Exp Mol Med.  2006 Dec;38(6):616-624.

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

• Kim HR
• Kim EJ
• Yang SH
• Jeong ET
• Park C
• Lee JH
• Youn MJ
• So HS
• Park R

Abstract

Trichostatin A (TSA), originally developed as an antifungal agent, is one of potent histone deacetylase (HDAC) inhibitors, which are known to cause growth arrest and apoptosis induction of transformed cells, including urinary bladder, breast, prostate, ovary, and colon cancers. However, the effect of HDAC inhibitors on human non-small cell lung cancer cells is not clearly known yet. Herein, we demonstrated that treatment of TSA resulted in a significant decrease of the viability of H157 cells in a dose-dependent manner, which was revealed as apoptosis accompanying with nuclear fragmentation and an increase in sub-G0/G1 fraction. In addition, it induced the expression of Fas/FasL, which further triggered the activation of caspase-8. Catalytic activation of caspase-9 and decreased expression of anti-aptototic Bcl-2 and Bcl-XL proteins were observed in TSA-treated cells. Catalytic activation of caspase-3 by TSA was further confirmed by cleavage of pro-caspase-3 and intracellular substrates, including poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, a characteristic phenomenon of mitochondrial dysfunction, including mitochondrial membrane potential transition and release of mitochondrial cytochrome c into the cytosol was apparent in TSA-treated cells. Taken together, our data indicate that inhibition of HDAC by TSA induces the apoptosis of H157 cells through signaling cascade of Fas/FasL-mediated extrinsic and mitocondria-mediated intrinsic caspases pathway.

Keyword

poptosis; histone deacetylases; lung neoplasms; trichostatin A

MeSH Terms

Signal Transduction
Receptors, Death Domain/*metabolism
Protein Isoforms/metabolism
Mitochondria/*drug effects/*metabolism
Lung Neoplasms/*metabolism/*pathology
Hydroxamic Acids/*pharmacology
Humans
Histones/metabolism
Enzyme Activation
Cell Line, Tumor
Catalysis
Caspase 9/metabolism
Caspase 8/metabolism
Caspase 3/metabolism
Apoptosis/*drug effects
Acetylation