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HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma

Oncogene volume 24, pages 4609–4623 (2005)Cite this article

Abstract

Histone deacetylase (HDAC) inhibitors induce differentiation and/or apoptosis in a variety of cell types by activating transcription of target genes. Activation of the death receptor (DR) pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis preferentially in cancer cells. Here, we investigated the intracellular mechanisms by which HDAC inhibitors (suberoylanilide hydroxamic acid, m-carboxycinnamic acid bis-hydroxamide, MS-275 and trichostatin A) enhance the apoptosis-inducing potential of TRAIL in breast cancer cells in vitro. A synergism in apoptosis was observed in both TRAIL-sensitive and -resistant cells upon sequential treatments with HDAC inhibitors followed by TRAIL. HDAC inhibitors synergized with TRAIL by inducing DRs DR4/TRAIL-R1 and DR5/TRAIL-R2 through NFκB activation and some of the proapoptotic members of the Bcl-2 family, and engaging the mitochondrial pathway. The ability of HDAC inhibitors to sensitize TRAIL-resistant cells suggests that HDAC inhibitors may induce fundamental alterations in cell signaling pathways. Thus, the sequential treatments with HDAC inhibitors followed by TRAIL may be used as a new therapeutic approach for the treatment of human cancers.

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Abbreviations

DR:

death receptor

DcR:

decoy receptor

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

Apo-2L:

Apo2 ligand

HDAC:

histone deacetylase

TSA:

trichostatin A

CBHA:

m-carboxycinnamic acid bis-hydroxamide

SAHA:

suberoylanilide hydroxamic acid

IAP:

inhibitor of apoptosis protein

PARP:

poly(ADP-ribose) polymerase

z-VAD-fmk:

z-Val-Ala-Asp-fluoromethylketone

z-IETD-fmk:

z-Ile-Glu-Thr-Asp-fluoromethylketone

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Acknowledgements

This work was supported by grants from the Susan G Komen Breast Cancer Foundation, and the Department of Defense. We extend our sincere thanks to Dr Warner C Greene (Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA) for providing mutant IκBα (S32/36). We also thank Craig Thompson (University of Pennsylvania, Philadelphia, PA, USA) and Stanley Korsmeyer (Dana-Farber Cancer Institute, Boston, MA) for providing the Bcl-XL and Bcl-2 expression vectors, respectively. We thank Dr Vishva Dixit (Genentech, South San Francisco, CA, USA) for providing dominant-negative FADD.

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  1. Department of Pharmaceutical Sciences, Molecular and Cellular Biology Program, Greenebaum Cancer Center, University of Maryland, Baltimore, MD, 21201-1180, USA

    Thiyam Ramsing Singh, Sharmila Shankar & Rakesh K Srivastava

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Singh, T., Shankar, S. & Srivastava, R. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24, 4609–4623 (2005). https://doi.org/10.1038/sj.onc.1208585

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