Histone deacetylase inhibitor downregulation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma

X. X. Cao, I. Mohuiddin, F. Ece, David McConkey, W. R. Smythe

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)562-568
Number of pages7
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume25
Issue number5
StatePublished - 2001
Externally publishedYes

Fingerprint

Histone Deacetylase Inhibitors
Mesothelioma
Cell death
Gene expression
Cell Death
Down-Regulation
Gene Expression
Assays
Fas Ligand Protein
Butyric Acid
Flow cytometry
Apoptosis
Caspases
Proteins
Flow Cytometry
Clone Cells
Messenger RNA
In Situ Nick-End Labeling
G1 Phase
Ribonucleases

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Histone deacetylase inhibitor downregulation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma. / Cao, X. X.; Mohuiddin, I.; Ece, F.; McConkey, David; Smythe, W. R.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 25, No. 5, 2001, p. 562-568.

Research output: Contribution to journalArticle

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