Induction of apoptosis and inhibition of telomerase activity by trichostatin A, a histone deacetylase inhibitor, in human leukemic U937 cells.
The objective of the present study was to investigate the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the cell growth and apoptosis and its effect on the telomerase activity in human leukemic cell line U937. Exposure of U937 cells to TSA resulted in growth inhibition and induction of apoptosis in a dose-dependent manner as measured by hemocytometer counts, fluorescence microscopy, agarose gel electrophoresis and flow cytometry analysis. The increase in apoptosis was associated with the up-regulation in proapoptotic Bax expression and down-regulation of antiapoptotic Bcl-2 and Bcl-X(L). TSA treatment inhibited the levels of cIAP family members and induced the proteolytic activation of caspase-3, which was associated with concomitant degradation of poly(ADP-ribose)-polymerase and beta-catenin protein. TSA treatment markedly inhibited the activity of telomerase in a dose-dependent fashion. Additionally, the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by TSA treatment. We therefore conclude that TSA demonstrated antiproliferative and apoptosis-inducing effects on U937 cells in vitro, and that changes in Bcl-2 family protein levels as well as telomerase activity may play an important role in its mechanism of action.
Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, South Korea.
Hyun Joo
HJ
Woo
Su Jae
SJ
Lee
Byung Tae
BT
Choi
Yeong-Min
YM
Park
Yung Hyun
YH
Choi
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006655:Histone Deacetylases / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007938:Leukemia / Q000201:enzymology*; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D019938:Cyclin D1; C012589:trichostatin A; D019098:Telomerase; D006655:Histone Deacetylases