Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCα
Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCα
复制标题
DOI：
10.1074/jbc.m107639200
复制
发表时间：
2002-01-04
影响因子：
4.8
通讯作者：
Kazanietz, MG
中科院分区：
文献类型：
--
作者：
Garcia-Bermejo, ML;Leskow, FC;Kazanietz, MG
佛波酯，原型（PKC）激活剂，诱导雄激素敏感的LNCaP前列腺癌细胞凋亡。在这项研究中，我们评估了一类新的PKC配体，甘油二酯（DAG）-内酯，作为诱导LNCaP细胞凋亡的影响。这些独特的配体设计使用新的药效团和受体引导的方法，以实现高效的DAG替代品。这些化合物中的两种HK 434和HK 654以比油酰-乙酰基-甘油或佛波醇12，13-二丁酸酯高得多的效力诱导LNCaP细胞凋亡。此外，不同的PKC同工酶被发现介导佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）和HK 654在LNCaP细胞的凋亡作用。使用PKC抑制剂和显性负性PKC亚型，我们发现，PKCalpha和PKC δ介导的PMA的凋亡作用，而只有PKCalpha参与的DAG-内酯的效果。HK 654在LNCaP细胞中的PKCalpha选择性与PKCalpha和PKC δ的体外结合和活化的类似效力形成对比。与完整细胞中异构体依赖性的差异相一致，PMA和HK 654在其转位PKC同工酶的能力方面显示出显著差异。PMA和HK 654均诱导PKCalpha向质膜的显著再分布。另一方面，与PMA不同，HK 654主要将PKC δ易位到核膜。因此，DAG-内酯具有用于诱导LNCaP细胞凋亡的PKC同工酶活化的独特特征，并且代表了细胞模型中经典PKC的选择性活化剂的第一个实例。一个有吸引力的假设是，PKC同工酶的选择性激活细胞中的药理学试剂可以通过不同的细胞内靶向每个PKC。
Phorbol esters, the archetypical (PKC) activators, induce apoptosis in androgen-sensitive LNCaP prostate cancer cells. In this study we evaluate the effect of a novel class of PKC ligands, the diacylglycerol (DAG)-lactones, as inducers of apoptosis in LNCaP cells. These unique ligands were designed using novel pharmacophore- and receptor-guided approaches to achieve highly potent DAG surrogates. Two of these compounds, HK434 and HK654, induced apoptosis in LNCaP cells with much higher potency than oleoyl-acetyl-glycerol or phorbol 12,13-dibutyrate. Moreover, different PKC isozymes were found to mediate the apoptotic effect of phorbol 12-myristate 13-acetate (PMA) and HK654 in LNCaP cells. Using PKC inhibitors and dominant negative PKC isoforms, we found that both PKCalpha and PKCdelta mediated the apoptotic effect of PMA, whereas only PKCalpha was involved in the effect of the DAG-lactone. The PKCalpha selectivity of HK654 in LNCaP cells contrasts with similar potencies in vitro for binding and activation of PKCalpha and PKCdelta. Consistent with the differences in isoform dependence in intact cells, PMA and HK654 show marked differences in their abilities to translocate PKC isozymes. Both PMA and HK654 induce a marked redistribution of PKCalpha to the plasma membrane. On the other hand, unlike PMA, HK654 translocates PKCdelta predominantly to the nuclear membrane. Thus, DAG-lactones have a unique profile of activation of PKC isozymes for inducing apoptosis in LNCaP cells and represent the first example of a selective activator of a classical PKC in cellular models. An attractive hypothesis is that selective activation of PKC isozymes by pharmacological agents in cells can be achieved by differential intracellular targeting of each PKC.