Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2012;7(2):e31714. doi: 10.1371/journal.pone.0031714. Epub 2012 Feb 27.
Protein kinase C (PKC) ε, a key signaling transducer implicated in mitogenesis, survival, and cancer progression, is overexpressed in human primary non-small cell lung cancer (NSCLC). The role of PKCε in lung cancer metastasis has not yet been established.
Here we show that RNAi-mediated knockdown of PKCε in H358, H1299, H322, and A549 NSCLC impairs activation of the small GTPase Rac1 in response to phorbol 12-myristate 13-acetate (PMA), serum, or epidermal growth factor (EGF). PKCε depletion markedly impaired the ability of NSCLC cells to form membrane ruffles and migrate. Similar results were observed by pharmacological inhibition of PKCε with εV1-2, a specific PKCε inhibitor. PKCε was also required for invasiveness of NSCLC cells and modulated the secretion of extracellular matrix proteases and protease inhibitors. Finally, we found that PKCε-depleted NSCLC cells fail to disseminate to lungs in a mouse model of metastasis.
Our results implicate PKCε as a key mediator of Rac signaling and motility of lung cancer cells, highlighting its potential as a therapeutic target.
蛋白激酶 C（PKC）ε是一种关键的信号转导分子，参与有丝分裂、存活和癌症进展，在人类原发性非小细胞肺癌（NSCLC）中过度表达。PKCε 在肺癌转移中的作用尚未确定。
在这里，我们表明，在 H358、H1299、H322 和 A549 NSCLC 中，RNAi 介导的 PKCε 敲低可损害 PMA、血清或表皮生长因子（EGF）刺激下小 GTPase Rac1 的激活。PKCε 耗竭显著削弱了 NSCLC 细胞形成膜皱襞和迁移的能力。用 εV1-2（一种特异性 PKCε 抑制剂）抑制 PKCε 也得到了类似的结果。PKCε 还需要 NSCLC 细胞的侵袭性，并调节细胞外基质蛋白酶和蛋白酶抑制剂的分泌。最后，我们发现 PKCε 耗尽的 NSCLC 细胞在转移的小鼠模型中无法扩散到肺部。
我们的结果表明 PKCε 是肺癌细胞 Rac 信号和运动的关键介质，突出了其作为治疗靶点的潜力。
