Trichostatin A sensitizes TRAIL-resistant myeloma cells by downregulation of the antiapoptotic Bcl-2 proteins.
OBJECTIVE
In this study, we have investigated the effect of trichostatin A (TSA) pretreatment on the cytotoxicity of TRAIL in TRAIL-resistant myeloma cells.


RESULTS
MM1S myeloma cells exhibited resistance to TRAIL-induced apoptosis even at high doses of TRAIL and was sensitive to low doses of TSA. Sequential treatment of myeloma cells with TSA followed by TRAIL enhanced TRAIL cytotoxicity. TSA induced the transcription of TRAIL death receptor DR5 without affecting the transcription of DR4 and the decoy receptors; DcR1 and DcR2. However, the surface expression of both DR4 and DR5 was not modulated by TSA treatment. TSA treatment repressed the transcription and downregulated the expression of the antiapoptotic Bcl-2 proteins; Bcl-2 and Bcl-XL. Surprisingly, the effect of TSA on the proapoptotic Bcl-2 proteins was mixed, the two isoforms of PUMA (alpha, beta), Noxa, Bax were downregulated, while Bim was upregulated. Although MM1S cells showed higher expression level of FLIP(S) than other TRAIL-sensitive myeloma cells, the enhancing effect of TSA was not accompanied by FLIP(S) downregulation.


CONCLUSIONS
In conclusion, TSA sensitized TRAIL-resistant myeloma cells by downregulating the antiapoptotic Bcl-2 protein without altering FLIP(S) expression.
Fandy
Tamer E
TE
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, 21201-1180, USA. tfand001@umaryland.edu
Srivastava
Rakesh K
RK
D000935:Antifungal Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C012589:trichostatin A; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases