Molecular Cancer Therapeutics, 2007, 6(8):2240-8.
Therapeutic targeting of nuclear receptor corepressor misfolding in acute promyelocytic leukemia cells with genistein
Angela Ping Ping Ng, Matiullah Khan, et al
We have recently reported that PML-RAR-induced misfolding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation-based therapy for APL. Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA-sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA-resistant NB4 cells and induced cell cycle arrest by blocking the G(2)-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR-induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR. These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA-sensitive and RA-resistant APL cells.
美国《分子癌症治疗》，2007年
用金雀异黄素靶向治疗细胞核受体共抑制因子错误折叠的急性早幼粒细胞白血病
安吉拉 平平，马蒂拉 坎，等
我们最近报道，PML-RAR诱导的N-CoR蛋白错误折叠可以被视黄酸（RA）逆转，视黄酸（RA）是促进急性早幼粒细胞白血病（APL）细胞分化的治疗剂。这一发现表明错误折叠的N-CoR在APL细胞分化停滞中的作用，并突出了其作为APL基于蛋白质构象的治疗的潜在分子靶点的意义。基于这一假设，我们调查了几种蛋白质构象修饰物对APL衍生的细胞系NB4和NB4-R1的治疗潜力。通过对这些选择的化合物的小规模筛选，我们鉴定了染料木黄酮作为RA敏感性和RA抗性APL细胞生长的有效抑制剂。染料木黄素通过其对细胞周期进程，分化和凋亡的集体调节作用来抑制NB4细胞的生长。染料木黄酮诱导的NB4细胞凋亡是由caspase-9和caspase-3的激活介导的，与线粒体跨膜电位和胞质释放的细胞色素c有关。染料木黄酮促进RA敏感性和RA抗性NB4细胞的分化，并通过阻断G（2）-M转换诱导细胞周期停滞。染料木黄酮上调PML和N-CoR蛋白的表达，促进PML-RAR的降解，并将PML致癌结构域的微观分布重组为NB4细胞中的正常点状图案。此外，染料木素通过可能抑制N-CoR与PML-RAR的选择性磷酸化依赖性结合，显着逆转了PML-RAR诱导的N-CoR蛋白错误折叠。这些发现将金雀异黄素鉴定为N-CoR蛋白构象的有效修饰因子，并突出了其在RA敏感性和RA抗性APL细胞中的治疗潜力。
