title: Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes.
abstract: FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-κB, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.|Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
authors.forename: Genevieve L
authors.initials: GL
authors.lastname: Coe
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.|Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.|Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Redd
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.|Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.|Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Paschall
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.|Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.|Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
authors.forename: Chunwan
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Lilly
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Pharmaceutical &Biomedical Sciences, University of Georgia, Athens, GA 30602, USA.
authors.forename: Houjian
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Chemistry and Physics, Augusta University, Augusta, GA 30912, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Albers
authors.affiliation: Department of Chemistry and Physics, Augusta University, Augusta, GA 30912, USA.
authors.forename: Iryna O
authors.initials: IO
authors.lastname: Lebedyeva
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.|Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.|Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D015195:Drug Design; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002518:Ceramides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505530:CASP8 protein, human; D053181:Caspase 8