Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
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DOI：
10.1371/journal.pone.0026135
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Tamanoi F
中科院分区：
文献类型：
--
作者：
Chan LN;Fiji HD;Watanabe M;Kwon O;Tamanoi F
蛋白质香叶基香叶基转移酶-I (GGTase-I) 的小分子抑制剂提供了一种有前景的抗癌药物。在这里，我们首先报告了一种新型四氢吡啶支架化合物 P61-E7 的鉴定，并确定了该化合物对胰腺癌细胞的作用。 P61-E7 是从通过膦催化环化反应制备的联烯酸酯衍生化合物库中鉴定出来的。 P61-E7 抑制蛋白质香叶基香叶基化并阻断香叶基香叶基化蛋白质的膜结合。 P61-E7 可有效抑制细胞增殖和细胞周期进程，并在人类癌细胞中诱导高 p21CIP1/WAF1 水平。 P61-E7 还增加 p27Kip1 蛋白水平并抑制 p27Kip1 Thr187 上的磷酸化。我们还报道，P61-E7 处理 Panc-1 细胞会导致细胞变圆，破坏肌动蛋白细胞骨架组织，消除粘着斑组装并抑制锚定独立生长。由于观察到的细胞效应表明 RhoA 的参与，RhoA 是一种香叶基香叶基化的小 GTP 酶蛋白，显示可影响许多细胞过程，包括肌动蛋白应激纤维组织、细胞粘附和细胞增殖，因此我们评估了抑制 RhoA 香叶基香叶基化对 GGTase-I (GGTI) 抑制剂的细胞效应的重要性。法尼基化 RhoA 突变体 (RhoA-F) 的稳定表达导致对 P61-E7 的抗增殖作用产生部分抵抗，并阻止 P61-E7 在 Panc-1 细胞中诱导 p21CIP1/WAF1 和 p27Kip1。此外，RhoA-F 的稳定表达可以使 Panc-1 细胞免受 P61-E7 引起的细胞变圆和粘着斑形成的抑制。总而言之，这些发现表明 P61-E7 是一种有前途的 GGTI 化合物，并且 RhoA 是 Panc-1 胰腺癌细胞中 P61-E7 的重要靶标。
Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was identified from a library of allenoate-derived compounds made through phosphine-catalyzed annulation reactions. P61-E7 inhibits protein geranylgeranylation and blocks membrane association of geranylgeranylated proteins. P61-E7 is effective at inhibiting both cell proliferation and cell cycle progression, and it induces high p21CIP1/WAF1 level in human cancer cells. P61-E7 also increases p27Kip1 protein level and inhibits phosphorylation of p27Kip1 on Thr187. We also report that P61-E7 treatment of Panc-1 cells causes cell rounding, disrupts actin cytoskeleton organization, abolishes focal adhesion assembly and inhibits anchorage independent growth. Because the cellular effects observed pointed to the involvement of RhoA, a geranylgeranylated small GTPase protein shown to influence a number of cellular processes including actin stress fiber organization, cell adhesion and cell proliferation, we have evaluated the significance of the inhibition of RhoA geranylgeranylation on the cellular effects of inhibitors of GGTase-I (GGTIs). Stable expression of farnesylated RhoA mutant (RhoA-F) results in partial resistance to the anti-proliferative effect of P61-E7 and prevents induction of p21CIP1/WAF1 and p27Kip1 by P61-E7 in Panc-1 cells. Moreover, stable expression of RhoA-F rescues Panc-1 cells from cell rounding and inhibition of focal adhesion formation caused by P61-E7. Taken together, these findings suggest that P61-E7 is a promising GGTI compound and that RhoA is an important target of P61-E7 in Panc-1 pancreatic cancer cells.