Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells
- 17 October 2006
- journal article
- Published by Springer Science and Business Media LLC in Apoptosis
- Vol. 11 (12), 2251-2265
- https://doi.org/10.1007/s10495-006-0283-6
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.Keywords
This publication has 39 references indexed in Scilit:
- Overcoming resistance of cancer cells to apoptosisJournal of Cellular Physiology, 2003
- How melanoma cells evade trail-induced apoptosisNature Reviews Cancer, 2001
- The CD95 (APO-1/Fas) and the TRAIL (APO-2L) Apoptosis SystemsExperimental Cell Research, 2000
- Safety and antitumor activity of recombinant soluble Apo2 ligandJCI Insight, 1999
- Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivoNature Medicine, 1999
- Caspases: Enemies WithinScience, 1998
- Death Receptors: Signaling and ModulationScience, 1998
- Mitochondria and ApoptosisScience, 1998
- Proteases to die forGenes & Development, 1998
- Apoptosis by Death FactorCell, 1997