Trichostatin A sensitizes TRAIL-resistant myeloma cells by downregulation of the antiapoptotic Bcl-2 proteins

Purpose: In this study, we have investigated the effect of trichostatin A (TSA) pretreatment on the cytotoxicity of TRAIL in TRAIL-resistant myeloma cells. Methods and 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-X-L. 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 FLIPS than other TRAIL-sensitive myeloma cells, the enhancing effect of TSA was not accompanied by FLIPS downregulation. Conclusion: In conclusion, TSA sensitized TRAIL-resistant myeloma cells by downregulating the antiapoptotic Bcl-2 protein without altering FLIPS expression.