title: Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling.
abstract: Suberoylanilide hydroxamic acid (SAHA) has been approved for the treatment of cutaneous T-cell lymphoma (CTCL), but its mode of action remained largely elusive. As shown here in four CTCL cell lines, loss of cell viability correlated with significant time- and dose-dependent induction of apoptosis, whereas cytotoxicity was less pronounced. Both extrinsic and intrinsic apoptosis pathways were activated, as seen by processing of initiator caspases 8 and 9, loss of mitochondrial membrane potential, and cytochrome c release. Characteristically, antiapoptotic mediators such as Mcl-1, XIAP, survivin, and c-FLIP were downregulated. Consistent with its critical function, c-FLIP overexpression resulted in a significant decrease of SAHA-mediated apoptosis. Enhanced sensitivity to TRAIL (TNF-related apoptosis-inducing ligand) and enhanced TRAIL signaling was seen in CTCL cell lines with high sensitivity, whereas cell lines with moderate response were characterized by downregulation of TRAIL-R2 and weaker TRAIL expression. Comparable proapoptotic responses to SAHA and to the combination with TRAIL were seen in ex vivo tumor T cells of CTCL patients. Thus, activation of extrinsic apoptosis pathways, related to c-FLIP downregulation and enhanced TRAIL signaling, appeared as characteristic for CTCL cell responsiveness to SAHA. An improved understanding of the pathways may facilitate its targeted use and the selection of suitable combinations.
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center Charité (HTCC), Charité-University Medical Center Berlin, Berlin, Germany.
authors.forename: Nadya
authors.initials: N
authors.lastname: Al-Yacoub
authors.forename: Lothar F
authors.initials: LF
authors.lastname: Fecker
authors.forename: Markus
authors.initials: M
authors.lastname: Möbs
authors.forename: Michael
authors.initials: M
authors.lastname: Plötz
authors.forename: Frank K
authors.initials: FK
authors.lastname: Braun
authors.forename: Wolfram
authors.initials: W
authors.lastname: Sterry
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eberle
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000077337:Vorinostat