Apoptosis Induction by SAHA in Cutaneous T-Cell Lymphoma Cells Is Related to Downregulation of c-FLIP and Enhanced TRAIL Signaling
| Autor: | Frank K. Braun, Michael Plötz, Lothar F. Fecker, Nadya Al-Yacoub, Wolfram Sterry, Jürgen Eberle, Markus Möbs |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Skin Neoplasms T cell Cell CASP8 and FADD-Like Apoptosis Regulating Protein Down-Regulation Antineoplastic Agents Dermatology Biology Hydroxamic Acids Biochemistry Inhibitor of Apoptosis Proteins TNF-Related Apoptosis-Inducing Ligand Downregulation and upregulation hemic and lymphatic diseases Survivin Tumor Cells Cultured medicine Humans Molecular Biology Aged Aged 80 and over Vorinostat Cutaneous T-cell lymphoma Intrinsic apoptosis Cell Biology Middle Aged medicine.disease Lymphoma T-Cell Cutaneous Up-Regulation Cell biology XIAP medicine.anatomical_structure Apoptosis Female Signal Transduction |
| Zdroj: | Journal of Investigative Dermatology. 132(9):2263-2274 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2012.125 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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