Am. J. Respir. Cell Mol. Biol., Volume 25, Number 5, November, 2001 562-568

Histone Deacetylase Inhibitor Downregulation of bcl-xl Gene Expression Leads to Apoptotic Cell Death in Mesothelioma

Xiaobo X. Cao, Imran Mohuiddin, Ferah Ece, David J. McConkey, and W. Roy Smythe

Department of Thoracic and Cardiovascular Surgery, Section of Thoracic Molecular Oncology, and Department of Cancer Biology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas

It has been shown that mesothelioma expresses the antiapoptotic protein BCL-XL, but not BCL-2, rendering bcl-xl gene expression a potential therapeutic target. Sodium butyrate (NaB) is a histone deacetylase inhibitor capable of alteration of bcl-2 family protein expression in other tumor types. Mesothelioma cell lines (REN, I-45) were exposed to NaB, and viability (colorimetric assay) and apoptosis (TUNEL, Hoescht staining, flow cytometry) were evaluated. Effects on bcl-2 family protein, fas-fas ligand, and caspases were examined by Western blot analysis and functional assay. An RNase assay evaluated bcl-2 family messenger RNA (mRNA) expression. Overexpressing BCL-XL mesothelioma clones were created by plasmid transfer. Cells were sensitive to NaB at low IC₅₀ (REN, 0.3 mM; I-45, 1 mM) and demonstrated apoptosis (percentage of cells below G1 phase by flow cytometry [sub-G1]: REN, 38.5%; I-45, 30.9%). A significant decrease in BCL-XL protein expression was noted with BAK, BAX, and BCL-2 unchanged, and this was corroborated at the transcriptional level with selectively decreased bcl-xl mRNA production after sodium butyrate exposure. Fas expression and fas-fas ligand sensitivity were unchanged. Caspases demonstrated low-level activation. Stable overexpressing BCL-XL clones were proportionally resistant to the NaB effect. This study suggests that mesothelioma cells are sensitive to the induction of apoptosis related to the attenuation of antiapoptotic bcl-xl gene and protein expression. Additional study of the therapeutic benefit of targeting bcl-xl gene expression in mesothelioma is warranted.

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