Early events in the induction of apoptosis in ovarian carcinoma cells by CD437: activation of the p38 MAP kinase signal pathway
Early events in the induction of apoptosis in ovarian carcinoma cells by CD437: activation of the p38 MAP kinase signal pathway
复制标题
DOI：
10.1038/sj.onc.1206694
复制
发表时间：
2003-09-25
期刊：
影响因子：
8
通讯作者：
Soprano, KJ
中科院分区：
文献类型：
--
作者：
Holmes, WF;Soprano, DR;Soprano, KJ
维甲酸类化合物在癌症治疗和化学预防领域具有巨大的潜力。6-[3-（1-admantyl）]-4-羟基苯基]2-萘羧酸（CD 437）是一种构象受限的合成类维生素A，已报道其在卵巢肿瘤细胞系中诱导生长停滞和凋亡，但诱导凋亡的整个机制尚未完全确定。我们着手鉴定CD 437诱导的CA-OV-3细胞系凋亡的早期事件，并确定这些事件是否发生在对CD 437具有抗性的CA-OV-3细胞系（CA-CD 437 R）中。使用MAP激酶级联抑制剂，我们确定MEK和p38抑制剂可以阻断CD 437诱导的CA-OV-3细胞系凋亡。此外，用CD 437处理CA-OV-3和CA-CD 437 R细胞导致p38磷酸化和活性增加，而不依赖于caspase-3活化。此外，在CD 437处理后，p38诱导CA-OV-3和CA-CD 437 R细胞中MEF 2的磷酸化。最后，GFP-TR 3蛋白易位到胞质溶胶中，并与线粒体在两个细胞系中响应于CD 437处理。这导致线粒体去极化和随后仅在CA-OV-3细胞中诱导凋亡。这些结果鉴定了CA-OV-3细胞中CD 437诱导细胞凋亡的许多初始分子事件，并证明CA-CD 437 R细胞中导致对CD 437抗性的改变在TR 3易位后但在线粒体去极化之前映射到这些早期事件的下游。
Retinoids have great potential in the areas of cancer therapy and chemoprevention. 6-[3-(1-admantyl)]-4-hydroxyphenyl]2-naphthalene carboxylic acid (CD437) is a conformationally restricted synthetic retinoid that has been reported to induce growth arrest and apoptosis in ovarian tumor cell lines but the entire mechanism for apoptotic induction has not been fully defined. We set out to identify the early events of CD437-induced apoptosis of the CA-OV-3 cell line and determine if these occur in a CA-OV-3 cell line resistant to CD437 (CA-CD437R). Using inhibitors for the MAP kinase cascade, we determined that MEK and p38 inhibitors could block CD437-induced apoptosis of the CA-OV-3 cell line. Moreover, treatment of CA-OV-3 and CA-CD437R cells with CD437 resulted in increased phosphorylation and activity of p38 independent of caspase-3 activation. Furthermore, p38 induced the phosphorylation of MEF2 in both CA-OV-3 and CA-CD437R cells after CD437 treatment. Finally, GFP-TR3 protein translocated to the cytosol and associated with mitochondria in both cell lines in response to CD437 treatment. This leads to depolarization of mitochondria and subsequent induction of apoptosis only in CA-OV-3 cells. These results identify a number of initial molecular events in the induction of apoptosis by CD437 in CA-OV-3 cells and demonstrate that the alteration in CA-CD437R cells, which results in resistance to CD437 maps downstream of these early events after TR3 translocation but prior to mitochondrial depolarization.