Institut Albert Bonniot, CRI INSERM/UJF U823, Team 3 Polarity, Development and Cancer, Rond-point de la Chantourne, La Tronche Cedex, France.
Cancer Res. 2012 Sep 1;72(17):4429-39. doi: 10.1158/0008-5472.CAN-11-3342. Epub 2012 Jul 3.
The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM kinase, which is the enzyme that phosphorylates and inactivates the actin-depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, inhibited cell motility in vitro and showed anticancer properties in vivo, in the absence of major side effects. Pyr1 inhibition of LIM kinase caused a microtubule-stabilizing effect, which was independent of any direct effects on the actin cytoskeleton. In addition, Pyr1 retained its activity in multidrug-resistant cancer cells that were resistant to conventional microtubule-targeting agents. Our findings suggest that LIM kinase functions as a signaling node that controls both actin and microtubule dynamics. LIM kinase may therefore represent a targetable enzyme for cancer treatment.
肿瘤对常规微管靶向药物的耐药性的出现限制了它们的临床应用。我们使用一种基于细胞的检测方法，该方法可识别微管聚合状态，以筛选与微管动力学调节剂相互作用的化学物质，从而鉴定出 Pyr1，这是一种可穿透细胞的 LIM 激酶抑制剂，可磷酸化并失活肌动蛋白解聚因子 cofilin。Pyr1 可逆地稳定微管，阻止肌动蛋白微丝动力学，抑制体外细胞迁移，并在体内具有抗癌特性，而没有明显的副作用。Pyr1 对 LIM 激酶的抑制作用产生了微管稳定作用，这与对肌动蛋白细胞骨架的任何直接影响无关。此外，Pyr1 在对常规微管靶向药物耐药的多药耐药癌细胞中保留其活性。我们的研究结果表明，LIM 激酶作为一个信号节点，可控制肌动蛋白和微管动力学。因此，LIM 激酶可能代表一种可靶向的癌症治疗酶。
