The chemopreventive agent N-(4-hydroxyphenyl) retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family
The chemopreventive agent N-(4-hydroxyphenyl) retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family
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DOI：
10.1038/sj.onc.1206827
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发表时间：
2003-09-18
期刊：
影响因子：
8
通讯作者：
Kroemer, G
中科院分区：
文献类型：
--
作者：
Boya, P;Morales, MC;Kroemer, G
N-(4-羟基苯基)维甲酰胺(4-HPR，Fenretinide)是一种有效的化学预防药物，其作用被认为与诱导细胞凋亡有关。4-HPR导致线粒体跨膜电位的丧失和caspase激活前线粒体细胞色素c的释放。通过转染Bcl2或巨细胞病毒UL37基因产物VMIA抑制线粒体膜通透性，可阻止caspase激活和细胞死亡。与其他类维A酸衍生物相比，4-HPR在加入到分离的线粒体或含有基质金属蛋白酶调节通透性转换孔复合体(PTPC)的脂质体中时，没有直接诱导基质金属蛋白酶的作用。此外，尽管活性氧物种(ROS)的过度产生似乎有助于4-HPR诱导的基质金属蛋白酶和细胞凋亡，但抑制NF-kappaB或P53介导的信号转导通路并不能调节4-HPR诱导的细胞凋亡。4-HPR可引起Bax和Bak的抗氧化剂抑制的构象改变，导致其N末端暴露和Bax的线粒体重定位。具有Bax(-/-)Bak(-/-)基因的细胞对4-HPR诱导的基质金属蛋白酶、ROS的过度产生和细胞死亡具有抵抗力。综上所述，这些数据表明，4-HPR通过ROS介导的途径诱导S线粒体膜电位，该途径涉及原凋亡性Bcl2家族成员BAX和/或BAK的强制性贡献。
N-(4-hydroxyphenyl) retinamide (4-HPR, fenretinide) is a potent chemopreventive agent whose effect has been suggested to involve apoptosis induction. 4-HPR induces a loss of the mitochondrial transmembrane potential and the mitochondrial release of cytochrome c before caspase activation. Inhibition of mitochondrial membrane permeabilization (MMP) by transfection with Bcl-2 or the Cytomegalovirus UL37 gene product vMIA prevented caspase activation and cell death. In contrast to other retinoid derivatives, 4-HPR has no direct MMP-inducing effects when added to isolated mitochondria or when added to proteoliposomes containing the MMP-regulatory permeability transition pore complex ( PTPC). Moreover, although reactive oxygen species (ROS) overproduction appears to be instrumental for 4-HPR-induced MMP and apoptosis, inhibition of the NF-kappaB or p53-mediated signal transduction pathways failed to modulate 4-HPR-induced apoptosis. 4-HPR was found to cause an antioxidant-inhibitable conformational change of both Bax and Bak, leading to the exposure of their N- termini and to the mitochondrial relocalization of Bax. Cells with a Bax(-/-) Bak(-/-) genotype were resistant against the 4-HPR-induced MMP, overproduction of ROS and cell death. Altogether, these data indicate that 4-HPR induce s MMP through an ROS-mediated pathway that involves the obligatory contribution of the proapopotic Bcl-2 family members Bax and/or Bak.