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Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells

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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-XL, Mcl-1 and XIAP, but up-regulated Bax, Bak, and the BH3-only protein BimEL. 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.

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Authors and Affiliations

  1. Immunology and Oncology Unit, Room 443, Newcastle Misericordiae Hospital, NSW, Australia

    Susan Gillespie, Jodie Borrow, Xu Dong Zhang & Peter Hersey

  2. Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, Newcastle, NSW, 2300, Australia

    Xu Dong Zhang & Peter Hersey

Authors
  1. Susan Gillespie
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  2. Jodie Borrow
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  3. Xu Dong Zhang
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  4. Peter Hersey
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Corresponding author

Correspondence to Peter Hersey.

Additional information

This work was supported by the NSW State Cancer Council, the Melanoma and Skin Cancer Research Institute Sydney, the Hunter Melanoma Foundation, NSW, and the National Health and Medical Research Council, Australia. X.D. Zhang is a Cancer Institute NSW Fellow.

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Gillespie, S., Borrow, J., Zhang, X.D. et al. Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis 11, 2251–2265 (2006). https://doi.org/10.1007/s10495-006-0283-6

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