³Department of Urology, Medical University of South Carolina, Charleston, SC 29425, USA
4. ⁴Cancer Gene Therapy Group, GKT Dental Institute, King's College London, London SE5 9NU, UK

Correspondence: James S. Norris, Department of Microbiology & Immunology, P.O. Box 250504, 173 Ashley Avenue, Charleston, SC 29425 USA. Fax: +1 843 792 4882. E-mail: norrisjs@musc.edu

Received 2 December 2005; Revised 6 June 2006; Accepted 6 June 2006.

Abstract

Despite local and systemic therapies, the National Cancer Institute estimates that prostate cancer will cause over 30,000 deaths in 2006. This suggests that additional therapeutic approaches are needed. The chicken anemia viral protein Apoptin causes tumor-selective apoptosis in human tumor lines independent of p53 and Bcl-2 status. Tet-regulated expression of Apoptin from an adenoviral vector showed cytotoxicity in DU145, PC-3, and LNCaP tumor cells regardless of expression of p53, Bcl-2, Bcl-xL, Bax, survivin, FLIP_S, XIAP, or CIAP. Apoptin expression caused an increase in the tumor suppressor lipid ceramide, which regulates the cellular stress response. Interestingly, 10 of 15 primary prostate cancers examined by Western blotting overexpressed acid ceramidase (AC), suggesting that ceramide deacylation might serve to negate elevated levels of ceramide, creating a more antiapoptotic phenotype. This was confirmed in AC-overexpressing cells in which we observed decreased sensitivity to apoptosis following treatment with Apoptin. Addition of the AC inhibitor LCL204, in combination with Apoptin, augmented cell killing. This effect was also demonstrated in vivo in that Apoptin and LCL204 cotreatment significantly reduced tumor growth in DU145 xenografts (P < 0.05). Taken together, our data demonstrated that Apoptin is a promising therapeutic agent for prostate cancer and that its function is improved when combined with acid ceramidase inhibitors.