期刊
MOLECULAR THERAPY
卷 14, 期 5, 页码 637-646出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2006.06.005
关键词
prostate cancer; Apoptin; ceramide; acid ceramidase; cancer gene therapy; LCL204; apoptosis; acid ceramidase inhibitor
资金
- NCI NIH HHS [1R24CA82933, P01 CA97132] Funding Source: Medline
- NCRR NIH HHS [C06 RR015455] Funding Source: Medline
- NIMHD NIH HHS [N6311601MD10004] Funding Source: Medline
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, FLIPS, 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.
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