High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells.
Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus (HTLV-1). SIRT1, a nicotinamide adenine dinucleotide(+)-dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF-κB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinol-induced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1-specific small interfering RNA caused apoptosis via activation of caspase-3 and PARP in MT-2 cells, HTLV-1-related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. kozako@fukuoka-u.ac.jp
Tomohiro
T
Kozako
Akiyoshi
A
Aikawa
Teruhisa
T
Shoji
Takahiro
T
Fujimoto
Makoto
M
Yoshimitsu
Senji
S
Shirasawa
Hiroaki
H
Tanaka
Shin-ichiro
S
Honda
Hiroshi
H
Shimeno
Naomichi
N
Arima
Shinji
S
Soeda
D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism*; D009284:Naphthols / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000037:antagonists & inhibitors
D001549:Benzamides; D009284:Naphthols; D034741:RNA, Small Interfering; C439060:sirtinol; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins