Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma
Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma
复制标题
DOI：
10.1038/sj.onc.1209515
复制
发表时间：
2006-08-17
期刊：
影响因子：
8
通讯作者：
Nakagawara, A.
中科院分区：
文献类型：
--
作者：
Niizuma, H.;Nakamura, Y.;Nakagawara, A.
视黄酸（RA）具有诱导神经元分化和/或凋亡的作用，被广泛用作治疗神经母细胞瘤的化疗药物。然而，RA的治疗效果仍然有限。为了揭示诱导神经母细胞瘤细胞分化和凋亡的分子机制，我们比较了全反式维甲酸（all-trans-RA，ATRA）诱导凋亡的CHP 134和NB-39-nu细胞系与诱导神经元分化的LAN-5和RTBM 1细胞系。在此，我们发现Bcl-2在CHP 134和NB-39-nu细胞中强烈下调，而在LA-N-5和RTBM 1细胞中大量表达。在CHP 134和NB-39-nu细胞中，ATRA介导的凋亡与caspase-9和caspase-3的显著激活以及细胞色素c以p53非依赖性方式从线粒体中释放有关。Bcl-2的强表达显著抑制ATRA介导的CHP 134细胞凋亡。此外，用Bcl-2抑制剂HA 14 -1处理RTBM 1细胞，增强ATRA诱导的凋亡反应。值得注意的是，10例散发性神经母细胞瘤中有2例表达bcl-2，表达水平不可检测，并在原代培养中对全反式维甲酸有反应而发生细胞死亡。因此，我们目前的研究结果表明，Bcl-2的过表达是神经母细胞瘤细胞抵抗ATRA介导的凋亡的关键机制之一。这可能为联合应用ATRA和Bcl-2抑制剂治疗ATRA耐药和侵袭性神经母细胞瘤提供一种新的治疗策略。
Retinoic acid (RA) has been shown to induce neuronal differentiation and/or apoptosis, and is widely used as a chemotherapeutic agent for treating the patients with neuroblastoma. However, the therapeutic effect of RA is still limited. To unveil the molecular mechanism(s) inducing differentiation and apoptosis in neuroblastoma cells, we compared CHP134 and NB-39-nu cell lines, in which all-trans-RA (ATRA) induces apoptosis, with LAN-5 and RTBM1 cell lines, in which it induces neuronal differentiation. Here, we found that Bcl-2 was strongly downregulated in CHP134 and NB-39-nu cells, whereas it was abundantly expressed in LA-N-5 and RTBM1 cells. ATRA-mediated apoptosis in CHP134 and NB-39-nu cells was associated with a significant activation of caspase-9 and caspase-3 as well as cytoplasmic release of cytochrome c from mitochondria in a p53-independent manner. Enforced expression of Bcl-2 significantly inhibited ATRA-mediated apoptosis in CHP134 cells. In addition, treatment of RTBM1 cells with a Bcl-2 inhibitor, HA14-1, enhanced apoptotic response induced by ATRA. Of note, two out of 10 sporadic neuroblastomas expressed bcl-2 at undetectable levels and underwent cell death in response to ATRA in primary cultures. Thus, our present results suggest that overexpression of Bcl-2 is one of the key mechanisms to give neuroblastoma cells the resistance against ATRA-mediated apoptosis. This may provide a new therapeutic strategy against the ATRA-resistant and aggressive neuroblastomas by combining treatment with ATRA and a Bcl-2 inhibitor.