Trichostatin A (TSA) sensitizes the human prostatic cancer cell line DU145 to death receptor ligands treatment

Agshin F Taghiyev; Natalya V Guseva; Mary T Sturm; Oskar W Rokhlin; Michael B Cohen

doi:10.4161/cbt.4.4.1615

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Trichostatin A (TSA) sensitizes the human prostatic cancer cell line DU145 to death receptor ligands treatment

Journal article

Open access

Peer reviewed

Trichostatin A (TSA) sensitizes the human prostatic cancer cell line DU145 to death receptor ligands treatment

Agshin F Taghiyev, Natalya V Guseva, Mary T Sturm, Oskar W Rokhlin and Michael B Cohen

Cancer biology & therapy, Vol.4(4), pp.382-396

04/01/2005

DOI: 10.4161/cbt.4.4.1615

PMID: 15846101

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Abstract

The human prostatic carcinoma cell line DU145 has previously been found to be resistant to treatment with TNF-family ligands. However, TRAIL, TNF-alpha and anti-Fas antibodies (Ab) treatment in combination with the histone deacetylase inhibitor Trichostatin A (TSA) converted the phenotype of DU145 from resistant to sensitive. TSA induced 15% cell death but simultaneous treatment with TRAIL, TNF-alpha and anti-Fas Ab resulted in 55%, 70% and 40% cell death, respectively. Simultaneous treatment did not increase the level of TSA-induced histone acetylation, but induced the release of acetylated histones from chromatin into the cytosol. This release was caspase dependent since it was abrogated by Z-VAD-fmk. In addition, treatment with TSA induced caspase-9 activation and resulted in the release of cytochrome c and Smac/DIABLO from mitochondria. To further investigate the role of caspase-9 in TSA-mediated apoptosis we used two different approaches: (1) cells were pretreated with the caspase-9 inhibitor Z-LEHD-fmk, and (2) cells were transfected with a dominant-negative form of caspase-9. Both approaches gave similar results: cells became resistant to treatment with TSA. These data indicate that TSA mediates its effect via the mitochondrial pathway. This was confirmed by examining DU145 overexpressing Bcl-2. These transfectants were resistant to TSA treatment. Taken together, our data shows that only simultaneous treatment with TNF-family ligands and TSA in DU145 resulted in caspase activity sufficient to induce apoptosis. The combination of TSA and TNF-family ligands could potentially be the basis for the treatment of prostate cancer.

Apoptosis - drug effects

Apoptosis Regulatory Proteins - pharmacology

Cell Line, Tumor

Cell Survival - drug effects

Enzyme Inhibitors - pharmacology

Histone Deacetylase Inhibitors

Humans

Hydroxamic Acids - pharmacology

Ligands

Male

Membrane Glycoproteins - pharmacology

Models, Biological

Prostatic Neoplasms - drug therapy

Prostatic Neoplasms - metabolism

TNF-Related Apoptosis-Inducing Ligand

Tumor Necrosis Factor-alpha - pharmacology

Details

Title: Subtitle: Trichostatin A (TSA) sensitizes the human prostatic cancer cell line DU145 to death receptor ligands treatment
Creators: Agshin F Taghiyev - University of Iowa
Natalya V Guseva
Mary T Sturm
Oskar W Rokhlin
Michael B Cohen
Resource Type: Journal article
Publication Details: Cancer biology & therapy, Vol.4(4), pp.382-396
DOI: 10.4161/cbt.4.4.1615
PMID: 15846101
ISSN: 1538-4047
eISSN: 1555-8576
Grant note: CA 87717 / NCI NIH HHS
Language: English
Date published: 04/01/2005
Academic Unit: Pathology
Record Identifier: 9984647058702771

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