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Comparative transcriptional study after treatment with the HDAC inhibitor Trichostatin A

ABSTRACT: Based on the hypothesis that a universal mechanism of cell death induction by HDAC inhibitors exists, a comparative study of differential gene expression after treatment with TSA has been conducted in both hematopoietic and solid tumor cell lines sensitive to TSA-induced cell death, in certain resistant cell lines, and in a sensitive cell line in the presence of the serine protease inhibitor AEBSF, which blocks TSA-induced cell death in all tested human and mouse models sensitive to the drug. The aim was to identify deregulated genes common to all TSA-sensitive models but not present in resistant lines, and whose deregulation is also prevented in the presence of AEBSF. We used Affymetrix arrays to analyze samples from cell lines derived from hematopoietic neoplasms and solid tumors, both murine and human, which were either sensitive or resistant to Trichostatin A-induced cell death, as well as some sensitive cell lines treated with the serine protease inhibitor AEBSF, which is capable of blocking this cell death in all tested systems. The aim was to identify a set of genes differentially regulated in all TSA-sensitive models, not deregulated in the resistant ones, and whose regulation was abolished in sensitive cells treated with AEBSF.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE302879 | GEO | 2026/08/03

REPOSITORIES: GEO

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Project description:We previously identified the induction of growth arrest with phenotypic characteristics of senescence in melanoma cell lines sensitive to diterpene esters, indicating a therapeutic potential. Here we compared the cytostatic effects of two diterpene esters namely TPA (12-O-tetradecanoylphorbol-13-acetate) and PEP008 (20-O-acetyl-ingenol-3-angelate) in sensitive and resistant cell lines derived from melanoma, breast cancer and colon cancer. We showed the diterpene esters to induce senescence-like growth arrest in the sensitive cells at 100-1000 ng/ml. Use of the pan-PKC inhibitor bisindolylmaleimide-l demonstrated that activation of PKC was required for growth arrest. Full genome expression profiling revealed that pivotal genes involved in DNA synthesis and cell cycle control were down-regulated by treatment in all three sensitive solid tumor models. At the protein level, prolonged down-regulation of E2F-1 and proliferating cell nuclear antigen (PCNA), sustained expression of p21WAF1/CIP1 and dephosphorylation of retinoblastoma (Rb) occurred in the sensitive cells. Although activation of extracellular signal-related kinase (ERK) 1/2 by the diterpene esters occurred in both sensitive and resistant cell lines, the HRASLS3 type II tumor suppressor, which appears to have a role in MAPK pathway suppression, was constitutively elevated in the resistant cell lines compared to their sensitive counterparts. Together, these results demonstrate the ability of the PKC activating drugs TPA and PEP008 to induce growth arrest with characteristics of senescence in solid tumor cell lines derived from a variety of tissue types through a similar mechanism. PKC-activating diterpene esters may therefore have therapeutic potential in a range of solid tumors. Experiment Overall Design: We analyzed the transcriptional profiles of the diterpene ester sensitive cell lines MCF7, COLO-205 and SK-MEL-5 following treatment with PEP008 using full genome expression profiling (Affymetrix, U133 Plus 2.0). Cells were treated for 24 h and 24 h plus 72 h recovery with 1000 ng/ml of the drug, before harvesting RNA for analysis. From the cell growth assays, all three cell lines demonstrated permanent growth arrest with diterpene ester treatments at the 1000 ng/ml dose. Mock controls were treated with solvent alone for 24 h. SK-MEL-5 cells were also treated with 1000 ng/ml TPA for 24 h.

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Comparative transcriptional study after treatment with the HDAC inhibitor Trichostatin A

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