Apoptosis induced by cadmium in human lymphoma U937 cells through Ca2+-calpain and caspase-mitochondria dependent pathways

被引:210
作者
Li, M
Kondo, T [1 ]
Zhao, QL
Li, FJ
Tanabe, K
Arai, Y
Zhou, ZC
Kasuya, M
机构
[1] Toyama Med & Pharmaceut Univ, Fac Med, Dept Radiol Sci, Sugitani, Toyama 9300197, Japan
[2] Toyama Med & Pharmaceut Univ, Fac Med, Dept Publ Hlth, Sugitani, Toyama 9300197, Japan
[3] Beijing Med Univ, Sch Publ Hlth, Dept Toxicol, Beijing 100083, Peoples R China
[4] China Med Univ, Sch Publ Hlth, Dept Ind Hyg & Occupat Dis, Shenyang 110001, Peoples R China
关键词
D O I
10.1074/jbc.M007369200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Apoptosis induced by cadmium has been shown in many tissues in vivo and in cultured cells in vitro. However, its molecular mechanism is not fully understood. When the human histiocytic lymphoma cell line U937 was treated with cadmium for 12 h, evidence of apoptotic features, including change in nuclear morphology, DNA fragmentation, formation of DNA ladder in agarose gel electrophoresis, and phosphatidylserine externalization, were obtained. Moreover, loss of the mitochondrial membrane potential (Delta psi (m)) was observed in the cadmium-treated cells and was inhibited by a broad caspase inhibitor (Z-VAD-FMK). Caspase inhibitors suppressed the DNA fragmentation in the order of Z-VAD-FMK > caspase-8 inhibitor > caspase-3 inhibitor. Expression of Bcl-x(L) and Bid decreased significantly in the cadmium-treated cells, although no apparent change in Bcl-2 and Bax expression was found. Tetrakis-(2-pyridylmethyl) ethylendiamine, a cell-permeable heavy metal chelator, partially reversed the increase of fluorescence of Fura-a in the cadmium-treated cells. In addition, verapamil (70 muM), a voltage-dependent Ca2+ channel blocker, inhibited the DNA fragmentation induced by cadmium less than 100 muM and decreased the fluorescence of Fura-8. Cadmium up-regulated the expression of type 1 inositol 1,4,5-trisphosphate receptor (IP3R) but not type 2 or type 3 IP3R Calpain inhibitors I and II partially prevented DNA fragmentation. No effects of Z-VAD-FMK on the expression of type 1 IP3R or of calpain inhibitors on the loss of Delta psi (m) were observed. These results suggest that cadmium possibly induced apoptosis in U937 cells through two independent pathways, the Ca2+-calpain-dependent pathway and the caspase-mitochondria-dependent pathway.
引用
收藏
页码:39702 / 39709
页数:8
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