Leptomycin B-induced apoptosis is mediated through caspase activation and down-regulation of Mcl-1 and XIAP expression, but not through the generation of ROS in U937 leukemia cells

Byeong-Churl JangJi-Hye PaikHye-Yun JeongHyun-Ji OhJong-Wook ParkTaeg Kyu KwonDae-Kyu SongJong-Gu ParkSang-Pyo KimJae-Hoon BaeKyo-Chul MunMin-Ho SuhMinoru YoshidaSeong-II Suh
Dept. of Molecular Medicine (분자의학); Dept. of Immunology (면역학); Dept. of Physiology (생리학); Dept. of Pathology (병리학); Dept. of Biochemistry (생화학); Dept. of Microbiology (미생물학); Institute for Medical Science (의과학연구소)
Issue Date
Biochemical Pharmacology, Vol.68(2) : 263-274, 2004
Leptomycin B (LMB), which is originally isolated from Streptomyces, possesses anti-tumor properties in vivo and in vitro. Though it was previously reported that LMB induces cell cycle arrest and p53-mediated apoptosis in certain cancer cells, however, the mechanism by which LMB induces apoptosis remains poorly understood. Here, we investigated the mechanisms of apoptosis induced by LMB in U937 cells. Treatment with LMB concentration-dependently induced cytotoxicity and apoptosis in U937 cells that correlated temporally with activation of caspases and down-regulation of Mcl-1 and XIAP. LMB did not change the expressions of Bcl-2 or Bax. A broad spectrum caspase inhibitor, z-VAD-fmk, blocked caspase-3 activation and elevated the survival in LMB-treated U937 cells, suggesting that caspase-3 activation is critical for LMB-induced apoptosis. Interestingly, Bcl-2 overexpression that blocked cytochrome c release by LMB effectively attenuated the apoptotic response to LMB, suggesting that LMB-induced apoptosis is mediated through the mitochondrial pathway. Antioxidants or antioxidant enzymes had no effects on LMB-induced apoptosis. Data of flow cytometry analysis using 2′,7′-dichlorofluorescein-diacetate further revealed no reactive oxygen species (ROS) generation by LMB, indicating that apoptosis induced by LMB is ROS-independent. However, the apoptotic response to LMB was not shown in U937 cells pretreated with the sulfhydryl group-containing antioxidant N-acetylcysteine (NAC). Further analysis suggested that NAC directly binds LMB and abolishes the apoptotic effects of LMB. Collectively, these findings suggest that LMB potently induces apoptosis in U937 cells, and LMB-induced apoptosis in U937 cells is related with cytochrome c release, activation of caspases, and selective down-regulation of Mcl-1 and XIAP. Keywords Leptomycin B; Apoptosis; Caspases; Mcl-1; XIAP; NAC
Appears in Collections:
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Microbiology (미생물학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Pathology (병리학)
1. Journal Papers (연구논문) > 1. School of Medicine (의과대학) > Dept. of Physiology (생리학)
1. Journal Papers (연구논문) > 3. Research Institutues (연구소) > Institute for Medical Science (의과학연구소)
Keimyung Author(s)
장병철; 박종욱; 권택규; 송대규; 박종구; 김상표; 배재훈; 문교철; 서민호; 서성일
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