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

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-apoptotic 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 mitochondria-mediated intrinsic caspases pathway.

• Authors: Hak-Ryul Kim, Eun-Jung Kim, Sei-Hoon Yang, Eun-Taik Jeong, Channy Park, Jae-Hyung Lee, Myung-Ja Youn, Hong-Seob So, Raekil Park
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 38 Issue 6 Pg. 616-24 (Dec 31 2006) ISSN: 1226-3613 [Print] United States
• PMID: 17202837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• Hydroxamic Acids
• Protein Isoforms
• Receptors, Death Domain
• trichostatin A
• Caspase 3
• Caspase 8
• Caspase 9

Topics

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