D,L-sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1
D,L-sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1
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DOI：
10.1093/carcin/bgl144
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发表时间：
2007-01-01
期刊：
影响因子：
4.7
通讯作者：
Singh, Shivendra V.
中科院分区：
文献类型：
--
作者：
Choi, Sunga;Lew, Karen L.;Singh, Shivendra V.
d，l-萝卜硫素（SFN）是十字花科植物衍生的异构体l-SFN的合成类似物，其通过引起细胞凋亡来抑制癌细胞的增殖，但细胞死亡的机制尚不完全清楚。我们使用LNCaP（野生型p53）和PC-3（p53缺陷）人前列腺癌细胞进一步了解SFN诱导的细胞凋亡的机制。与PC-3相比，LNCaP细胞系对SFN诱导的凋亡相对更敏感。SFN处理引起LNCaP细胞中p53蛋白的稳定，但SFN介导的凋亡并不因p53蛋白的敲低而减弱。相反，这些细胞对SFN诱导的凋亡的不同敏感性与Bax构象变化动力学的差异相关。Bcl-2的异位表达未能提供对SFN诱导的LNCaP细胞死亡的保护。用SFN处理PC-3细胞导致凋亡抑制因子（IAP）家族蛋白（cIAP 1、cIAP 2和XIAP）的水平显著降低，这伴随着p65-核因子κ B（NF kappa B）的核转位的抑制。SFN对IAP家族蛋白水平以及NF κ B B转录活性的影响在LNCaP细胞中是双相的。SFN处理的LNCaP和PC-3细胞表现出Apaf-1蛋白水平的显著增加，这伴随着E2 F1转录活性的增加。SFN诱导的细胞凋亡在两个细胞系中显着减弱Apaf-1蛋白敲低。总之，本研究揭示了一个复杂的信号转导机制，涉及Bax的激活，IAP家族蛋白的下调和Apaf-1诱导调节SFN诱导的细胞死亡。
d,l-Sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived isomer l-SFN, suppresses proliferation of cancer cells by causing apoptosis but the mechanism of cell death is not fully understood. We used LNCaP (wild-type p53) and PC-3 (p53 deficient) human prostate cancer cells to gain further insights into the mechanism of SFN-induced apoptosis. The LNCaP cell line was relatively more sensitive to SFN-induced apoptosis compared with PC-3. The SFN treatment caused stabilization of p53 protein in LNCaP cells, but SFN-mediated apoptosis was not attenuated by knockdown of p53 protein. Instead, the differential sensitivity of these cells to SFN-induced apoptosis correlated with difference in kinetics of Bax conformational change. Ectopic expression of Bcl-2 failed to confer protection against SFN-induced cell death in LNCaP cells. Treatment of PC-3 cells with SFN resulted in a marked decrease in the levels of inhibitor of apoptosis (IAP) family proteins (cIAP1, cIAP2 and XIAP), which was accompanied by inhibition of nuclear translocation of p65-nuclear factor kappa B (NF kappa B). The effect of SFN on levels of IAP family proteins as well as transcriptional activity of NF kappa B was biphasic in LNCaP cells. The SFN-treated LNCaP and PC-3 cells exhibited a marked increase in protein level of Apaf-1, which was accompanied by an increase in transcriptional activity of E2F1. The SFN-induced apoptosis in both cell lines was significantly attenuated by Apaf-1 protein knockdown. In conclusion, the present study reveals a complex signaling mechanism involving Bax activation, downregulation of IAP family proteins and Apaf-1 induction in regulation of SFN-induced cell death.