title: Modulation of ceramide metabolism enhances viral protein apoptin's cytotoxicity in prostate cancer.
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.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Elojeimy
authors.forename: A M
authors.initials: AM
authors.lastname: El-Zawahry
authors.forename: D H
authors.initials: DH
authors.lastname: Holman
authors.forename: A
authors.initials: A
authors.lastname: Bielawska
authors.forename: J
authors.initials: J
authors.lastname: Bielawski
authors.forename: S
authors.initials: S
authors.lastname: Rubinchik
authors.forename: G-W
authors.initials: GW
authors.lastname: Guo
authors.forename: J-Y
authors.initials: JY
authors.lastname: Dong
authors.forename: T
authors.initials: T
authors.lastname: Keane
authors.forename: Y A
authors.initials: YA
authors.lastname: Hannun
authors.forename: M
authors.initials: M
authors.lastname: Tavassoli
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D002517:Galactosylgalactosylglucosylceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010768:Phosphoserine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013107:Sphingolipids / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D036022:Capsid Proteins; D002518:Ceramides; D004791:Enzyme Inhibitors; D013107:Sphingolipids; D016159:Tumor Suppressor Protein p53; C091717:VP3 protein, Chicken anemia virus; D010768:Phosphoserine; D002517:Galactosylgalactosylglucosylceramidase; D020169:Caspases