Back to Search
Start Over
Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells.
- Source :
-
Apoptosis : an international journal on programmed cell death [Apoptosis] 2006 Dec; Vol. 11 (12), pp. 2251-65. - Publication Year :
- 2006
-
Abstract
- The wide variation in sensitivity of cancer cells to TRAIL- or histone deacetylase (HDAC) inhibitor - induced apoptosis precludes successful treatment of cancer with these agents. We report here that TRAIL and SBHA synergistically induce apoptosis of melanoma cells as revealed by quantitative analysis using the normalized isobologram method. This is supported by enhanced activation of caspase-3 and cleavage of its substrates, PARP and ICAD. Co-treatment with SBHA and TRAIL did not enhance formation of the death-inducing signaling complex (DISC) and processing of caspase-8 and Bid, but potentiated activation of Bax and release of Cytochrome C and Smac/DIABLO from mitochondria into the cytosol. SBHA down-regulated Bcl-X(L), Mcl-1 and XIAP, but up-regulated Bax, Bak, and the BH3-only protein Bim(EL). Up-regulation of the latter by SBHA was attenuated by the presence of TRAIL, which was inhibitable by the pan-caspase inhibitor z-VAD-fmk. Inhibition of Bim by siRNA attenuated conformational changes of Bax, mitochondrial apoptotic events, and activation of caspase-3, leading to marked inhibition of the synergy between SBHA and TRAIL. Thus, Bim plays an essential role in synergistic induction of apoptosis by SBHA and TRAIL in melanoma.
- Subjects :
- BH3 Interacting Domain Death Agonist Protein metabolism
Bcl-2-Like Protein 11
Caspase 8 metabolism
Down-Regulation drug effects
Histone Deacetylases metabolism
Humans
Mitochondria drug effects
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasm Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
RNA, Small Interfering metabolism
Up-Regulation
X-Linked Inhibitor of Apoptosis Protein
bcl-2 Homologous Antagonist-Killer Protein metabolism
bcl-2-Associated X Protein metabolism
bcl-X Protein metabolism
Apoptosis drug effects
Apoptosis Regulatory Proteins metabolism
Enzyme Inhibitors pharmacology
Histone Deacetylase Inhibitors
Hydroxamic Acids pharmacology
Melanoma pathology
Membrane Proteins metabolism
Proto-Oncogene Proteins metabolism
TNF-Related Apoptosis-Inducing Ligand pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1360-8185
- Volume :
- 11
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Apoptosis : an international journal on programmed cell death
- Publication Type :
- Academic Journal
- Accession number :
- 17051334
- Full Text :
- https://doi.org/10.1007/s10495-006-0283-6