Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway.
- Author:
Hak Ryu KIM
1
;
Eun Jung KIM
;
Sei Hoon YANG
;
Eun Taik JEONG
;
Channy PARK
;
Jae Hyung LEE
;
Myung Ja YOUN
;
Hong Seob SO
;
Raekil PARK
Author Information
1. Department of Internal Medicine, Wonkwang University School of Medicine, Jeonbuk 570-749, Korea. rkpark@wku.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
poptosis;
histone deacetylases;
lung neoplasms;
trichostatin A
- MeSH:
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
- From:Experimental & Molecular Medicine
2006;38(6):616-624
- CountryRepublic of Korea
- Language:English
-
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.
